FERREG: ferroptosis-based regulation of disease occurrence, progression and therapeutic response.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/.

Co-administration of tacrolimus and low molecular weight heparin in patients with a history of implantation failure and elevated peripheral blood natural killer cell proportion.

AIM: To investigate the therapeutic effect of co-administration of tacrolimus (TAC) and low-molecular-weight heparin (LMWH) or LMWH only on pregnancy outcomes in the female with a history of implantation failure and elevated peripheral blood natural killer (pNK) cell proportion in frozen-thawed embryo transfer cycles. METHODS: To evaluate the pregnancy parameters for 249 patients with ≥2 implantation failures and pNK cell proportion ≥12% by analyzing a retrospective observational cohort study. Sixty patients had received the co-administration TAC and LMWH (TAC & LMWH group), 85 others had only taken LMWH (LWMH group), and the rest did not take any particular drugs (control group). RESULTS: The experimental finding indicated that the TAC & LMWH group and the LMWH group showed higher clinical pregnancy rates than the control group (p < 0.05), and TAC & LMWH group had a much higher live birth rate. According to the binary logistic regression analysis, the combination of TAC and LMWH was conducive to clinical pregnancy and live birth rate and reduced the possibility of miscarriage. It would not affect the result of spontaneous abortion and live birth, although the LMWH was only beneficial to clinical pregnancy. In addition, these findings were similar for these three groups' obstetrical and neonatal outcomes. CONCLUSIONS: The combination of TAC and LMWH can improve clinical pregnancy and live birth rates and reduce the risk of spontaneous miscarriage in patients with a history of implantation failure and elevated pNK ratio. LMWH is also beneficial to clinical pregnancy.

Brain circuit dysfunction in specific symptoms of depression.

Since the depressive disorder manifests complex and diverse symptoms clinically, its pathological mechanism and therapeutic options are difficult to determine. In recent years, the advent of optogenetics, chemogenetics and viral tracing techniques, along with the well-established rodent model of depression, has led to a shift in the focus of depression research from single molecules to neural circuits. In virtue of the powerful tools above, psychiatric disorder such as depression could be well related to the disfunction of brain's connection. Moreover, compelling studies also support that the diversity of depressive behaviour could be involved with the discrete changes in a distinct circuit of the brain. Therefore, summarising the differential changes of the neural circuits in mice with depression-like behaviour may provide a better understanding of the causal relationships between neural circuit and depressive behaviour. Here, we focus on the changes in the neural circuitry underlying various depression-like phenotypes, including motivation, despair, social avoidance and comorbid sequelae, which may provide an explanation to circuit-specific discrepancy in depression-like behaviour.

Sortilin deletion in the prefrontal cortex and hippocampus ameliorates depressive-like behaviors in mice via regulating ASM/ceramide signaling.

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent mood despondency and loss of motivation. Although numerous hypotheses have been proposed, the possible pathogenesis of MDD remains unclear. Several recent studies show that a classic transporter protein, sortilin, is closely associated with depression. In the present study, we investigated the role of sortilin in MDD using a well-established rodent model of depression. Mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. We showed that the expression levels of sortilin were significantly increased in the prefrontal cortex and hippocampus of CUMS mice. The depressive-like behaviors induced by CUMS were alleviated by specific knockdown of sortilin in the prefrontal cortex and hippocampus. We revealed that sortilin facilitated acid sphingomyelinase (ASM)/ceramide signaling, which activated RhoA/ROCK2 signaling, ultimately causing the transformation of dendritic spine dynamics. Specific overexpression of sortilin in the prefrontal cortex and hippocampus induced depressive-like behaviors, which was mitigated by injection of ASM inhibitor SR33557 (4 µg/µL) into the prefrontal cortex and hippocampus. In conclusion, sortilin knockdown in the prefrontal cortex and hippocampus plays an important role in ameliorating depressive-like behavior induced by CUMS, which is mainly evidenced by decreasing the trafficking of ASM from the trans-Golgi network to the lysosome and reducing the ceramide levels. Our results provide a new insight into the pathology of depression, and demonstrate that sortilin may be a potential therapeutic target for MDD.

Associations of FSHR and LHCGR gene variants with ovarian reserve and clinical pregnancy rates.

RESEARCH QUESTION: Are there any associations between the variants of FSHR c.2039 G>A (p. Ser680Asn, rs6166) and LHCGR c.935A>G (p. Asn312Ser, rs2293275) and ovarian reserve, ovarian response, clinical pregnancy rate and POSEIDON group? DESIGN: A total of 210 infertile women were enrolled in this prospective study. The gene variants were analysed by the Sanger method. The clinical parameters were analysed based on genotypes. RESULTS: The frequency of heterozygous and homozygous G allele for FSHR c.2039 G>A in the low prognosis group was significantly higher than that in other response groups (P = 0.034); there was no significant association between LHCGR c.935 A>G and ovarian response. Moreover, the serum anti-Müllerian hormone (AMH) concentration, antral follicle count (AFC), oocytes retrieved, metaphase II (MII) oocytes and two-pronuclear (2PN) oocytes in patients with AG genotype for FSHR c.2039 G>A were significantly lower than those with AA genotype. The serum LH concentrations and clinical pregnancy rate of fresh embryo transfer in patients with GG genotype for LHCGR c.935 A>G were significantly higher than that of the AG genotype. In POSEIDON analysis, the low prognosis women with AA genotype for FSHR c.2039 G>A were more likely to appear in subgroup 1 (P = 0.038). CONCLUSION: The FSHR c.2039 G>A variant has a significant beneficial influence on ovarian reserve and ovarian response. The LHCGR c.935 A>G variant is associated with increased clinical pregnancy rate of fresh embryo transfer in infertile women. In addition, the low prognosis women with AA genotype for FSHR c.2039 G>A tend to show better ovarian reserve and prognosis.

Influence Factors of Sexual Intercourse Frequency in Infertile Couples without Sexual Dysfunction in Southwest China: A Retrospective Study.

INTRODUCTION: The aim of this study was to investigate the sexual intercourse frequency (SIF) of infertile couples without sexual dysfunction and analyze its related influencing factors. MATERIALS AND METHODS: We retrospectively analyzed the data of a total number of 4,923 infertile couples without sexual dysfunction who received treatment in our assisted reproductive center from October 2016 to October 2018. Both partners of couples were inquired about their information of demographic statistics, occupations, lifestyles, education backgrounds, psychological characteristics, and testostrone levels of male patients. The multivariable linear regression analysis was applied to evaluate the influence of various variables on SIF. RESULTS: The median (interquartile range) SIF of infertile couples without sexual dysfunction was 7 (6.5-8) times per month. Lower academic qualification and younger age were predictive of increased SIF in both partners. The SIF of Chinese Han women and Chinese Zang women is higher than that of other ethnic groups. Men with lower testosterone (<10 nmol/L) were associated with lower SIF. The BMI, occupation, alcohol consumption, races of both partners of couples, and smoking status of males were not associated with SIF. Multivariable linear regression analysis indicated that only the age and the education level of men played an important role in SIF, and educational level of men had the greatest impact, followed by men's age. CONCLUSION: In our study, we analyzed demographics data, occupational characteristics, and lifestyle behaviors of both partners, as well as men's testosterone levels; we also reported the related SIF. According to our research, men's education level was the most important factor in predicting SIF, followed by men's age. Testosterone levels of men do not appear to play a substantial role in predicting SIF in infertile couples.

Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways.

BACKGROUND: Pirfenidone (PFD) is effective for pulmonary fibrosis (PF), but its action mechanism has not been fully explained. This study explored the signaling pathways involved in anti-fibrosis role of PFD, thus laying a foundation for clinical application. METHODS: Pulmonary fibrosis mice models were constructed by bleomycin (BLM), and TGF-ß1 was used to treat human fetal lung fibroblasts (HLFs). Then, PFD was added into treated mice and cells alone or in combination with ß-catenin vector. The pathological changes, inflammatory factors levels, and Collagen I levels in mice lung tissues were assessed, as well as the activity of HLFs was measured. Levels of indices related to extracellular matrix, epithelial-mesenchymal transition (EMT), Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways were determined in tissues or cells. RESULTS: After treatment with BLM, the inflammatory reaction and extracellular matrix deposition in mice lung tissues were serious, which were alleviated by PFD and aggravated by the addition of ß-catenin. In HLFs, PFD reduced the activity of HLFs induced by TGF-ß1, inhibited levels of vimentin and N-cadherin and promoted levels of E-cadherin, whereas ß-catenin produced the opposite effects to PFD. In both tissues and cells, Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways were activated, which could be suppressed by PFD. CONCLUSIONS: PFD alleviated pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways, which might further improve the action mechanism of anti-fibrosis effect of PFD.

Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.

BACKGROUND: Elective single embryo transfer (eSET) has been increasingly advocated, but concerns about the lower pregnancy rate after reducing the number of embryos transferred have encouraged transfer of multiple embryos. Extended embryo culture combined with electively freezing all embryos and undertaking a deferred frozen embryo transfer might increase pregnancy rate after eSET. We aimed to establish whether elective frozen single blastocyst transfer improved singleton livebirth rate compared with fresh single blastocyst transfer. METHODS: This multicentre, non-blinded, randomised controlled trial was undertaken in 21 academic fertility centres in China. 1650 women with regular menstrual cycles undergoing their first cycle of in-vitro fertilisation were enrolled from Aug 1, 2016, to June 3, 2017. Eligible women were randomly assigned to either fresh or frozen single blastocyst transfer. The randomisation sequence was computer generated, with block sizes of two, four, or six, stratified by study site. For those assigned to frozen blastocyst transfer, all blastocysts were cryopreserved and a delayed frozen-thawed single blastocyst transfer was done. The primary outcome was singleton livebirth rate. Analysis was by intention to treat. This trial is registered at the Chinese Clinical Trial Registry, number ChiCTR-IOR-14005405. FINDINGS: 825 women were assigned to each group and included in analyses. Frozen single blastocyst transfer resulted in higher rates of singleton livebirth than did fresh single blastocyst transfer (416 [50%] vs 329 [40%]; relative risk [RR] 1·26, 95% CI 1·14-1·41, p<0·0001). The risks of moderate or severe ovarian hyperstimulation syndrome (four of 825 [0·5%] in frozen single blastocyst transfer vs nine of 825 [1·1%] in fresh single blastocyst transfer; p=0·16), pregnancy loss (134 of 583 [23·0%] vs 124 of 481 [25·8%]; p=0·29), other obstetric complications, and neonatal morbidity were similar between the two groups. Frozen single blastocyst transfer was associated with a higher risk of pre-eclampsia (16 of 512 [3·1%] vs four of 401 [1·0%]; RR 3·13, 95% CI 1·06-9·30, p=0·029). INTERPRETATION: Frozen single blastocyst transfer resulted in a higher singleton livebirth rate than did fresh single blastocyst transfer in ovulatory women with good prognosis. The increased risk of pre-eclampsia after frozen blastocyst transfer warrants further studies. FUNDING: The National Key Research and Development Program of China.

Antitumoral Activity of (20R)- and (20S)-Ginsenoside Rh2 on Transplanted Hepatocellular Carcinoma in Mice.

Hepatocellular carcinoma is one of the leading causes of malignancy-related death in China. Its therapy in clinics is a big challenge. Ginsenoside Rh2 is one of the most notable cancer-preventing components from red ginseng and it has been reported that ginsenoside Rh2 exhibited potent cytotoxicity against human hepatoma cells. Rh2 exists as two different stereoisomeric forms, (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2. Previous reports showed that the Rh2 epimers demonstrated different pharmacological activities and only (20S)-ginsenoside Rh2 showed potent proliferation inhibition on cancer cells in vitro. However, the in vivo anti-hepatoma activity of (20R)-ginsenoside Rh2 and (20S)-ginsenoside Rh2 has not been reported yet. This work assessed and compared the anti-hepatoma activities of (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2 using H22 a hepatoma-bearing mouse model in vivo. In addition, hematoxylin and eosin staining, the deoxynucleotidyl transferase dUTP nick-end labeling assay, and the semiquantitative reverse transcriptase polymerase chain reaction method were used to further study the apoptosis of the tumors. The results showed that both (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2 suppressed the growth of H22 transplanted tumors in vivo, and the highest inhibition rate could be up to 42.2 and 46.8 %, respectively (p < 0.05). Further, hematoxylin/eosin staining and the deoxynucleotidyl transferase dUTP nick-end labeling assay indicated that both (20R)-ginsenoside Rh2 and (20S)-ginsenoside Rh2 could induce H22 hepatoma tumor cell apoptosis, with apoptosis indexes of 3.87 %, and 3.80 %, respectively (p < 0.05). Moreover, this effect was accompanied by downregulating the level of Bcl-2 mRNA. In conclusion, both (20S)-ginsenoside Rh2 and (20R)-ginsenoside Rh2 can suppress the growth of H22 hepatomas without causing severe side effects, and this effect is associated with the induction of apoptosis.

RBPJ inhibition impairs the growth of lung cancer.

The exact effects of the modulation of Notch signaling pathway on cell growth have been shown to depend on tumor cell type. Recombination signal-binding protein Jκ (RBPJ) is a key transcription factor downstream of receptor activation in Notch signaling pathway. Here, we evaluated the effects of RBPJ inhibition on the growth of lung cancer cells. We found that a short hairpin interfering RNA (shRNA) for RBPJ efficiently inhibited RBPJ expression in lung cancer cells, resulting in a significant decrease in the cell growth. Further analyses showed that RBPJ inhibition altered the levels of its downstream targets, including p21, p27, CDK2, Hes1, Bcl-2, and SKP2, to prevent the cells from growing. Our data thus suggest that shRNA intervention of RBPJ expression could be a promising therapeutic approach for treating human lung cancer.

Body-mass index and obesity in infertile couples in southwest China.

To investigate body mass index (BMI) of infertile couples and analyze its related influencing factors in Southwest China, so as to prevent and control the obesity. We analyzed the data of a total number of 8877 infertile couples who received treatment in our assisted reproductive center from October 2012 to March 2022. The mean age and BMI of men and women were 33.5 years, 23.9 kg/m2 and 31.6 years, 21.9 kg/m2. The prevalence of overweight (BMI 25-29.9) was 30.9% in men and 14.7% in women, 3.7% of men and 1.6% of women were obese (BMI ≥ 30), while 3.6% of men and 10.8% of women were underweight (BMI<18.5). Multivariable linear regression analysis indicated that the age and educational background of both women and men had an impact on BMI. In our study, the proportion of male obesity and overweight is much higher than that of female. On the other hand, the proportion of females with low weight was higher than that of males. The age and educational background of men and women have a certain correlation with BMI.

Ginsenoside Rg3 alleviates the migration, invasion, and angiogenesis of lung cancer cells by inhibiting the expressions of cyclooxygenase-2 and vascular endothelial growth factor.

Lung cancer (LC) is a common cancer with high incidence and mortality rates. In recent years, ginsenoside Rg3 (Rg3), a traditional medicine, is widely used for the treatment of LC. Herein, we concentrate on assessing the effect of Rg3 on LC cell migration and invasion. The effects of Rg3 (0, 25, 50, and 100 µg/ml) on the viability, migration, invasion, angiogenesis, and expressions of epithelial-mesenchymal transition (EMT)-related proteins, cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) of LC cell lines were evaluated by cell counting kit-8 (CCK-8), scratch, transwell, tube formation, and western blot assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to assess transfection efficiency. COX2 overexpression plasmid and short hairpin RNA for VEGF (shVEGF) were applied to evaluate whether the effect of Rg3 is related to COX2 and VEGF through rescue assay. In this study, Rg3 significantly dose-dependently suppressed the viability, migration, invasion, angiogenesis, and protein expressions of N-cadherin, vimentin, COX2, and VEGF in H1299 and A549 cells, while promoting the expression of E-cadherin protein. COX2 overexpression markedly reversed the effects of Rg3 on the viability, migration, invasion, angiogenesis, and EMT-related protein expression levels in LC cells; however, such effects of COX2 overexpression were offset by VEGF knockdown. In sum, Rg3 alleviates the migration, invasion, and angiogenesis of LC cells by inhibiting the expressions of COX2 and VEGF.

Preparation of mesoporous submicrometer silica capsules via an interfacial sol-gel process in inverse miniemulsion.

Mesoporous silica capsules with submicrometer sizes were successfully prepared via the interfacial hydrolysis and condensation reactions of tetraethoxysilane (TEOS) in inverse miniemulsion by using hydrophilic liquid droplets as template. The inverse miniemulsions containing pH-controlled hydrophilic droplets were first prepared via sonication by using poly(ethylene-co-butylene)-b-poly(ethylene oxide) (P(E/B)-PEO) or SPAN 80 as surfactant. TEOS was directly introduced to the continuous phase of an inverse miniemulsion. The silica shell was formed by the deposition of silica on the surface of droplets. The formation of capsule morphology was confirmed by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM). The mesoporous structure was verified by nitrogen sorption measurements. The specific surface area could be tuned by the variation of the amount of cetyltrimethylammonium bromide (CTAB) and TEOS, and the pore size by the amount of CTAB. The influences of synthetic parameters on the particle size and morphology were investigated in terms of the amount of CTAB, pH value in the droplets, TEOS amount, surfactant amount, and type of solvent with low polarity. A formation mechanism of silica capsules was proposed.

The impact of two different thaw protocols on outcomes of vitrified cleavage-stage embryos transfer.

The objective of this study was to evaluate the gestational results obtained with vitrified-thawed human cleavage-stage embryo by two different thaw protocols. Embryo development was observed to cleavage-stage and embryos were cryopreserved by vitrification on day 3 after oocyte retrieval. 51 cycles were thawed using vitrification warming kit with decreasing concentrations of sucrose in 3 dilutions ( 1.0, 0.5 and 0 mol per L respectively) as group 1, 56 cycles were thawed with decreasing concentrations of sucrose in 5 dilutions ( 0.8, 0.6, 0.33, 0.2 and 0 mol per L respectively) as group 2. Embryo survival (> 50 percent intact blastomeres), complete embryo survival (100 percent intact blastomeres), pregnancy and implantation rates were compared, and development rates the day after thawing were also compared. Multivariate analysis showed a significant difference in embryo immediate morphological survival rate, complete survival and clinical pregnancies rate between the two groups respectively (87.0 vs. 98.6 percent, p=0.000; 71.0 vs 82.0 percent embryo subsequent development rates, mean number of transferred embryos was similar between the two groups. (61.4 vs. 61.3 percent, p=0.502; 2.2 +/ 0.5 vs. 2.4 +/- 0.6, p=0.113). In addition, no differences in implantation rate were observed between two groups (17.7 vs. 25.6 percent, P=0.138). No difference in the multiple pregnancy rates was found among the two groups also.

Evaluation of Clinical Outcomes of Icotinib in Patients With Clinically Diagnosed Advanced Lung Cancer With EGFR-Sensitizing Variants Assessed by Circulating Tumor DNA Testing: A Phase 2 Nonrandomized Clinical Trial.

Importance: The inability to obtain a pathological diagnosis in a certain proportion of patients with clinically diagnosed advanced lung cancer impedes precision treatment in clinical practice. Objective: To evaluate the clinical outcome of first-line icotinib in patients with clinically diagnosed advanced lung cancer with unknown pathological status and positive epidermal growth factor receptor (EGFR)-sensitizing variants assessed by circulating tumor DNA (ctDNA). Design, Setting, and Participants: The Efficiency of Icotinib in Plasma ctDNA EGFR Mutation-Positive Patients Diagnosed With Lung Cancer (CHALLENGE) trial is a prospective, multicentered, open-label, single-arm phase 2 nonrandomized clinical trial conducted between July 1, 2017, and July 31, 2019. Patients with systemic treatment-naive, clinically diagnosed advanced peripheral lung cancer, unknown pathological status, and positive pretreatment plasma EGFR-sensitizing variants were eligible. A total of 391 potentially eligible Chinese patients from 19 centers in China were screened for ctDNA EGFR variants by 3 independent detection platforms (Super amplification refractory mutation system [SuperARMS] polymerase chain reaction, droplet digital polymerase chain reaction, and next-generation sequencing), and those with EGFR variants tested by any platform were included. Analyses were conducted from September 9 to December 31, 2021. Interventions: Enrolled patients were treated with oral icotinib tablets (125 mg 3 times daily) until disease progression, death, or treatment discontinuation due to various reasons, such as toxic effects and withdrawing consent. Main Outcomes and Measures: The primary end point was objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and the concordance among the 3 detection platforms. Results: Of 116 included patients, 76 (65.5%) were female, and the median (range) age was 64 (37-85) years. The median (IQR) follow-up duration was 36.3 (30.2-40.7) months. The ORR was 52.6% (95% CI, 43.1%-61.9%). The median PFS and OS were 10.3 months (95% CI, 8.3-12.2) and 23.2 months (95% CI, 17.7-28.0), respectively, and the DCR was 84.5% (95% CI, 76.6%-90.5%). The concordance rate among the 3 detection platforms was 80.1% (313 of 391), and the clinical outcomes in patients identified as positive by any platform were comparable. Conclusions and Relevance: This prospective phase 2 nonrandomized clinical trial suggests that for patients with clinically diagnosed advanced lung cancer with unknown pathological status, ctDNA-based EGFR genotyping could help decision-making in particular clinical situations, while still warranting future larger-scaled real-world exploration. Trial Registration: ClinicalTrials.gov Identifier: NCT03346811.

Single blastocyst stage versus single cleavage stage embryo transfer following fresh transfer: A systematic review and meta-analysis.

OBJECTIVES: To compare the available evidence of the effectiveness of single blastocyst stage transfer against the effectiveness of single cleavage stage embryo transfer. STUDY DESIGN: A systematic research based on Pubmed, Embase and the Cochrane Library was performed until May 2, 2020 to identify all relevant studies. The Cochrane Collaboration's Review Manager (RevMan) 5.0.2 software was used for statistical analysis. RESULTS: Five randomized controlled trials (RCTs) were included in analysis, involving 1784 patients in total, who were divided into 2 groups, which were the single blastocyst stage transfer (SBT) group of 932, and the single cleavage stage transfer (SCT) group of 852. Our meta-analysis concluded that SBT group had a significantly higher clinical pregnancy rate (RR 1.26; 95%CI: 1.14-1.39), ongoing pregnancy rate (RR 1.19; 95%CI: 1.05-1.35) and delivery rate (RR 1.4; 95%CI: 1.13-1.75) than SCT group during the fresh transfer. While miscarriage rate (RR 0.93; 95% CI: 0.66-1.33), multiple pregnancy rate (RR, 1.12; 95% CI, 0.51-2.45) and ectopic pregnancy rate (RR, 0.5; 95% CI: 0.13-1.90) between two groups showed no significant difference. However, the SCT group contained notably more cryopreserved embryos than the SBT group. (RR -0.68, 95% CI: -0.95 to -0.41). CONCLUSIONS: Our results indicate that single blastocyst stage transfer is associated with higher ongoing pregnancy rate and delivery rate comparing to single cleavage stage transfer in the clinical practice. Due to the low quality of the evidence of the primary outcomes, other higher-quality lager RCTs are necessary before a fully informed decision is made.

Discovering the Role of FZD4 Gene in Human Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Frizzled 4 (FZD4) is an important receptor for Wnt proteins that stimulate several downstream signaling pathways. It has been known that the FZD4-Wnt interaction is involved in many types of cancers. However, the role of FZD4 in cutaneous squamous cell carcinoma (CSCC) has not been well studied. AIMS: We sought to investigate the association between FZD4 expression level and tumor cell proliferation and apoptosis rates in CSCC. METHODS: Expression of FZD4 at mRNA level in CSCC tissues and controls was measured. Colo16 cell proliferation and viability were measured by CCK-8 assay and flow cytometry respectively after siRNA and plasmid transfection. RESULTS: We discovered a significant downregulation of FZD4 expression in CSCC tissues and cell lines compared to controls. Furthermore, our data suggested that over expression of FZD4 inhibited proliferation and promoted apoptosis of Colo16 cells. CONCLUSION: The results indicated that FZD4 may play as a tumor suppressor gene in the pathogenesis of CSCC.

Indacaterol/glycopyrronium affects lung function and cardiovascular events in patients with chronic obstructive pulmonary diseases: A meta-analysis.

BACKGROUND: Bronchodilators are the cornerstone for treating patients with chronic obstructive pulmonary diseases (COPD), although some studies have shown that dual bronchodilators may exacerbate incidence of adverse cardiovascular events. Here, we evaluated the cardiopulmonary safety of indacaterol/glycopyrronium (IND/GLY) using a meta-analysis. METHODS: We searched PubMed, OVID, Cochrane Library and Web of Science databases, using "indacaterol/glycopyrronium", "indacaterol/glycopyrrolate", "IND/GLY", "QVA149", "chronic obstructive pulmonary diseases", "COPD", "chronic obstructive airway disease", "chronic obstructive lung disease" as key words. Acute exacerbation of COPD and FEV1 as indicators of pulmonary function and occurrence of hypertension, atrial fibrillation, myocardial infarction and heart failure as indicators of cardiovascular safety. RESULTS: A total of 23 articles, comprising 21,238 participants, were included in the analysis. FEV1 values were significantly different compared to IND/GLY and single bronchodilator therapy (LABA or LAMA), with the MD 0.11 L (95%CI: 0.10-0.13, P<0.01). Hypertension was more frequent in the IND/GLY, than the single bronchodilator therapy group, although this difference was insignificant (IND/GLY vs LABA, RR=1.88, P = 0.09; IND/GLY vs LAMA, RR=1.42, P = 0.08; IND/GLY vs LABA+ICS, RR=1.85, P = 0.23). In addition, IND/GLY did not significantly increase the risk of myocardial infarction (IND/GLY vs LAMA or double therapy, total RR: 1.49, 95%CI: 0.72-3.08, P = 0.28), atrial fibrillation (IND/GLY vs LAMA, RR: 1.62, 95%CI: 0.64-4.10, P = 0.31) and heart failure (IND/GLY vs LAMA, RR: 0.40, 95%CI: 0.07-2.33, P = 0.31) in COPD patients. CONCLUSIONS: IND/GLY significantly reduced incidence of acute COPD exacerbations, and slowed down the decline of FEV1. Adequate safety measures are needed to control incidence of adverse cardiovascular events.

Biological functions of m6A methyltransferases.

M6A methyltransferases, acting as a writer in N6-methyladenosine, have attracted wide attention due to their dynamic regulation of life processes. In this review, we first briefly introduce the individual components of m6A methyltransferases and explain their close connections to each other. Then, we concentrate on the extensive biological functions of m6A methyltransferases, which include cell growth, nerve development, osteogenic differentiation, metabolism, cardiovascular system homeostasis, infection and immunity, and tumour progression. We summarize the currently unresolved problems in this research field and propose expectations for m6A methyltransferases as novel targets for preventive and curative strategies for disease treatment in the future.

The woody plant poplar has a functionally conserved salt overly sensitive pathway in response to salinity stress.

In Arabidopsis thaliana, the salt overly sensitive (SOS) pathway plays an essential role in maintaining ion homeostasis and conferring salt tolerance. Here we identified three SOS components in the woody plant Populus trichocarpa, designated as PtSOS1, PtSOS2 and PtSOS3. These putative SOS genes exhibited an overlapping but distinct expression pattern in poplar plants and the transcript levels of SOS1 and SOS2 were responsive to salinity stress. In poplar mesophyll protoplasts, PtSOS1 was specifically localized in the plasma membrane, whereas PtSOS2 was distributed throughout the cell, and PtSOS3 was predominantly targeted to the plasma membrane. Heterologous expression of PtSOS1, PtSOS2 and PtSOS3 could rescue salt-sensitive phenotypes of the corresponding Arabidopsis sos mutants, demonstrating that the Populus SOS proteins are functional homologues of their Arabidopsis counterpart. In addition, PtSOS3 interacted with, and recruited PtSOS2 to the plasma membrane in yeast and in planta. Reconstitution of poplar SOS pathway in yeast cells revealed that PtSOS2 and PtSOS3 acted coordinately to activate PtSOS1. Moreover, expression of the constitutively activated form of PtSOS2 partially complemented the sos3 mutant but not sos1, suggesting that PtSOS2 functions genetically downstream of SOS3 and upstream of SOS1. These results indicate a strong functional conservation of SOS pathway responsible for salt stress signaling from herbaceous to woody plants.