Impact of progesterone concentration on human chorionic gonadotropin trigger day on clinical outcomes with one top-quality cleavage-stage embryo or blastocyst transfer in fresh in vitro fertilization cycles.

Objective: To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol. Methods: The retrospective cohort study included a total of 1,550 fresh autologous ART cycles with one top-quality embryo transfer. Multivariate regression analysis, curve fitting, and threshold effect analysis were performed. Results: A significant association was found between the progesterone concentration and clinical pregnancy rate (adjusted OR, 0.77; 95% CI, 0.62-0.97; P = 0.0234), especially in blastocyst transfer (adjusted OR, 0.56; 95% CI, 0.39-0.78; P = 0.0008). The association between the progesterone concentration and the ongoing pregnancy rate was insignificant. The clinical pregnancy rate showed a linear relationship with an increased progesterone concentration in cleavage-stage embryo transfer. In blastocyst transfer, as the progesterone concentration increased, the clinical and ongoing pregnancy rates showed a parabolic reverse-U curve; the curve initially increased before declining at high progesterone concentrations. The clinical pregnancy rate increased with a progesterone concentration up to 0.80 ng/mL rather than tended to be stable. The clinical pregnancy rate significantly decreased when the progesterone concentration was ≥0.80 ng/mL. Conclusion: The progesterone concentration on the hCG trigger day exhibits a curvilinear relationship with pregnancy outcomes in blastocyst transfer cycles, and the optimal threshold of the progesterone concentration is 0.80 ng/mL.

The clinical effect evaluation of multidisciplinary collaborative team combined with palliative care model in patients with terminal cancer: a randomised controlled study.

OBJECTIVE: To evaluate the clinical effect of a multidisciplinary collaboration team combined with a palliative care model in patients with terminal cancer. METHOD: A total of 84 patients diagnosed with terminal cancer in our hospital were included and randomly divided into an intervention group and a control group, with 42 cases in each group. Patients in the intervention group were treated by a multidisciplinary collaborative team combined with the palliative care model, and patients in the control group were treated by routine nursing intervention. The Self-rating Anxiety Scale (SAS) and the Self-rating Depression Scale (SDS) were used to evaluate negative emotions and anxiety and depression of patients before and after intervention. The Quality of Life Scale (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30) and Social Support Scale (SSRS) were used to evaluate the quality of life and social support of patients. This study has been registered in 13/01/2023 (ClinicalTrials.gov Identifier: NCT05683236). RESULT: The general data of the two groups were comparable. After intervention, the SAS (43.7 ± 7.4 vs. 54.2 ± 9.3) and SDS scores (38.4 ± 6.5 vs. 53.1 ± 8.4) of the intervention group were significantly lower than those of the control group. The total SSRS score, subjective support score, objective support score and utilisation of support of the intervention group were significantly higher than those of the control group (P < 0.05). The overall quality of life score of the intervention group was higher than that of the control group, and the difference was statistically significant (79.5 ± 4.5 vs. 73.2 ± 3.6, P < 0.05). The scores of each functional scale were significantly higher than those of the control group (P < 0.05). CONCLUSION: Compared with conventional nursing, the application of the multidisciplinary collaborative team combined with tranquilisation therapy in patients with terminal cancer can significantly reduce the anxiety and depression of patients, enable patients to obtain comprehensive social support, and effectively improve the quality of life of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT05683236, 13/01/2023, Retrospectively registered.

Metrnl deficiency retards skin wound healing in mice by inhibiting AKT/eNOS signaling and angiogenesis.

Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.

Effects of smoking on the retina of patients with dry age-related macular degeneration by optical coherence tomography angiography.

BACKGROUND: The macula of the retina is analysed using optical coherence tomography angiography (OCTA) to provide clinical basis and explain the mechanism of smoking as a risk factor in dry age-related macular degeneration (AMD). METHODS: This cross-sectional study included 49 normal control nonsmokers, 12 normal control smokers, 38 dry AMD nonsmokers and 35 dry AMD smokers. The foveal avascular zone (FAZ), foveal density (FD) in a 300 µm region around FAZ, vessel densities of the superficial (SCP) and deep (DCP) capillary plexuses and central fovea retinal thickness (FRT) were compared using OCTA. The bivariate correlation analysis was used to evaluate the effect of pack-year history on retina-related indices. RESULTS: The vessel densities of whole, foveal and parafoveal of SCP and whole and parafoveal of DCP in the control nonsmoking group were all significantly higher than those in the dry AMD nonsmoking group (all P < 0.05), whereas the whole vessel density of SCP in the normal smoking group was higher than that in the dry AMD smoking group (P = 0.04). The thickness values of the inner and full-layer FRT in the normal nonsmoking group were significantly thicker than those in the dry AMD nonsmoking group (all P < 0.01). The pack-year history was negatively correlated with the parafoveal vessel density of DCP (r = - 0.224, P < 0.01). CONCLUSIONS: FD, SCP, DCP and FRT are sensitive indices for the detection of early and intermediate dry AMD. DCP is a sensitive indicator that reflects the effects of smoking on the retina. Considerable changes are observed in retinal vessels, suggesting that dry AMD may affect the retinal tissue to a certain extent.

F,N-Doped carbon dots as efficient Type I photosensitizers for photodynamic therapy.

Photodynamic therapy (PDT) is a promising and emerging method for the treatment of cancer. Usually, Type II PDT is used in the clinic, and mainly involves three key elements: a photosensitizer, molecular oxygen and laser light. However, it is known that tumor tissue is deficient in oxygen molecules which is why Type I PDT is mostly preferred in the therapy of tumors in which the hypoxic tissue plays a major role. Fluorescent carbon dots (CDs) have shown great potential in cancer theranostics, acting as bioimaging agents and photosensitizers. Herein, we have synthesized novel kinds of fluorine and nitrogen co-doped carbon dots (F,NCDs) that emit bright green fluorescence under ultra-violet light. The F,NCDs have excellent water solubility and low cytotoxicity. They can generate hydroxyl radicals (˙OH) and superoxide anions (˙O2-) under LED light (400-500 nm, 15 mW cm-2) irradiation, making them ideal photosensitizers for Type I PDT. Furthermore, upon using the HepG2 cell line as an in vitro model, the F,NCDs exhibit a better cell imaging effect and higher PDT efficiency than the control sample of CDs without F and N doping. This work has illustrated that the F,NCDs are promising in achieving the image-guided PDT of cancers, usually in a hypoxia tumor microenvironment.

Cerebral organoids transplantation improves neurological motor function in rat brain injury.

BACKGROUND AND PURPOSE: Cerebral organoids (COs) have been used for studying brain development, neural disorders, and species-specific drug pharmacology and toxicology, but the potential of COs transplantation therapy for brain injury remains to be answered. METHODS: With preparation of traumatic brain injury (TBI) model of motor dysfunction, COs at 55 and 85 days (55 and 85 d-CO) were transplanted into damaged motor cortex separately to identify better transplantation donor for brain injury. Further, the feasibility, effectiveness, and underlying mechanism of COs transplantation therapy for brain injury were explored. RESULTS: 55 d-CO was demonstrated as better transplantation donor than 85 d-CO, evidenced by more neurogenesis and higher cell survival rate without aggravating apoptosis and inflammation after transplantation into damaged motor cortex. Cells from transplanted COs had the potential of multilinage differentiation to mimic in-vivo brain cortical development, support region-specific reconstruction of damaged motor cortex, form neurotransmitter-related neurons, and migrate into different brain regions along corpus callosum. Moreover, COs transplantation upregulated hippocampal neural connection proteins and neurotrophic factors. Notably, COs transplantation improved neurological motor function and reduced brain damage. CONCLUSIONS: This study revealed 55 d-CO as better transplantation donor and demonstrated the feasibility and efficacy of COs transplantation in TBI, hoping to provide first-hand preclinical evidence of COs transplantation for brain injury.

Cerebral Organoids Repair Ischemic Stroke Brain Injury.

Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.

PlncRNA-1 is overexpressed in retinoblastoma and regulates retinoblastoma cell proliferation and motility through modulating CBR3.

PlncRNA-1 has been suggested to function as an oncogenic role in prostate cancer, colorectal cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and gastric cancer. The expression pattern of PlncRNA-1 in retinoblastoma remained unknown. Therefore, the aim of this study was to explore the clinical significance of PlncRNA-1 in retinoblastoma patient and the biological function and molecular mechanism of PlncRNA-1 in regulating retinoblastoma cell proliferation, migration, and invasion. The results showed the level of PlncRNA-1 expression was obviously increased in retinoblastoma tissues and cell lines compared with compared with normal retina tissues and retina cell lines, respectively. Meanwhile, patients with advanced stage retinoblastoma had higher levels of PlncRNA-1 expression than patients with early stage retinoblastoma. There was an inverse correlation between PlncRNA-1 expression and CBR3 expression in retinoblastoma tissues, and PlncRNA-1 negatively regulated mRNA and protein expressions of CBR3. The in vitro experiments showed that down-regulation of PlncRNA-1 expression suppressed retinoblastoma cell proliferation, migration and invasion through up-regulating CBR3. In conclusion, PlncRNA-1 serves as an oncogenic lncRNA in regulating retinoblastoma cell proliferation, migration, and invasion through proliferation, migration, and invasion through up-regulating CBR3. © 2018 IUBMB Life, 70(10):969-975, 2018.

LncRNA AFAP1-AS1 is a prognostic biomarker and serves as oncogenic role in retinoblastoma.

The actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been found to serve as an oncogenic long noncoding RNA (lncRNA) in most types of human cancer. The role of AFAP1-AS1 in retinoblastoma remains unknown. The purpose of the present study is to explore the clinical significance and biological function of AFAP1-AS1 in retinoblastoma. Levels of AFAP1-AS1 expression were measured in retinoblastoma tissues and cell lines. Loss-of-function study was performed to observe the effects of AFAP1-AS1 on retinoblastoma cell proliferation, cell cycle, migration, and invasion. In our results, AFAP1-AS1 expression was elevated in retinoblastoma tissues and cell lines, and associated with tumor size, choroidal invasion, and optic nerve invasion. Moreover, high expression of AFAP1-AS1 was an independent unfavorable prognostic factor in retinoblastoma patients. The experiment in vitro suggested down-regulation of AFAP1-AS1 inhibited retinoblastoma cell proliferation, migration and invasion, and blocked cell cycle. In conclusion, AFAP1-AS1 functions as an oncogenic lncRNA in retinoblastoma.

Discovery of Novel Inhibitors and Fluorescent Probe Targeting NAMPT.

Nicotinamide phosphoribosyltransferase (NAMPT) is a promising antitumor target. Novel NAMPT inhibitors with diverse chemotypes are highly desirable for development of antitumor agents. Using high throughput screening system targeting NAMPT on a chemical library of 30000 small-molecules, we found a non-fluorescent compound F671-0003 and a fluorescent compound M049-0244 with excellent in vitro activity (IC50: 85 nM and 170 nM respectively) and anti-proliferative activity against HepG2 cells. These two compounds significantly depleted cellular NAD levels. Exogenous NMN rescued their anti-proliferative activity against HepG2 cells. Structure-activity relationship study proposed a binding mode for NAMPT inhibitor F671-0003 and highlighted the importance of hydrogen bonding, hydrophobic and π-π interactions in inhibitor binding. Imaging study provided the evidence that fluorescent compound M049-0244 (3 µM) significantly stained living HepG2 cells. Cellular fluorescence was further verified to be NAMPT dependent by using RNA interference and NAMPT over expression transgenic mice. Our findings provide novel antitumor lead compounds and a "first-in-class" fluorescent probe for imaging NAMPT.

Co-culture with endometrial stromal cells enhances the differentiation of human embryonic stem cells into endometrium-like cells.

In vitro differentiation of human embryonic stem cells (hESCs) into endometrium-like cells may provide a useful tool for clinical treatment. The aim of the present study was to investigate the differentiation potential of hESCs into endometrium-like cells using three methods, which included induction by feeder cells, co-culture with endometrial stromal cells and induction with embryoid bodies. Following differentiation, the majority of cells positively expressed cytokeratin and epithelial cell adhesion molecule (EPCAM). Factors associated with endometrium cell function, namely the estrogen and progesterone receptors (ER and PR), were also detected. At day 21 following the induction of differentiation, the expression levels of cytokeratin, EPCAM, ER and PR were significantly increased in the co-culture method group, as compared with the other two methods. Furthermore, these cells became decidualized in response to progesterone and prolactin. In addition, the number of cytokeratin-positive or EPCAM-positive cells significantly increased following the induction of differentiation using the co-culture method, as compared with the other two methods. The mRNA expression levels of Wnt members that are associated with endometrial development were subsequently examined, and Wnt5a was found to be significantly upregulated in the differentiated cells induced by feeder cells and co-culture with endometrial stromal cells; however, Wnt4 and Wnt7a expression levels were unaffected. Additionally, the mRNA expression levels of Wnt5a in the differentiated cells co-cultured with endometrial stromal cells were higher when compared with those induced by feeder cells. In conclusion, the present findings indicated that the co-culture system is the optimal protocol for the induction of hESC differentiation into endometrium-like cells, and Wnt5a signaling may be involved in this process.

Expression and distribution of immunoglobulin G and its receptors in an immune privileged site: the eye.

It has recently been demonstrated that not only mature B lymphocytes, but also non-lymphoid cells, including cancer cells and neurons, express IgG. In the eye, an important immune privileged site, the presence of IgG has been ascribed to IgG entering the eye through breaches of the blood­ocular barrier. Here we demonstrate that the eye itself can produce IgG intrinsically. Applying immunohistochemistry, in situ hybridization, and RT-PCR, several intraocular structures were found to express proteins and mRNA transcripts of IgG heavy chains, light chains, V(D)J rearrangements, and enzymes required for V(D)J recombination. IgG receptors were also detected in the intraocular epithelium and endothelium. The extensive distribution of IgG and its receptors in intraocular structures indicates that locally produced IgG could play a significant role in maintaining the ocular microenvironment and protection of the eyes, and it might also be involved in the pathogenesis of age-related macular degeneration and some inflammatory diseases.