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Aim Age and lower folate concentrations are well-known risk factors for cardiovascular disease (CVD), but the potential roles of age and folate deficiency in hyperhomocysteinemia (HHcy), especially in HHcy patients with abnormal methylation levels of key enzyme genes promoter in homocysteinemia (Hcy) pathway, have not been thoroughly evaluated. The purpose of this study was to evaluate the relationship between the promoter methylation levels of six key enzyme genes and age and serum folate level to better understand the pathogenesis of HHcy. Methods In 299 HHcy patients, six key enzyme genes promoter methylation was analyzed by PCR amplification and MethylTarget.sup.TM methods. Results The betaine homocysteine methyltransferase (BHMT), Cystathionine [beta]-synthase (CBS), and Methionine synthasegene (MTR) promoter methylation levels were positively associated with age and a negative correlation was found between CBS promoter methylation level and folate levels. However, these associations were not significant after Bonferroni correction. The stratified analysis showed that the methylation level of CBS gene promoter was positively correlated with age in males, and a positive correlation was also found between BHMT gene promoter methylation level and age in HHcy patients with a history of diabetes or hypertension. Moreover, stratified analysis according to sex revealed that the methylation levels of three CpG regions of BHMT_2, CBS_2, and CBS_3 were positively correlated with age in males after Bonferroni correction. Conclusions Our data suggested that age and folate deficiency may increase the risk of HHcy by mediating methylation of the promoter regions of key enzyme genes in the one-carbon metabolism pathway., Author(s): Xiaowen Huang [sup.1] , Qinglin Zhao [sup.1] , Dankang Li [sup.1] , Bingnan Ren [sup.1] , Limin Yue [sup.1] , Fengxian Shi [sup.1] , Xiliang Wang [sup.1] , Caifang [...]

Introduction: In recent years, oral antineoplastic agents are commonly used in antitumor therapy. The interaction between drugs may affect the efficacy of drugs or lead to adverse reactions. We describe the case of a patient who presented acute liver injury, possibly induced by the concomitant use of metoprolol and dacomitinib. Case report: A 62-year-old male patient with non-small cell lung cancer was admitted for anti-cancer treatment. He regularly took metoprolol tartrate 12.5 mg, 2/day for hypertension. He was treated with dacomitinib according to EGFR Exon21 L858R positive. After 3 days of dacomitinib, the patient's alanine aminotransferase (ALT) and glutathione aminotransferase (AST) increased, and the heart rate and systolic blood pressure of the patient decreased significantly. The patient was diagnosed with acute liver injury. Management and outcomes: Dacomitinib was discontinued and glutathione, magnesium isoglycyrrhizinate were given to treat acute liver injury. Two days after discontinued dacomitinib, the patient's heart rate increased, but the ALT and AST of the patient elevated again. Metoprolol tartrate was subsequently discontinued and the ALT and AST gradually decreased and the patient discharged from the hospital eight days later with his liver function improved. Discussion: To our knowledge, this is the first case in the literature of acute liver injury possibly induced by the interaction between metoprolol and dacomitinib. The interaction most likely arose because dacomitinib is a CYP2D6 strong inhibitor and could therefore impair the metabolism of metoprolol (a CYP2D6 substrate) and increase its serum concentration. Therefore, hepatic function should be carefully monitored in patients treated with dacomitinib and metoprolol and other inhibitors or inducers of CYP2D6. [ABSTRACT FROM AUTHOR]

To investigate whether there is a relationship between TSH levels on the 14th day post embryo transfer (D14 TSH levels) and the reproductive outcomes in euthyroid women who are free from levothyroxine (LT4) treatment and undergo the first in vitro fertilization /intracytoplasmic sperm injection embryo transfer (IVF/ICSI-ET) cycles with the homogeneous ovarian stimulation protocols. This was a prospective study including a total of 599 euthyroid women undergoing the first IVF/ICSI ET cycles. Serum samples were collected and frozen on the 14th day post embryo transfer. TSH levels were measured after the confirmation of clinical pregnancy. The patients were divided into three groups (low-normal ≤ 2.5 mIU/L; high-normal 2.5–4.2 mIU/L; and high > 4.2 mIU/L) based on D14 TSH levels. Reproductive outcomes were compared among the three groups. Binary logistic regression analyses and generalized additive mixed models with smoothing splines were used to investigate the relationship between TSH levels and reproductive outcomes. D14 TSH levels were significantly elevated compared to basal TSH levels, and the degree of TSH elevation was significantly higher in pregnant women compared to that in non-pregnant women. The clinical pregnancy and live birth rates increased significantly in the high-normal D14 TSH groups, and doubled in the high D14 TSH groups compared to the low TSH groups. When adjusted by age, basal TSH, AMH, E2, endometrial thickness, type and causes of infertility, and transferred embryos, the dose-dependent relationships between D14 TSH and clinical pregnancy and live birth were observed. Obstetric outcomes in singleton or twins live birth among the different D14 TSH groups were similar. Elevated D14 TSH levels were associated with better clinical pregnancy and live birth rates, and were not associated with worse obstetric outcomes. The mechanisms to explain the phenomenon remained to be studied. [ABSTRACT FROM AUTHOR]

Bicalutamide (BCL) has been approved for treatment of advanced prostate cancer (Pca), and vitamin D is inevitably used in combination with BCL in Pca patients for skeletal or anti-tumor strategies. Therefore, it is necessary to study the effect of vitamin D application on the pharmacokinetics of BCL. We developed and validated a specific, sensitive and rapid UHPLC–MS/MS method to investigate the pharmacokinetic behaviours of BCL in rat plasma with and without the combined use of vitamin D. Plasma samples were extracted by protein precipitation with ether/dichloromethane (2:1 v/v), and the analytes were separated by a Kinetex Biphenyl 100A column (2.1 × 100 mm, 2.6 μm) with a mobile phase composed of 0.5 mM ammonium acetate (PH 6.5) in water (A) and acetonitrile (B) in a ratio of A:B = 35:65 (v/v). Analysis of the ions was run in the multiple reactions monitoring (MRM) mode. The linear range of BCL was 5–2000 ng mL−1. The intra- and inter-day precision were less than 14%, and the accuracy was in the range of 94.4–107.1%. The mean extraction recoveries, matrix effects and stabilities were acceptable for this method. The validated method was successfully applied to evaluate the pharmacokinetic behaviours of BCL in rat plasma. The results demonstrated that the pharmacokinetic property of BCL is significantly affected by combined use of vitamin D, which might help provide useful evidence for the clinical therapy and further pharmacokinetic study. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate whether blastocyst morphology and developmental rate are associated with euploidy and live birth rates (LBRs) in single euploid frozen–thawed embryo transfer (FET) cycles. Design: Retrospective cohort study. Methods: This study included 431 preimplantation genetic testing for aneuploidy (PGT-A) cycles followed by 393 FET cycles performed at our center from June 2017 to March 2021. All cycles were analyzed for euploidy based on blastocyst morphology (good, average and poor), developmental stage (day 5 and 6) and maternal age (< 35 and ≥ 35 years old). Multivariate logistic analysis models were used to identify the independent effects of conventional blastocyst morphology, developmental rate and morphological parameters (degree of blastocoele expansion, and grade of inner cell mass and trophectoderm (TE)) on LBRs. Results: In the group of women aged < 35 years, compared with poor-quality blastocysts, good-quality blastocysts (62.90% vs. 32.46%; odds ratio (OR) 3.163, 95% confidence interval (CI) 2.247–4.451; P < 0.001) and average-quality blastocysts (46.70% vs. 32.46%; OR 1.665, 95% CI 1.287–2.154; P < 0.001) had significantly higher euploidy rates. Additionally, day 5 blastocysts were associated with higher euploidy rates than day 6 blastocysts (49.28% vs. 35.02%; OR 1.506, 95% CI 1.191–1.903; P = 0.001). In the group of women aged ≥ 35 years, euploidy rates were also associated with blastocyst morphology, with 41.86%, 45.65% and 24.39% of good, average and poor-quality embryos, respectively, exhibiting euploidy. However, no relationship was seen between euploidy and blastocyst developmental rate. Multiple logistic regression analysis show that overall blastocyst morphology of euploid embryos was not associated with LBR, only embryos with A-grade TE had significantly higher LBRs than those with C-grade TE (62.71% vs. 45.40%; OR 2.189, 95% CI 1.166–4.109; P =0.015). Similarly, LBRs were significantly higher when day 5 blastocysts were transferred than when day 6 blastocysts were transferred (57.75% vs. 41.67%; OR 2.132, 95% CI 1.370–3.318; P = 0.001). Conclusion: Poor-quality embryos have reduced rates of euploidy. However, blastocyst developmental rate only significantly associates with euploidy rates in women aged younger than 35. Furthermore, only TE grade and blastocyst developmental rate are significantly associated with LBRs following FET cycles. [ABSTRACT FROM AUTHOR]

Background: With the increasing use of frozen embryo transfer (FET), the best endometrial preparation protocol is continuously being discussed. The hormone replacement therapy (HRT) cycle and letrozole-induced ovulation (L-OI) cycle are available protocols for patients with abnormal ovulation. Previous comparisons of the two protocols have focused on pregnancy outcomes, with less attention to perinatal outcomes, and population heterogeneity was large; thus, convincing conclusions about which protocol is more appropriate could not be drawn. Methods: We performed a retrospective cohort study using propensity score matching (PSM) analysis for a population of patients undergoing FET cycles in the reproductive center of the Third Affiliated Hospital of Zhengzhou University from January 2016 to September 2020. The main outcome measures were clinical pregnancy rate, live birth rate, very preterm delivery (VPTD), preterm delivery (PTD), low birth weight (LBW), macrosomia, small for gestational age (SGA), large for gestational age (LGA), hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), premature rupture of membranes (PROM), placenta previa, and congenital abnormality. Results: A total of 8010 women were enrolled. Due to the large heterogeneity among the patients, we conducted 1:1 PSM, and 1461 women matched in each group. Compared with the HRT group, the L-OI group had a smaller proportion of thin endometrium (27.38% vs. 41.07%) and thicker endometrium on the day of embryo transfer (9.63 ± 1.82 vs. 8.91 ± 1.38). There were no significant differences in clinical pregnancy rate, early abortion rate or live birth rate between the groups. There was no significant difference in perinatal outcomes of singleton live birth, including VPTD, PTD, postterm delivery, LBW, macrosomia, SGA, LGA, GDM, HDP, placenta previa, and congenital malformation. Conclusion: For women with abnormal ovulation, the pregnancy and perinatal outcomes of HRT and L-OI protocols are reassuring. It seems that both protocols are safe and effective for endometrial preparation in frozen-thawed embryo transfer in the clinic. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether patients with a history of recurrent implantation failure (RIF) are associated with adverse perinatal outcomes in singleton live births following frozen-thawed embryo transfer (FET) cycles. Design: Retrospective cohort study. Methods: This study analyzed the obstetric and neonatal outcomes of patients with and without a history of RIF who underwent FET cycles in a single reproductive center between January 2017 and October 2020. A total of 1,100 women with singleton live births beyond 28 weeks of gestation were included. The primary outcome measures were perinatal outcomes, especially gestational age, birthweight, preterm birth (PTB), large for gestational age (LGA), small for gestational age (SGA), congenital malformation rates, and premature rupture of the membranes (PROM). Multiple logistic regression was used to establish relationships between RIF and adverse perinatal outcomes after adjusting for relevant baseline demographics and cycle characteristics. Result(s): The RIF group showed a preferred transfer of two embryos and cleavage embryos compared with the control group (P < 0.05). Regarding perinatal outcomes in singleton deliveries, women with RIF had increased rates of LBW (adjusted odds ratio [aOR] 2.027; 95% confidence interval [CI], 1.025–4.009), PTB (aOR 1.785; 95% CI, 1.050–3.036), and PROM (aOR 2.259; 95% CI, 1.142–4.467). The incidence of congenital malformations was similar between the two groups (4.1% vs. 2.4%; P = 0.759). Furthermore, multiple intrauterine procedures were associated with a statistically significant increased risk of PROM in RIF patients (aOR 1.537; 95% CI, 1.105–2.137). Conclusions: Women with a history of RIF were associated with an increased risk of LBW, PTB, and PROM in singleton live births after FET cycles. In addition, multiple intrauterine procedures were independent risk factors for PROM. [ABSTRACT FROM AUTHOR]

Because traditional Chinese medicine (TCM) is a complex mixture of multiple components, the application of methodologies for evaluating single‐component Western medicine in TCM studies may have certain limitations. Appropriate strategies that recognize the integrality of TCM and connect to TCM theories remain to be developed. Yang–Xin–Ding–Ji (YXDJ) capsule is originally from a classical TCM formula used for the treatment of arrhythmia. In this study, we used UPLC‐Q–TOF–MS detection method, coupled with the metabolic research and network pharmacology analysis, to study the scientific connotation of the YXDJ capsule. A total of 33 absorbed constituents and 23 metabolites were identified or tentatively characterized in dosed plasma and urine, and the possible metabolic pathways were mainly methylation, oxidation, sulfation, glucuronidation, and deglucosylation. We optimized the conventional process ways of network pharmacology by collecting targets based on absorbed constituents into the blood. The constituents‐target disease and Kyoto Encyclopedia of Genes pathway analysis revealed that 24 absorbed constituents, 32 target genes, and 10 key pathways were probably related to the efficacy of the YXDJ capsule against arrhythmia. The results provided a scientific basis for understanding the bioactive compounds and the pharmacological mechanism of the YXDJ capsule. [ABSTRACT FROM AUTHOR]

Background: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain.Objective and Rationale: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI.Search Methods: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET).Outcomes: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies.Wider Implications: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical outcomes of dydrogesterone (DYG) and medroxyprogesterone (MPA) in the progestin-primed ovarian stimulation (PPOS) protocol for patients with poor ovarian response (POR). Patients and Methods: This was a retrospective cohort study. Women with POR who underwent IVF/ICSI at the Reproductive Center of Third Affiliated Hospital of Zhengzhou University between January 2020 and January 2021 were included. The primary outcome measure of our study was the number of oocytes retrieved. The secondary outcome measures in the present study were the number of 2PN, number of available embryos, oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved, cancellation rate and pregnancy outcomes of the first embryo transfer cycle, including the biochemical pregnancy, clinical pregnancy and miscarriage rates. Results: In total, 118 women underwent hMG +DYG protocols, and 692 women who underwent hMG +MPA met the Bologna criteria for POR. After baseline characteristics were balanced using the PSM model, 118 hMG +DYG protocols were matched to 118 hMG +MPA protocols, and the baseline characteristics were comparable between the two groups. The numbers of oocytes retrieved, 2PN, and available embryos and the oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved and cancellation rate of the hMG+DYG and hMG+MPA protocols were comparable. Altogether, 66 women in the hMG+DYG group and 87 women in the hMG+MPA group underwent first embryo transfers. In the hMG+DYG group, 81.8% (54/66) of the patients underwent cleavage embryo transfers; similarly, 79.3% (69/87) of patients in the hMG+MPA group had cleavage embryo transfers (P=0.70).The biochemical pregnancy rate of the hMG+DYG group was 42.4%, and this was comparable to the rate in the hMG+DYG group, at 34.5% (P=0.32). The clinical pregnancy rates were similar between the two groups (36.4% vs. 31.0%, P=0.49), and there was no significant difference in the rate of miscarriage between the two groups (12.5% vs. 29.6%, P=0.14). Conclusion: For women with POR, the clinical outcome of the hMG + DYG group was similar to that of the hMG + MPA group, indicating that both combinations can be useful options for PPOS protocols. [ABSTRACT FROM AUTHOR]

Background: A decrease in cystathionine beta‐synthase (CBS) enzyme activity could lead to hyperhomocysteinemia (HHcy). Studies have revealed that DNA methylation has a mediating effect on the development of diseases. The present study aimed to explore CBS promoter methylation‐mediating effects on the efficacy of folate treatment for HHcy. Methods: HHcy patients were treated with folate (5 mg/day) for 90 days and then divided into a failure group (Hcy ≥ 15 μmol/l) and a success group (Hcy < 15 μmol/l) according to post‐treatment plasma Hcy levels. Genotyping of CBS gene (rs2851391 and rs706209) in patients (n = 638) was detected using a MassArray system (Sequenom, San Diego, CA, USA). The baseline DNA methylation levels of patients (n = 299) were detected using MethylTarget™ technology (Genesky Biotechnologies Inc., Shanghai, China). Results: The CBS rs2851391 TC + CC genotype was related to a 57% reduction of failure risk in HHcy treatment compared to the TT genotype (95% confidence interval [CI] = 0.19–0.97). The CBS rs706209 CT + TT genotype had a 2.97‐fold increased risk of failure to treatment compared to the CC genotype (95% CI = 1.52–5.80). After adjustment for confounding factors, the odds ratio (95% CI) for the risk of failure in HHcy treatment in total and male patients was 0.55 (0.32–0.93) and 0.34 (0.16–0.69), respectively, for patients with higher methylation levels (≥ methylation median). Additionally, baseline CBS promoter methylation mediated 33.39% of the effect of rs2851391 on the efficacy of folate treatment for HHcy (ACME [average causal mediation effects]: –0.05, 95% CI = –0.11 to 0.00, p = 0.046). Conclusions: The present study indicates that CBS gene polymorphism and promoter methylation could affect the efficacy of HHcy. There were potentially causal effects of genetic, epigenetic variations at the CBS rs2851391 locus on the efficacy of HHcy therapy with folate. [ABSTRACT FROM AUTHOR]

Oral folate is currently the most common treatment for hyperhomocysteinemia (HHcy), which seriously threatens human health, but its efficacy is unsatisfactory. Betaine‐homocysteine methyltransferase (BHMT) is a key enzyme that regulates Hcy metabolism. We investigated the association between the BHMT rs3733890 and the efficacy of oral folate therapy for HHcy in the Chinese Han population and analysed the effects of gene–environmental interactions on the efficacy. Blood samples were collected from 1071 eligible patients at baseline, and these individuals received subsequent folate treatment for 90 days. A total of 638 patients included in the final analysis were grouped into the treatment success group or the treatment failure group based on posttreatment Hcy levels. Hcy concentrations were measured by fluorescence polarization immunoassay. Time‐of‐flight mass spectrometry (MassArray system) was used to assess the genotype of BHMT rs3733890. Stratified analyses based on additive models and generalized multifactor dimensionality reduction were used to explore gene–environmental interactions. The genotype distribution presented distinct differences in the two groups. The mutant genotype and allele had significantly increased risk of treatment failure (p < 0.05). Furthermore, synergistic effects of the BHMT rs3733890 polymorphism with environmental risk factors (smoking, drinking, past history) on the efficacy of therapy were also found. However, future, large well‐designed studies, as well as mechanistic studies, are still needed to validate our findings. [ABSTRACT FROM AUTHOR]

No risk assessment tools for the efficacy of folic acid treatment for hyperhomocysteinaemia (HHcy) have been developed. We aimed to use two common genetic risk score (GRS) methods to construct prediction models for the efficacy of folic acid therapy on HHcy, and the best gene–environment prediction model was screened out. A prospective cohort study enrolling 638 HHcy patients was performed. We used a logistic regression model to estimate the associations of two GRS methods with the efficacy. Performances were compared using area under the receiver operating characteristic curve (AUC). The simple count genetic risk score (SC-GRS) and weighted genetic risk score (wGRS) were found to be independently associated with the efficacy of folic acid treatment for HHcy. Using the SC-GRS, per risk allele increased with a 1·46-fold increased failure risk (P < 0·001) after adjustment for traditional risk factors, including age, sex, BMI, smoking, alcohol consumption, history of diabetes, history of hypertension, history of hyperlipidaemia, history of stroke and history of CHD. When used the wGRS, the association was strengthened (OR = 2·08, P < 0·001). Addition of the SC-GRS and wGRS to the traditional risk model significantly improved the predictive ability by AUC (0·859). A precise gene–environment predictive model with good performance was developed for predicting the treatment failure rate of folic acid therapy for HHcy. [ABSTRACT FROM AUTHOR]

In this research, curcumin microcrystal was produced using the wet milling method, and its pharmacokinetic behavior was compared after intramuscular (i.m.) and oral administration. The effects of milling time on the prepared curcumin microcrystal were investigated. Curcumin microcrystal was characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), FTIR, and in vitro dissolution. The results showed that there were no obvious changes in the crystal structure between bulk curcumin and curcumin microcrystal. Significantly higher dissolution rate from curcumin microcrystal (83.5%) at 90 min was observed, compared with that of bulk curcumin (74.1%). Furthermore, the in vivo pharmacokinetic behavior and muscular irritation after i.m. administration were also evaluated. The results showed that the release of curcumin lasted for 1 week by processing into microcrystal. The histological examination implied that curcumin microcrystal was safe for i.m. injection and was appropriate for the i.m. delivery of curcumin. [ABSTRACT FROM AUTHOR]

The present study aimed to explore the biological characteristics of non-small cell lung cancer (NSCLC) cells and the mechanism of chemosensitivity through the role of the PI3K/Akt/mTOR signaling pathway mediated by BRAF gene silencing. Following cell transfection and grouping, an MTT assay detected the activity of NSCLC cells, a scratch wound test assessed the migration ability, flow cytometry using PI staining detected the cell cycle phase, TUNEL and flow cytometry through Annexin V-PI staining assessed the apoptosis, and colony formation was used to detect the sensitivity of lung cancer cells to cisplatin chemotherapy. Furthermore, the relative expression levels of BRAF, PTEN, PI3K, mTOR mRNA were assessed by RT-qPCR, and the protein expression levels of BRAF, PTEN, PI3K, phosphorylated (p)-PI3K, Akt, p-Akt, mTOR, p-mTOR, cisplatin resistance-related enzymes ERCC1 and BRCA1, apoptotic proteins Bax and Bcl-2 were assessed by western blotting. Compared with the control group and NC group, there were differences in decreased BRAF mRNA expression levels in the small interfering (si)BRAF group and siBRAF + IGF-1 group (both P<0.05). In addition, compared with the control group, the siBRAF, NVP-BEZ235 and siBRAF + NVP-BEZ235 groups had significant decreased cell viability at 2–6 days, decreased migration ability, shortened proportion of S-phase cells, increased proportion of G1/G0-phase cells, increased apoptosis rate, decreased number of colony-forming cells, decreased mRNA expression of PI3K, Akt and mTOR, increased PTEN mRNA expression, decreased protein expression levels of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR, ERCC1, BRCA1 and Bcl-2, and increased protein expression levels of PTEN and Bax (all P<0.05); and more obvious trends were revealed in the siBRAF + NVP-BEZ235 group (all P<0.05); whereas opposite results were detected in the siBRAF + IGF-1 group when compared with the siBRAF group and NVP-BEZ235 group (all P<0.05). Silencing of BRAF gene expression to inhibit the activation of the PI3K/Akt/mTOR signaling pathway exerted a synergistic effect decreasing cell viability, inhibiting the cell cycle and migration, increasing the apoptosis rate, decreasing the number of colony-forming cells and increasing chemosensitivity of NSCLC. Activation of the PI3K/Akt/mTOR signaling pathway may reverse the role of silencing of BRAF gene expression, providing a potential approach for improving the chemosensitivity of NSCLC. The present study for the first time, to the best of our knowledge, clarified the possible mechanism of NSCLC cell biological characteristic changes and chemosensitivity from the perspective of BRAF gene silencing and PI3K/Akt/mTOR signaling pathway activation, providing a potential reference for suppressing tumor aggravation and improving the therapeutic outcomes of NSCLC at the genetic level. [ABSTRACT FROM AUTHOR]

Various genetic and environmental factors or their interactions may result in the failure of folic acid therapy for hyperhomocysteinemia (HHcy). We hypothesized that an optimal predictive model of gene-environment interactions could be constructed to predict the efficacy of folic acid therapy in HHcy. A prospective cohort study of 638 HHcy patients was performed. The patients were treated with oral folic acid (5 mg/d) for 90 days. We used conditional inference tree model to stratify the failure risk of folic acid therapy synthesizing information from a weighted genetic risk score (wGRS) and environmental exposures, simultaneously interpreting the gene-environment interaction network in predicting the efficacy of HHcy. We detected high-order interactions between medical history of stroke, coronary heart disease (CHD), wGRS, and baseline total homocysteine (tHcy) on the failure risk of folic acid therapy. The wGRS in fourth quartile had 3.73-fold increased failure risk of folic acid treatment (odds ratio = 3.73, 95% confidence interval: 1.47-9.45). Stroke was identified as the key discriminator among the variables examined. A total of 3.3% of participants in failure group were at the lowest failure risk of folic acid therapy (nonstroke, non-CHD, baseline tHcy ≤ 31.1 μ mol/L, wGRS ≤ 1.05). Individuals with stroke but with wGRS > 1.05 were at the highest failure risk of folic acid therapy (91.0% of participants in failure group). Medical history of stroke, CHD, wGRS, and baseline tHcy were consistently identified as significant risk factors for the failure risk of folic acid therapy. The multiple interactions between genetic and environmental factors can be visually presented via the conditional inference tree model. [ABSTRACT FROM AUTHOR]

Background and Objectives: Hyperhomocysteinaemia (HHcy) is an independent risk factors for several disorders, including cardiovascular disease. The understanding of the relationship among genetic, epigenetic and the efficacy of folate therapy for HHcy remain unclear. This study aim to investigate whether betaine-homocysteine methyltransferase (BHMT) single-nucleotide polymorphisms (SNPs) and DNA methylation are related to the efficacy of folate therapy for HHcy and whether BHMT DNA methylation mediates the SNP-folate therapy efficacy association.Methods and Study Design: A total of 638 patients with HHcy were involved in this prospective cohort study. Logistic and linear regression was used to explore associations among SNPs, DNA methylation, and folate therapy efficacy. Finally, mediation analysis was performed to investigate whether DNA methylation of BHMT mediates the association between SNPs and folate therapy efficacy.Results: BHMT rs3733890 was significantly associated with folate therapy efficacy (p<0.05). BHMT and BHMT_1 DNA methylation level was significantly associated with folate therapy efficacy (p=0.017 and p=0.028). DNA methylation of BHMT and BHMT_1 mediated 34.84% and 33.06% of the effect of rs3733890 on folate therapy efficacy, respectively.Conclusions: There has a consistent interrelationship among BHMT genetic variants, methylation levels of BHMT, and folate therapy efficacy. BHMT and BHMT_1 DNA methylation proportionally mediated the effects of rs3733890 SNPs on the efficacy of folate therapy for HHcy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the associations of thyroid autoimmunity (TAI) with the number of oocytes retrieved (NOR), fertilization rate (FR), and embryo quality (EQ) in euthyroid women with infertility and diminished ovarian reserve (DOR)., Methods: This retrospective cohort study involved 1,172 euthyroid women aged 20-40 years with infertility and DOR who underwent an oocyte retrieval cycle. TAI was diagnosed in the presence of serum thyroperoxidase antibody (TPOAb) concentrations higher than 34 IU/ml and/or serum thyroglobulin antibody (TgAb) concentrations exceeding 115.0 IU/ml. Among these women, 147 patients with TAI were classified as the TAI-positive group, while 1,025 patients without TAI were classified as the TAI-negative group. Using generalized linear models (GLMs) adjusted for confounding factors, we evaluated the associations of TAI and the serum TPOAb and TgAb concentrations and NOR, FR, and EQ in this study's subjects. The TPOAb and TGAb values were subjected to log10 transformation to reduce skewness. Logistic regression models were used to estimate the effects of TPOAb and TgAb concentrations on the probabilities of achieving a high NOR (≥7) and high FR (>60%)., Results: For the whole study population, women with TAI had a significantly lower NOR and poorer EQ than women without TAI ( P < 0.001 for both). Interestingly, in the TSH ≤2.5 subgroup, the TAI-positive group also had a significantly lower NOR and poorer EQ than the TAI-negative group ( P < 0.001 for both). Furthermore, negative associations were observed between log10(TPOAb) concentrations and NOR and the number of high-quality embryos and available embryos ( P < 0.05 for all). The log10(TgAb) concentrations were inversely associated with NOR and the number of high-quality embryos ( P < 0.05 for all). In the regression analysis, the log10(TPOAb) concentrations had lower probabilities of achieving a high NOR [adjusted odds ratio (aOR): 0.56; 95% confidence interval (95% CI) 0.37, 0.85; P = 0.007]., Conclusions: TAI and higher TPOAb and TgAb concentrations were shown to be associated with reductions in the NOR and EQ in the study population. Our findings provide further evidence to support systematic screening and treatment for TAI in euthyroid women with infertility and DOR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Zhang, Su, Ren, Yu, Li, Xu and Lou.)

Objective: To compare the neonatal outcomes of progestin-primed ovarian stimulation (PPOS) and flexible gonadotropin-releasing hormone (GnRH) antagonist protocols., Methods: This was a retrospective propensity score-matched (PSM) cohort study. Women who underwent their first frozen embryo transfer (FET) cycle with freezing of all embryos followed by PPOS or GnRH antagonist protocols between January 2016 and January 2022 were included. Patients using PPOS were matched with the patients using GnRH antagonist at a 1:1 ratio. The main focus of this study was the neonatal outcomes of singleton live births, including preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), macrosomia and large for gestational age (LGA)., Results: After 1:1 PSM, a total of 457 PPOS and 457 GnRH antagonist protocols were included for analysis. The average starting dose of gonadotropin (275.1 ± 68.1 vs. 249.3 ± 71.3, P<0.01) and total dose of gonadotropin (2799.6 ± 579.9 vs. 2634.4 ± 729.1, P<0.01) were significantly higher in the PPOS protocol than in the GnRH antagonist protocol. The other baseline and cycle characteristics were comparable between the two protocols. The rates of PTB (P=0.14), LBW (P=0.11), SGA (P=0.31), macrosomia (P=0.11) and LGA (P=0.49) did not differ significantly between the two groups. A total of 4 patients in the PPOS group and 3 patients in the GnRH antagonist group qualified as having congenital malformations., Conclusion: PPOS resulted in singleton neonatal outcomes similar to those of a GnRH antagonist protocol. The application of the PPOS protocol is a safe option for infertility patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Du, Zhang, Ren and Guan.)

Objective: To determine whether preimplantation genetic testing for aneuploidy (PGT-A) can improve the pregnancy outcomes of patients aged under 38 years who have a history of recurrent implantation failure(RIF)., Design: Retrospective cohort study., Methods: We retrospectively studied the pregnancy outcomes of RIF patients aged under 38 years from January 2017 to December 2021.178 patients were divided into two groups according to whether they underwent PGT-A: the PGT-A group(n=59)and the control group(n=119).In the PGT-A group, we compared the euploidy rate of the different quality and developmental rate blastocysts. In both groups,the patients were the first frozen-thaw single blastocysts transfer after the diagnosis of RIF. Among the pregnancy outcomes, the clinical pregnancy rate was assessed as the primary outcome. The spontaneous abortion rate and ongoing pregnancy rate were the secondry outcomes. The generalized estimation equation was used to adjust for the blastocysts derived from the same patients. Multivariate logistic analysis models were used to compare the pregnancy outcomes between the two groups., Results: In the PGT-A group, 293 blastocysts obtained from59 patients underwent PGT-A. The proportions of euploidy, aneuploidy and mosaic blastocysts were 56.31%, 25.60% and 18.09%, respectively. A comparison of the euploidy rates of different quality blastocysts showed that the rate of good-quality blastocysts was significantly higher than that of poor-quality blastocysts (67.66% vs 46.88%; odds ratio [OR], 2.203; 95%confidence interval[CI], 0.943-3.612; P=0.002). However, no significant difference was observed in the different developmental rates blastocysts. Compared with Day 5 blastocysts, the euploidy rates of Day 6 and Day 7 blastocysts were not significantly different(61.54%vs51.91%; OR,0.945; 95%CI, 0.445-2.010; P=0.884; and 61.54%vs47.37%; OR, 1.106; 95%CI, 0.774-1.578; P=0.581, respectively).As for the pregnancy outcomes, the clinical pregnancy rate was significantly increase after the use of PGT-A compared with the control group(71.19%vs56.30%; OR, 0.538; 95%CI, 0.262-1.104; P=0.039). However, the spontaneous abortion rates and ongoing pregnancy rates were not significantly different between the control and PGT-A groups (21.43% vs 19.40%; aOR,0.727; 95%CI,0.271-1.945; P=0.525; and55.93% vs 45.38%; aOR, 0.649; 95%CI, 0.329-1.283; P = 0.214,respectively)., Conclusion: PGT-A improved the clinical pregnancy rate after blastocyst transfer in RIF patients aged under 38 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Du, Guan, Li, Shi, Zhang, Ren, Liu and Lou.)

Purpose: The aim of this study was to determine whether a 60-day weight reduction intervention prior to in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) and a higher weight loss ratio effectively improved perinatal outcomes for infertile overweight or obese women., Methods: This was a retrospective cohort study conducted at a university-affiliated fertility center. Two thousand three hundred and eighty-one overweight or obese infertile women who underwent or did not undergo a 60-day weight reduction intervention prior to IVF/ICSI between February 27, 2017 and November 11, 2020 were included in this study. All of these women achieved clinical pregnancy and delivered a single child after assisted reproductive technology (ART). Primary outcomes included neonatal birth weight and the incidence of pregnancy complications, premature delivery, and low birth weight., Results: The body mass index (BMI), blood glucose concentration, serum insulin level, and homeostasis model assessment of insulin resistance (HOMA-IR) of the intervention group decreased significantly after the weight reduction intervention. Neonatal birth weight was significantly higher in the intervention group (3519.6 g ±484.8 g) than the control group (3406.8 g ± 554.2 g; P < 0.001). There was no significant difference in the incidence of pregnancy complications between the two groups. Linear regression analysis found that the weight reduction intervention prior to IVF/ICSI and lower HOMA-IR at ovulation induction were associated with increased birth weight. As the weight loss ratio increased, the incidence of hypertensive disorders of pregnancy, premature membrane rupture, premature delivery, stillbirth, and low birth weight showed a downward trend., Conclusions: A 60-day weight reduction intervention prior to IVF/ICSI may increase neonatal birth weight, reduce maternal blood glucose concentration, and improve maternal insulin resistance in infertile overweight or obese women. This results require to be further verified by prospective randomized controlled trials with a larger sample size., Competing Interests: Author NL was employed by company Zhejiang Nutriease Health Technology Company Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Yang, Zheng, Zu, Ran, Wu, Ren, Lv, Kuang, Li, Du and Guan.)

Objective: To evaluate whether singleton live births achieved following in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in women with late moderate-to-severe ovarian hyperstimulation syndrome (OHSS) is associated with adverse perinatal outcomes., Methods: This was a single-center retrospective cohort study conducted from January 2016 to June 2021. A total of 4,012 IVF/ICSI-fresh embryo transfer cycles that achieved singleton live births were included. According to the diagnosis of OHSS, the cycles were divided into two groups: late moderate-to-severe OHSS (MS-OHSS) group ( n = 114) and non-OHSS group ( n = 3,898). Multiple baseline covariates were controlled by propensity score matching, yielding 114 late MS-OHSS singleton live births matched to 337 non-OHSS singleton live births. The primary outcome of the study was normal term infant. The secondary outcomes were perinatal complications, gestational age at birth, birth weight, and birth height., Results: Before propensity score matching, no significant difference in perinatal outcomes was identified between late MS-OHSS group and non-OHSS group. After matching maternal age, BMI, basal serum FSH level, basal serum AMH level, basal antral follicle count, type of stimulation protocol, day of embryo development for embryo transfer, number of embryo transfer, and number of oocytes retrieved, there was still no significant difference in obstetric outcomes and neonatal outcomes between the two groups., Conclusions: The findings demonstrate that the perinatal outcomes were similar between the two groups. However, because the sample size of patients with late MS-OHSS was limited in this study, further investigations are warranted using a larger sample size., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ran, Zu, Wu, Zheng, Yang, Yang, Ren, Zhang, Du and Guan.)

Objective: To compare cumulative live birth rates and perinatal outcomes of young IVF/ICSI patients with low anti-Mullerian hormone (AMH) levels on a gonadotropin-releasing hormone antagonist (GnRH-ant) regimen with those on a high progesterone state of ovulation (PPOS) regimen., Methods: We retrospectively analyzed 798 patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm microinjection (ICSI) between January 2015 and December 2020 at the Third Affiliated Hospital of Zhengzhou University. A total of 798 cycles of complete clinical data from patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) at the Reproductive Medicine Center of Zhengzhou University Hospital between January 2015 and December 2020 and were eligible for AMH < 1.2 ng/ml at age < 35 years, Group A1: very low AMH levels (AMH < 0.5 ng/mL) and GnRH antagonist regimen; Group A2, very low AMH level (AMH < 0.5 ng/mL) and PPOS regimen; Group B1, low AMH level (0.5 ng/mL ≤ AMH < 1.2 ng/mL) and GnRH antagonist regimen; and Group B2, low AMH level (0.5 ng/mL ≤ AMH < 1.2 ng/mL), and the PPOS regimen., Results: At very low levels of AMH (< 0.5 ng/mL), the CLBR of the GnRH antagonist regimen was not significantly different from that of the PPOS regimen (P > 0.05), at 0.5 ng/mL ≤ AMH < 1.2 ng/mL. Statistics showed that the CLBR of the GnRH antagonist regimen was significantly higher than that of the PPOS regimen (49.7% vs. 35.7%, P=0.002). Logistic regression analysis showed that in Group A: the younger the female partner, the higher the CLBR (OR = 0.972, 95% CI = 0.923-1.042, P = 0.022), and the more the AFC, the higher the CLBR (OR = 1.166, 95% CI = 1.091-1.336, P < 0.001). Group B: the higher the number of good-quality embryos, the higher the CLBR (OR = 2.227, 95% CI = 1.869-2.654, P < 0.001). Compared with PPOS regimens, the antagonist regimen was able to increase the CLBR. The analysis of Group A showed that the antagonist regimen had a shorter TTP than the PPOS regimen (P < 0.001); however, the PPOS regimen had a lower cost of ovulation (4311.91 vs. 4903.81, P = 0.023). The antagonist regimen in Group B had a shorter TTP than the PPOS regimen, and there was no significant difference in the cost of ovulation. In the analysis of perinatal outcomes, there were no statistically significant differences in preterm birth, low birth weight, very low birth weight, and pregnancy complications among the four groups., Conclusion: Young patients with very low AMH levels (< 0. 5 ng/mL), the GnRH antagonist regimen was comparable to the PPOS regimen in CLBR outcomes; the antagonist regimen shortens the time to clinical pregnancy, and the PPOS regimen is more cost-effective. In young patients with low AMH levels of 0.5 ng/mL and <1.2 ng/mL, the GnRH antagonist regimen can more appropriate to improve CLBR, and the perinatal outcomes were similar for both regimens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2022 Li, Jia, Wang, Zhang, Ren and Guan.)