A comparison of pregnancy outcomes and congenital malformations in offspring between patients undergoing intracytoplasmic sperm injection and conventional in vitro fertilization: a retrospective cohort study.

OBJECTIVE: To explore whether intracytoplasmic sperm injection (ICSI) would increase the malformation risk in fetuses and live births compared with conventional in vitro fertilization (IVF). DESIGN: Retrospective cohort study. PATIENT(S): Data were collected from couples who underwent conventional IVF or ICSI from January 2009 to December 2019 at the Center for Reproductive Medicine of Peking University Third Hospital in the People's Republic of China. A total of 46,167 conventional IVF fresh transfer cycles and 33,247 ICSI fresh transfer cycles were included. INTERVENTION(S): Intracytoplasmic sperm injection and conventional IVF. MAIN OUTCOME MEASURE(S): The primary outcomes were congenital abnormalities in live births. The secondary outcomes included the pregnancy outcomes, the malformations among the miscarriages, specific types of malformations in live births, birth weight, and sex. RESULT(S): The rates of congenital malformations in conventional IVF and ICSI were 5.44‰ and 5.78‰, respectively. There was no statistically significant difference between the two groups, as indicated by the adjusted odds ratio of 1.098 (95% confidence interval 0.787, 1.532). The rates of specific malformations were comparable between ICSI and IVF. Additionally, no discernible disparities were noted in pregnancy outcomes, the malformations among the miscarriages,birth weight between the two groups. CONCLUSION: Our study suggested the safety of ICSI and provided novel evidence by comparing pregnancy outcomes and congenital malformations in offspring between patients undergoing conventional IVF and ICSI.

Reproductive Outcomes of Conventional In Vitro Fertilization and Intracytoplasmic Sperm Injection in Patients with Non-Severe Male Infertility Across Poor and Different Sub-Optimal Ovarian Response Categories: A Cohort Study Based on 30,352 Fresh Cycles from 2009-2019.

Due to the influence of economic, social and many other factors, there are more and more reproductive problems. Originally introduced for managing male factor infertility, intracytoplasmic sperm injection had become the most commonly used fertilization treatment in the world, with broadened indications including low oocyte yield, prior fertilization failure with conventional in vitro fertilization etc. However, academic evidence for better live-birth outcomes of intracytoplasmic sperm injection over conventional in vitro fertilization is limited. Thus, we aimed to compare the reproductive outcomes of conventional in vitro fertilization and intracytoplasmic sperm injection in patients with non-severe male factor infertility across poor and different sub-optimal ovarian response categories. The fertility rate, implantation rate, clinical pregnancy rate, live birth rate and other obstetric outcomes were mainly compared. Our results showed that independent of the number of oocytes retrieved, intracytoplasmic sperm injection significantly increased the fertilization rate, while conventional in vitro fertilization cycles showed a higher implantation rate, clinical pregnancy rate, and live birth rate. No differences were observed in most obstetric outcomes. Our study indicates that poor ovarian response is not an indication for intracytoplasmic sperm injection in couples with non-severe male infertility.

Guanylate-binding proteins signature predicts favorable prognosis, immune-hot microenvironment, and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: The role of guanylate-binding proteins (GBPs) in various cancers has been elucidated recently. However, our knowledge of the clinical relevance and biological characteristics of GBPs in hepatocellular carcinoma (HCC) remains limited. METHODS: A total of 955 HCC patients were enrolled from five independent public HCC cohorts. The role of GBP molecules in HCC was preliminarily investigated, and a GBP family signature, termed GBPs-score, was constructed by principal component analysis to combine the GBP molecule values. We revealed the effects of GBP genes and GBPs-score in HCC via well-established bioinformatics methods and validated GBP1-5 experimentally in a tissue microarray (TMA) cohort. RESULTS: GBPs molecules were closely associated with the prognosis of patients with HCC, and a high GBPs-score highly inferred a favorable survival outcome. We also revealed high GBPs-score was related to anti-tumor immunity, the immune-hot tumor microenvironment (TME), and immunotherapy response. Among the GBPs members, GBP1-5 rather than GBP6/7 may be dominant in these fields. The TMA analysis based on immunohistochemistry showed positive correlations between GBP1-5 and the immune-hot TME with abundant infiltration of CD8+ T cells in HCC. CONCLUSIONS: Our integrative study revealed the genetic and immunologic characterizations of GBPs in HCC and highlighted their potential values as promising biomarkers for prognosis and immunotherapy.

Clinical outcome of different embryo transfer strategies after late rescue ICSI procedure: a 10-year total fertilisation failure cohort study.

BACKGROUND: Late rescue intracytoplasmic sperm injection (r-ICSI) has not been widely accepted as an alternative solution for unexpected total fertilisation failure (TFF) after in vitro fertilisation (IVF), due to the time-dependent in vitro deterioration of oocyte quality and endometrial growth not being synchronised with embryo development. This study aimed to evaluate the safety profile and effectiveness of freeze-all blastocyst transfer in combination with late r-ICSI. METHODS: This was a retrospective cohort study carried out at the Reproductive Centre of Peking University Third Hospital, Beijing, China. All participants received treatment between 2009 and 2019. 2,270 patients in the aggregate encountered unexpected TFF during 149,054 cycles of IVF and adopted a late r-ICSI procedure. Among these patients, 263 women did not have cleavage-stage embryos available for evaluation. The remaining patients were grouped according to different embryo transfer (ET) strategies (926 women in Group 1 underwent fresh ET, 365 women in Group 2 underwent freeze-all ET, 716 women in Group 3 experienced blastulation failure). Patients received different ET strategies after r-ICSI, with the main outcome measures included live birth rate (LBR), cumulative live birth rate (cLBR), and conservative cLBR. RESULTS: TFF occurred in 7.4% of all IVF cycles. Group 1 tended to be older at oocyte retrieval, with more infertile years, higher follicle-stimulating hormone (FSH) levels, higher gonadotropin consumption, and fewer oocytes retrieved. Group 2 exhibited considerably better LBRs following the first ET cycle (37.53% vs. 4.64%) and cLBRs (52.60% vs. 8.21%). After adjustment for covariates using binary logistic regression analyses, Group 2 still showed better obstetric performance in LBRs [OR:11.77, 95% CI (8.42-16.45)], cLBRs (OR:11.29, 95% CI (7.84-16.27)], and conservative cLBRs (OR:2.55, 95% CI (1.83-3.55)]. Additionally, the two groups showed similar miscarriage rates, whilst no new-borns with malformations or congenital diseases were reported. CONCLUSIONS: Freeze-all blastocyst stage ET serves as an optimal strategy to support late r-ICSI. However, for women with limited oocytes available for r-ICSI use, weighing the benefits against the costs of the procedure might be prudent before implementing in vitro blastulation.

The excitatory effect of 5-HT1A and 5-HT2B receptors on the caudal neurosecretory system Dahlgren cells in olive flounder, Paralichthys olivaceus.

The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) plays an essential role in the regulation of neural activity via multiple receptors. Here, we investigated the functional role of serotoninergic input on the Dahlgren cell population in the caudal neurosecretory system (CNSS) of olive flounder. In this study, the effect of 5-HT on the firing activity of Dahlgren cells was explored in terms of changes in firing frequency and firing pattern using multicellular recording electrophysiology ex vivo, and the role of several 5-HT receptor subtypes in the regulation was determined. The results revealed that 5-HT increased the firing frequency in a concentration-dependent manner and altered the firing pattern of Dahlgren cells. The effect of 5-HT on the firing activity of Dahlgren cells was mediated through the 5-HT1A and 5-HT2B receptors, selective agonists of both receptors effectively increased the firing frequency of Dahlgren cells, and selective receptor antagonists could also effectively inhibit the increase in firing frequency caused by 5-HT. In addition, the mRNA levels of major signaling pathway-related genes, ion channels, and major secretion hormone genes were significantly upregulated in CNSS after treatment with 5-HT. These findings demonstrate that 5-HT acts as an excitatory neuromodulator on Dahlgren cells and enhances neuroendocrine activity in CNSS.

Subtyping of microsatellite stability colorectal cancer reveals guanylate binding protein 2 (GBP2) as a potential immunotherapeutic target.

BACKGROUNDS: Proficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a member of the GTPase family and is crucial to host immunity against pathogens. However, the correlations between GBP2 and immunosurveillance and immunotherapy for pMMR/MSS CRC have not been reported. METHODS: Unsupervised clustering was employed to classify immune class and non-immune class in 1424 pMMR/MSS patients from six independent public datasets. This binary classification was validated using immune cells or response related signatures. The correlation between GBP2 and immune microenvironment was explored using well-established biological algorithms, multiplex immunohistochemistry (mIHC), in vitro and in vivo experiments. RESULTS: We classified 1424 pMMR/MSS CRC patients into two classes, 'immune' and 'non-immune', and GBP2 was identified as a gene of interest. We found that lower GBP2 expression was correlated with poor prognosis and metastasis. GBP2 expression was also upregulated in the immune class and highly associated with interferon-γ (IFN-γ) signaling pathway and CD8 +T cell infiltration using gene set enrichment analysis, gene ontology analysis, single-cell sequencing and mIHC. Moreover, reduced GBP2 expression inhibited the antigen processing and presentation machinery and CXCL10/11 expression in MSS CRC cells on IFN-γ stimulation. A Transwell assay revealed that deletion of GBP2 in murine MSS CRC cells reduced CD8 +T cell migration. Mechanistically, GBP2 promoted signal transducer and transcription activator 1 (STAT1) phosphorylation by competing with SHP1 for binding to STAT1 in MSS CRC cells. Finally, an unsupervised subclass mapping (SubMap) algorithm showed that pMMR/MSS patients with high GBP2 expression may correlate with a favorable response to anti-PD-1 therapy. We further confirmed that GBP2 knockout reduced CD8 +T cell infiltration and blunted the efficacy of PD-1 blockade in tumor-bearing mice. CONCLUSIONS: Our study reveals that pMMR/MSS CRC is immunogenically heterogeneous and that GBP2 is a promising target for combinatorial therapy with ICB.

Decreased complement C3 levels are associated with poor prognosis in patients with COVID-19: A retrospective cohort study.

OBJECTIVES: To describe the humoral immune feature of patients with coronavirus disease 2019 (COVID-19). METHODS: The levels of total immunoglobulins (IgG, IgM, IgA, and IgE), complement (C3, C4) results were retrospectively analyzed in COVID-19 patients. Univariable and multivariable logistic regression were performed to explore the risk factors associated with the in-hospital death. RESULT: A total of 236 patients were enrolled in this study, of which 169 were transferred to another institution or discharged (survival group) and 67 died in hospital (non-survival group). Compared with survivors, the levels of IgA and IgE in non-survivors increased significantly, and level of complement C3 decreased. Non-survivors also showed higher incidence of chest tightness, breath shortness and dyspnoea; higher levels of inflammatory indicators, leukocytes and neutrophils; and low levels of lymphocyte subsets. Multivariable regression showed increasing odds of in-hospital death associated with older age (HR: 1.099; 95%CI: 1.057-1.143; p < 0.0001), d-dimer greater (HR: 1.294; 95%CI: 1.138-1.473; p < 0.0001) and decreased complement C3 level (HR: 0.073; 95%CI: 0.007-0.722; p = 0.025) on admission. Finally, in survival COVID-19 patients whose humoral immunity was re-examined, C3 levels tended to increase, while in non-survivors it decreased. CONCLUSION: Low level of complement C3 may be an alert to the admitted COVID-19 patients with additional management. Inhibition of the complement pathway might be an effective therapeutic to COVID-19 patients.

Inhibition of Heat Shock Protein 90 as a Novel Platform for the Treatment of Cancer.

Heat shock protein 90 (Hsp90) plays an essential role in various physiological and pathological processes. It activates client proteins to participate in tumor progression. Blocking Hsp90 could enable effective antitumor effects in many tumor types, such as multiple myeloma and colon cancer. Recently, it has motivated an interest in Hsp90 inhibitors that bind to the N-terminal or C-terminal ATP pocket as antitumor drugs. We reviewed the data from experimental and clinical trials on Hsp90 inhibitors in the treatment of different malignancies to explore and summarize their antitumor mechanisms.

Efficacy and Safety of Argon Plasma Coagulation for Hemorrhagic Chronic Radiation Proctopathy: A Systematic Review.

Hemorrhagic chronic radiation proctopathy (CRP) is a common complication after pelvic radiotherapy in patients with prostate or gynecological cancers. This systematic review was conducted to evaluate the efficacy and safety of argon plasma coagulation (APC) in treating hemorrhagic CRP. The databases of PubMed, Embase, and Cochrane Library were searched for related studies from inception to July 2017. Finally, 33 studies were identified with a total of 821 hemorrhagic CRP patients. After APC treatment, hemoglobin levels increased from 7.7-13.4 g/L to 11-14 g/L (including 15 studies). All (n = 33) studies reported an effective rate in rectal bleeding, among which five studies had a rate of 100%. Short-term complications were reported in 31 studies, while long-term complications in 33 studies and no complication in 11 studies. As for the severe complications, perforation was reported by 2 out of 33 studies, and the incidences were 3.3% (1/30) and 3.7% (1/27), respectively. As for APC setting, argon gas flow rate (median 1.5 L/min) and electric power (median 50 W) had no significant influence on complications and hemostasis. In conclusion, current literature indicated that APC therapy was an effective and safe strategy for hemorrhagic CRP, and large-scale prospective studies are needed to warrant our study.