Constructing and validating a risk model based on neutrophil-related genes for evaluating prognosis and guiding immunotherapy in colon cancer.

BACKGROUND: Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients. METHODS: We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues. RESULTS: We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy. CONCLUSIONS: The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy.

Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3ß pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway.

Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.

Kallistatin leads to cognition impairment via downregulating glutamine synthetase.

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.

A nomogram model for predicting the efficacy of cyclosporine in patients with pure red cell aplasia.

Pure red cell aplasia (PRCA) is a rare bone marrow disorder characterized by a severe reduction or absence of erythroid precursor cells, without affecting granulocytes and megakaryocytes. Immunosuppressive therapies, particularly cyclosporine, have demonstrated efficacy as a primary treatment. This study aims to develop a predictive model for assessing the efficacy of cyclosporine in acquired PRCA (aPRCA). This retrospective study encompasses newly treated aPRCA patients at the General Hospital of Tianjin Medical University. Diagnosis criteria include severe anemia, and absolute reticulocyte count below 10 × 109/L, with normal white blood cell and platelet counts, and a severe reduction in bone marrow erythroblasts. Cyclosporine therapy was administered, with dose adjustments based on blood concentration. Response to cyclosporine was evaluated according to established criteria. Statistical analysis involved logistic multi-factor regression, generating a predictive model. The study included 112 aPRCA patients with a median age of 63.5 years. Patients presented with severe anemia (median Hb, 56 g/L) and reduced reticulocyte levels. Eighty-six patients had no bone marrow nucleated erythroblasts. Primary PRCA accounted for 62 cases (55.4%), and secondary PRCA accounted for 50 cases (44.6%). Univariate analysis revealed that ferritin, platelet to lymphocyte ratio (PLR), and CD4/CD8 ratio influenced treatment response. Multivariate analysis further supported the predictive value of these factors. A prediction model was constructed using ferritin, PLR, and CD4/CD8 ratio, demonstrating high sensitivity and specificity. The ferritin, PLR, and CD4/CD8-based nomogram showed good predictive ability for aPRCA response to cyclosporine. This model has potential clinical value for individualized diagnosis and treatment of aPRCA patients.

Macrophages Promote Subtype Conversion and Endocrine Resistance in Breast Cancer.

BACKGROUND: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype conversion during lymph node metastasis (LNM) and the underlying mechanism remains unclear. METHODS: We compared clinical subtypes in paired primary tumors and positive lymph nodes (PLNs) in BC patients and further validated them in the mouse model. Bioinformatics analysis and macrophage-conditioned medium treatment were performed to investigate the role of macrophages in subtype conversion. RESULTS: During LNM, hormone receptors (HRs) were down-regulated, while HER2 was up-regulated, leading to the transformation of luminal A tumors towards luminal B tumors and from luminal B subtype towards HER2-enriched (HER2-E) subtype. The mouse model demonstrated the elevated levels of HER2 in PLN while retaining luminal characteristics. Among the various cells in the tumor microenvironment (TME), macrophages were the most clinically relevant in terms of prognosis. The treatment of a macrophage-conditioned medium further confirmed the downregulation of HR expression and upregulation of HER2 expression, inducing tamoxifen resistance. Through bioinformatics analysis, MNX1 was identified as a potential transcription factor governing the expression of HR and HER2. CONCLUSION: Our study revealed the HER2-E subtype conversion during LNM in BC. Macrophages were the crucial cell type in TME, inducing the downregulation of HR and upregulation of HER2, probably via MNX1. Targeting macrophages or MNX1 may provide new avenues for endocrine therapy and targeted treatment of BC patients with LNM.

The pathogenic role of succinate-SUCNR1: a critical function that induces renal fibrosis via M2 macrophage.

BACKGROUND: Renal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis. METHODS: Male C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms. RESULTS: Succinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3ß/ß-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells. CONCLUSIONS: The causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3ß/ß-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.

The Clinical Significance and the Potential Regulatory Mechanism of the LncRNA OIP5-AS1 in Paediatric Severe Community-Acquired Pneumonia Blood Through the MiR-150-5p/PDCD4 Axis.

BACKGROUND: This study aimed to elucidate the clinical significance and regulatory mechanism of the long non-coding RNA OIP5-AS1 in severe community-acquired pneumonia (SCAP) among paediatric patients. METHODS: qRT-PCR was used to assess the mRNA levels of OIP5-AS1. ROC curve analysis was used to assess the diagnostic significance of OIP5-AS1. Short-term prognostic significance was evaluated through Kaplan-Meier survival. An in vitro cell model was developed using LPS-induced MRC-5 cells. CCK-8, flow cytometry, and ELISA were conducted to measure cell viability, apoptosis, and inflammatory factor levels. The association between miR-150-5p and PDCD4 was confirmed through DLR assays. RESULTS: Elevated OIP5-AS1 were observed in paediatric patients with SCAP, which enabled effective differentiation from healthy individuals. High expression of OIP5-AS1 correlated with reduced survival rates. OIP5-AS1 knockdown attenuated cell viability suppression and the promotion of apoptosis and inflammatory factors induced by LPS. However, this attenuation was reversed by reduced levels of miR-150-5p. miR-150-5p was identified as a target of PDCD4 and OIP5-AS1. CONCLUSION: Increased OIP5-AS1 levels show potential as a valuable diagnostic and prognostic biomarker for paediatric patients with SCAP. This study illustrates its role in regulating cell viability, apoptosis, and the inflammatory response via the miR-150-5p/PDCD4 axis, acting as a ceRNA.

The critical role of BTRC in hepatic steatosis as an ATGL E3 ligase.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is one of the commonest causes of liver dysfunction. Adipose triglyceride lipase (ATGL) is closely related to lipid turnover and hepatic steatosis as the speed-limited triacylglycerol lipase in liver lipolysis. However, the expression and regulation of ATGL in NAFLD remain unclear. Herein, our results showed that ATGL protein levels were decreased in the liver tissues of high-fat diet (HFD)-fed mice, naturally obese mice, and cholangioma/hepatic carcinoma patients with hepatic steatosis, as well as in the oleic acid-induced hepatic steatosis cell model, while ATGL mRNA levels were not changed. ATGL protein was mainly degraded through the proteasome pathway in hepatocytes. Beta-transducin repeat containing (BTRC) was upregulated and negatively correlated with the decreased ATGL level in these hepatic steatosis models. Consequently, BTRC was identified as the E3 ligase for ATGL through predominant ubiquitination at the lysine 135 residue. Moreover, adenovirus-mediated knockdown of BTRC ameliorated steatosis in HFD-fed mouse livers and oleic acid-treated liver cells via upregulating the ATGL level. Taken together, BTRC plays a crucial role in hepatic steatosis as a new ATGL E3 ligase and may serve as a potential therapeutic target for treating NAFLD.

Cepharanthine, a regulator of keap1-Nrf2, inhibits gastric cancer growth through oxidative stress and energy metabolism pathway.

Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.

Locoregional therapy combined with systemic therapy (LRT + ST) for unresectable and metastatic intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND: The outcome of systemic therapy (ST) for unresectable and metastatic intrahepatic cholangiocarcinoma (iCCA) is poor. This study aims to further evaluate the efficacy and safety of locoregional therapy combined with systemic therapy (LRT + ST) compared with only ST in unresectable and metastatic iCCA by performing a systematic literature review and meta-analysis. METHODS: A comprehensive search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 3, 2022. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). RESULTS: Ten retrospective cohort studies with 3,791 unresectable or metastatic iCCA patients were enrolled in this study, including 1,120 who received ablation, arterially directed therapy (ADT), or external beam radiation therapy (EBRT) combined with ST. The meta-analysis showed that the LRT + ST group had a better OS (HR = 0.51; 95% CI =0.41-0.64; p value < 0.001), PFS (HR = 0.40, 95% CI = 0.22-0.71, p value = 0.002) and ORR (RR = 1.68; 95% CI = 1.17-2.42; p value = 0.005). Subgroup analysis showed that both ST combined with ADT (HR = 0.42, 95% CI = 0.31-0.56, p value < 0.001) and EBRT (HR = 0.67, 95% CI = 0.63-0.72, p value < 0.001) could improve OS. Neutropenia, thrombocytopenia, anemia, anorexia, and vomiting did not show significant differences between the groups (p value > 0.05). CONCLUSIONS: Compared with only ST, LRT + ST improved survival outcomes for unresectable and metastatic iCCA patients without increasing severe AEs, which can further provide a basis for guidelines.

The worthy role of hepatic arterial infusion chemotherapy in combination with anti-programmed cell death protein 1 monoclonal antibody immunotherapy in advanced hepatocellular carcinoma.

Systemic therapy remains the primary therapeutic approach for advanced hepatocellular carcinoma (HCC). Nonetheless, its efficacy in achieving control of intrahepatic lesions is constrained. Hepatic arterial infusion chemotherapy (HAIC) is a therapeutic approach that combines localized treatment with systemic antitumor effects, which aim is to effectively manage the progression of cancerous lesions within the liver, particularly in patients with portal vein tumor thrombosis (PVTT). Combining HAIC with anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) immunotherapy is anticipated to emerge as a novel therapeutic approach aimed at augmenting the response inside the localized tumor site and achieving prolonged survival advantages. In order to assess the effectiveness, safety, and applicability of various therapeutic modalities and to address potential molecular mechanisms underlying the efficacy of HAIC-sensitizing immunotherapy, we reviewed the literature about the combination of HAIC with anti-PD-1 mAb therapies.

Role of Kinetochore Scaffold 1 (KNL1) in Tumorigenesis and Tumor Immune Microenvironment in Pan-Cancer: Bioinformatics Analyses and Validation of Expression.

Purpose: Kinetochore scaffold 1 (KNL1), a crucial protein during cell mitosis participating in cell division, was widely expressed in multiple kinds of cancers. However, the expression profile, the effect on cell biological function, tumor immune microenvironment, and predictive value of clinical prognosis in pan-cancer of KNL1 still require a comprehensive inquiry. Methods: The mRNA and protein expression profile of KNL1 was validated in pan-cancer using different databases. Six algorithms were used to explore the correlation between KNL1 and immune infiltration and the relationship between KNL1 and tumor mutation burden (TMB), microsatellite instability (MSI), and TIDE score were calculated. The diagnostic and clinical prognostic predictive ability of KNL1 was assessed. Differentially expressed genes (DEGs) of KNL1 were screened out and function enrichment analyses were performed in pancreatic adenocarcinoma (PAAD), stomach adenocarcinoma (STAD), and bladder urothelial carcinoma (BLCA). Finally, 8 cases of pancreatic adenocarcinoma tissues and paired adjacent tissues were collected for immunohistochemical (IHC) staining and the histological score (H-score) was calculated. Real-time PCR was performed in gastric cancer and bladder cancer cell lines. Results: KNL1 was abnormally upregulated in more than half of cancers across different databases. IHC and real-time PCR verified the up-regulated expression in cancer tissues in PAAD, gastric cancer, and BLCA. The satisfactory diagnostic value of KNL1 was indicated in 30 cancers and high KNL1 expression was associated with poorer overall survival (OS) in 12 cancers. The prognostic role of KNL1 as a predictive biomarker of PAAD was clarified. KNL1 played an active part in the cell cycle and cell proliferation. Moreover, KNL1 was likely to mold the Th2-dominant suppressive tumor immune microenvironment and was associated with TMB, MSI, and immune checkpoint-related genes in pan-cancer. Conclusion: Our study elucidated the anomalous expression of KNL1 and revealed that KNL1 was a promising prognostic biomarker in pan-cancer.

Kallistatin Deficiency Induces the Oxidative Stress-Related Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells: A Novel Protagonist in Age-Related Macular Degeneration.

Purpose: Retinal pigment epithelium (RPE) dysfunction induced by oxidative stress-related epithelial-mesenchymal transition (EMT) of RPE is the primary underlying mechanism of age-related macular degeneration (AMD). Kallistatin (KAL) is a secreted protein with an antioxidative stress effect. However, the relationship between KAL and EMT in RPE has not been determined. Therefore we aimed to explore the impact and mechanism of KAL in oxidative stress-induced EMT of RPE. Methods: Sodium iodate (SI) was injected intraperitoneally to construct the AMD rat model and investigate the changes in RPE morphology and KAL expression. KAL knockout rats and KAL transgenic mice were used to explain the effects of KAL on EMT and oxidative stress. In addition, Snail overexpressed adenovirus and si-RNA transfected ARPE19 cells to verify the involvement of Snail in mediating KAL-suppressed EMT of RPE. Results: AMD rats induced by SI expressed less KAL in the retina, and KAL knockout rats showed RPE dysfunction spontaneously where EMT and reactive oxygen species (ROS) production increased in RPE. In contrast, KAL overexpression attenuated EMT and ROS levels in RPE, even in TGF-ß treatment. Mechanistically, Snail reversed the beneficial effect of KAL on EMT and ROS reduction. Moreover, KAL ameliorated SI-induced AMD-like pathological changes. Conclusions: Our findings demonstrated that KAL inhibits oxidative stress-induced EMT by downregulating the transcription factor Snail. Herein, KAL knockout rats may be an appropriate animal model for observing spontaneous RPE dysfunction for AMD-like retinopathy, and KAL may represent a novel therapeutic target for treating dry AMD.

Identification of Plasma Thrombopoietin Level and Its Significance in Patients with Aplastic Anemia and Myelodysplastic Syndrome.

Objective Our objective was to investigate the concentration of plasma thrombopoietin (TPO) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS), as well as its relationship with patients' responses to recombined human TPO (rhTPO) therapy. Methods We detected the concentration of plasma TPO in 31 patients with AA, 27 patients with MDS, and 11 normal controls using enzyme-linked immunosorbent assay. Results The median concentration of plasma TPO in patients with AA, MDS, and controls was (841.08 ± 768.64), (212.41 ± 338.93), and (35.09 ± 18.21) pg/mL, respectively. The TPO concentration in patients with AA and MDS was significantly higher than that in controls ( p < 0.05). The median platelet (PLT) counts were (184 ± 34) ×10 9 /L in the control group and (24 ± 19) ×10 9 /L and (80 ± 71) ×10 9 /L in AA and MDS patients, respectively. Negative correlations were found between plasma TPO concentration and PLT counts as well as megakaryocytes in bone marrow ( p < 0.05). In AA patients treated with rhTPO, a negative correlation was observed between increased PLT counts and pretreatment TPO levels ( p < 0.05). Conclusion Plasma TPO concentration in AA and MDS was significantly higher than that in normal controls. Plasma TPO was negatively correlated with peripheral blood PLT counts and bone marrow megakaryocyte counts. The pretreatment TPO level may serve as a prognostic indicator for the therapeutic effect of rhTPO in AA patients.

Pigment Epithelium-Derived Factor, a Novel Adipokine, Contributes to Gestational Diabetes Mellitus.

CONTEXT: Excessive insulin resistance, inadequate insulin compensation, or both could result in gestational diabetes mellitus (GDM). Levels of pigment epithelium-derived factor (PEDF), a novel adipokine that could induce insulin resistance, are high in patients with obesity and diabetes. However, the impact of PEDF in pregnancy remains unknown. OBJECTIVE: This study aimed to elucidate the role of PEDF on insulin resistance and compensatory elevation of insulin levels during normal pregnancy and in patients with GDM. METHODS: In this population-based and cohort study, logistic regression analysis was performed to determine the association of PEDF/adiponectin/leptin levels with the risk of developing GDM and to predict postpartum prediabetes. PEDF protein, PEDF transgenic mice, PEDF knockout mice, and PEDF-neutralized antibodies were used to observe changes in insulin resistance and insulin levels with pregnancy. RESULTS: Plasma PEDF levels were increased in normal pregnancy and higher in GDM women. Higher PEDF levels were associated with the increased risk of developing GDM and emerged as a significant independent determinant of postpartum prediabetes in GDM women. Mechanistically, in vivo and in vitro experiments revealed that PEDF induced insulin resistance by inhibiting the insulin signaling pathway. CONCLUSION: In addition to insulin resistance and upregulated insulin levels in normal pregnancy and GDM, aberrant PEDF levels can serve as a "fingerprint" of metabolic abnormalities during pregnancy. Thus, PEDF is a valuable biomarker but could interfere with the time course for early diagnosis and prognosis of GDM.

Efficacy of transcatheter arterial chemoembolization combined with sirolimus for treating Kasabach-Merritt phenomenon in infants, a retrospective study.

OBJECTIVE: This retrospective study aimed to observe the efficacy of transcatheter arterial chemoembolization (TACE) combined with sirolimus in the treatment of haemangioma combined with the Kasabach-Merritt phenomenon (KMP). METHODS: A total of 11 infants with KMP who were treated at our hospital from January 2016 to September 2021 were selected and treated with arteriosclerosis embolotherapy using a microsphere emulsion formed by bleomycin + ultra-fluid lipiodol + dexamethasone + contrast agent or bleomycin mixed microspheres as the embolising agent. The patients were administered sirolimus orally after TACE. The clinical efficacy and examination indicators before and after treatment were observed and compared. RESULTS: The 11 infants underwent TACE treatment by arteriosclerosis embolotherapy a total of 21 times; of these cases, 10 were cured, and 1 showed a moderate response. There were no cases of non-response or death. The platelet count rose from 10.0 (7.0, 18.0) x 109/L before TACE to 236.0 (188.0, 275.0) x 109/L six months after the first TACE, and the tumour size decreased from 49.0 (43.0, 111.7) cm3 before TACE to 7.0 (3.5, 17.0) cm3 six months after the first TACE. The differences were statistically significant (the Z values were -2.943 and -2.934, respectively, p < 0.05). CONCLUSION: The combination of TACE and sirolimus has significant efficacy on critical children with KMP.

C9 regulates the complement-mediated cell lysis in association with CD59 to resist bacterial infection in a primary animal.

Complement component 9 (C9), as an essential component of terminal membrane attack complex of complement system, plays an important role in innate immune defense. However, the function and regulatory mechanism of C9 in the antimicrobial immune response of teleost fish remain unclear. In this study, the open reading frame of Nile tilapia (Oreochromis niloticus) C9 (OnC9) gene was amplified. The mRNA and protein expression of OnC9 were significantly changed upon infection with Streptococcus agalactiae and Aeromonas hydrophila in vivo and in vitro. Upon bacterial challenge, the OnC9 knockdown could lead to rapid proliferation of the pathogenic bacteria, ultimately resulting in tilapia death. However, the phenotype was rescued by re-injection of OnC9, which restored the healthy status of the knockdown tilapia. Further, the OnC9 was an essential component in complement-mediated cell lysis and associated with OnCD59 to regulate the efficiency of lysis. Overall, this study indicates that OnC9 is involved in host defense against bacterial infection, and provides a valuable reference for further exploration of the molecular regulatory mechanism of C9 in innate immune defense in a primary animal.