Associations of clinical subtypes and bile acid levels of intrahepatic cholestasis of pregnancy with pregnancy outcomes.

Intrahepatic cholestasis of pregnancy (ICP) can lead to many adverse pregnancy outcomes, and the influencing factors remain unclear at present. This study retrospectively analyzed clinical data from 1815 pregnant women with ICP and evaluated the relationship between ICP subtypes, gestational age at onset, and pregnancy outcomes. The results of this study show that during pregnancy, the levels of biochemical indicators (TBA, DBIL and ALT) in the serum of pregnant women initially diagnosed with subtypes of ICP were noted to constantly change, and the subtype of ICP and its severity also changed. The incidence of adverse pregnancy outcomes [meconium-stained amniotic fluid (MSAF), NICU transfer, Apgar score ≤ 7 at 1 min, and preterm birth] in patients with ICP1 (icteric type) was significantly higher than for patients with ICP2, ICP3 or ICP4. The preterm birth rate of early-onset ICP was higher than that of late-onset ICP in ICP1 and ICP3 subtypes. In conclusion, the outcome of pregnancy in women with ICP is closely related to the serum TBA level and ICP subtype, which should be recognized in the clinic.

FPR1 Antagonist (BOC-MLF) Inhibits Amniotic Epithelial-mesenchymal Transition.

OBJECTIVE: Premature rupture of membranes (PROM) is a common pregnancy disorder that is closely associated with structural weakening of fetal membranes. Studies have found that formyl peptide receptor 1 (FPR1) activates inflammatory pathways and amniotic epithelialmesenchymal transition (EMT), stimulates collagen degradation, and leads to membrane weakening and membrane rupture. The purpose of this study was to investigate the anti-inflammatory and EMT inhibitory effects of FPR1 antagonist (BOC-MLF) to provide a basis for clinical prevention of PROM. METHODS: The relationship between PROM, FPR1, and EMT was analyzed in human fetal membrane tissue and plasma samples using Western blotting, PCR, Masson staining, and ELISA assays. Lipopolysaccharide (LPS) was used to establish a fetal membrane inflammation model in pregnant rats, and BOC-MLF was used to treat the LPS rat model. We detected interleukin (IL)-6 in blood from the rat hearts to determine whether the inflammatory model was successful and whether the anti-inflammatory treatment was effective. We used electron microscopy to analyze the structure and collagen expression of rat fetal membrane. RESULTS: Western blotting, PCR and Masson staining indicated that the expression of FPR1 was significantly increased, the expression of collagen was decreased, and EMT appeared in PROM. The rat model indicated that LPS caused the collapse of fetal membrane epithelial cells, increased intercellular gaps, and decreased collagen. BOC-MLF promoted an increase in fetal membrane collagen, inhibited EMT, and reduced the weakening of fetal membranes. CONCLUSION: The expression of FPR1 in the fetal membrane of PROM was significantly increased, and EMT of the amniotic membrane was obvious. BOC-MLF can treat inflammation and inhibit amniotic EMT.

Combined Application of Exosomes and FPR2 Agonist LXA4 in Controlling Fetal Membrane Inflammation and Promoting Fetal Membrane Tissue Repair.

Preterm premature rupture of membranes (pPROM) is a common pregnancy disease closely related to inflammation. The formyl peptide receptor 2 (FPR2), a member of the G protein-coupled receptor family involved in defense responses, inflammation, and disturbances in glucose and lipid metabolism, is associated with pregnancy diseases. Lipoxin A4 (LXA4) can activate FPR2 and inhibit the inflammatory signals. Exosomes derived from mesenchymal stem cells are good materials for anti-inflammatory and tissue repair. This study aims to investigate the anti-inflammatory and tissue repair effects of the combined application of exosomes derived from human umbilical cord mesenchymal stem cells and FPR2 agonist LXA4. In this study, LPS was used to establish the inflammation model of pregnant mice and HTR8 cells, and LXA4 and exosome treatment were carried out to observe the fetal membranes' tissue repair. The scanning and transmission electron microscopy of fetal membrane tissue indicated that the structure of pPROM tissue was disordered, and the cell gap was significantly increased. The results of the inflammatory mice model suggested that LPS can cause damage to the fetal membrane structure. LXA4 combined with exosome treatment can inhibit the production of MMP2 and MMP9, and promote neovascularization by inhibiting the p38 MAPK/Nuclear factor kB p65 (NFkB) pathway in the inflammation model of HTR8 cells and pregnant mice, thus helping to control inflammation and tissue repair.

Comprehensive analysis of tumor mutation burden and immune microenvironment in prostate cancer

Purpose: Prostate adenocarcinoma (PRAD) is a high incidence of malignant tumor of the urinary system and the second most common male cancer in the world. Immune checkpoint inhibitor (ICIS) therapy is becoming a new hope for cancer treatment.MethodsTo realize the possibility of PRAD patients benefiting from ICIS treatment, we analyzed the mutation spectrum of all PRAD patients, calculated the TMB of each PRAD patient, and divided the patients into high TMB group and low TMB group. Differentially expressed genes (DEGs) between the two groups were identified and path analysis was carried out. The immune cell infiltration of each PRAD patient was evaluated and survival analysis was performed to explore the effect of immune cell infiltration on the prognosis.ResultsWe found that high TMB was associated with better survival outcomes, with higher TMB scores in young patients, T2 and N0 patients. 28 hub genes were screened by the overlap between 229 DEGs and immune-related genes. T cells CD8 and CD4 memory activated in the high TMB group were higher than those in the low TMB group, while Mast cells resting in the low TMB group were higher than that in the high TMB group. High neutrophil infiltration is associated with poor prognosis in patients with PRAD. Finally, from the immune genes used to construct the prognostic risk model of TMB, it is found that CHP2 and NRG1 are independent prognostic factors of PRAD.ConclusionsThis study provides new insights into the immune microenvironment and potential immunotherapy of PRAD. (AU)

Comprehensive analysis of tumor mutation burden and immune microenvironment in prostate cancer.

PURPOSE: Prostate adenocarcinoma (PRAD) is a high incidence of malignant tumor of the urinary system and the second most common male cancer in the world. Immune checkpoint inhibitor (ICIS) therapy is becoming a new hope for cancer treatment. METHODS: To realize the possibility of PRAD patients benefiting from ICIS treatment, we analyzed the mutation spectrum of all PRAD patients, calculated the TMB of each PRAD patient, and divided the patients into high TMB group and low TMB group. Differentially expressed genes (DEGs) between the two groups were identified and path analysis was carried out. The immune cell infiltration of each PRAD patient was evaluated and survival analysis was performed to explore the effect of immune cell infiltration on the prognosis. RESULTS: We found that high TMB was associated with better survival outcomes, with higher TMB scores in young patients, T2 and N0 patients. 28 hub genes were screened by the overlap between 229 DEGs and immune-related genes. T cells CD8 and CD4 memory activated in the high TMB group were higher than those in the low TMB group, while Mast cells resting in the low TMB group were higher than that in the high TMB group. High neutrophil infiltration is associated with poor prognosis in patients with PRAD. Finally, from the immune genes used to construct the prognostic risk model of TMB, it is found that CHP2 and NRG1 are independent prognostic factors of PRAD. CONCLUSIONS: This study provides new insights into the immune microenvironment and potential immunotherapy of PRAD.

Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway to induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.

PURPOSE: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy complication. However, the pathogenesis of ICP is currently unclear. METHODS: We analyzed the placenta samples of 10 normal and 10 ICP pregnant women. the expressions of circ0060731, miR-21-5p, and their downstream target genes PDCD4, ESR1, and apoptotic protein cleaved-caspase3 were detected in the cell model. RESULTS: The expression of Circ_0060731, PDCD4, ESR1, and caspase-3 was higher in the ICP placenta tissue than in the control group, and the expression of miR-21-5p was lower in the ICP group than in the control group. In HTR8/Svneo cells treated with TCA, the expression/levels of Circ_0060731, PDCD4, ESR1, and caspase-3 were significantly higher in the ICP group than in the control group, and miR-21-5p was significantly lower in the ICP group than in the control group. Lentiviral knockdown of miR-21-5p significantly increased the expressions of its downstream genes of PDCD4 and ESR1, and also increased cell apoptosis. Overexpression of miR-21-5p significantly reduced the expression of PDCD4 and ESR1 and reduced cell apoptosis. The dual-luciferase experiment showed that both PDCD4 and ERS1 were the target genes of miR-21-5p. CONCLUSION: Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway could induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.