[Research advances on B-cell activating factor and its targeted agents in inflammatory bowel disease]. / Bç»†èƒžæ¿€æ´»å› å­åŠå ¶é¶å‘è¯ç‰©ä¸Žç‚Žç—‡æ€§è‚ ç— çš„ç ”ç©¶è¿›å±•.

B-cell activating factor (BAFF), a critical regulator of B cells, is involved in various autoimmune diseases. Inflammatory bowel disease (IBD) is a group of chronic and recurrent intestinal inflammatory disorders with unclear etiology, and its global incidence has been increasing in recent years. Abnormal immune responses triggered by multiple factors are closely related to the pathogenesis of IBD. Previous studies have confirmed the association of B-cell abnormal activation and increased production of autoantibodies with the development of ulcerative colitis. However, the involvement of BAFF in the mechanisms of IBD remains unclear. This review summarizes the potential role of BAFF in the pathogenesis of IBD and provides an overview of targeted therapies on BAFF in IBD, aiming to contribute insights for targeted treatments of IBD.

Inetetamab combined with tegafur as second-line treatment for human epidermal growth factor receptor-2-positive gastric cancer: A case report.

BACKGROUND: Human epidermal growth factor receptor-2 (HER-2) plays a vital role in tumor cell proliferation and metastasis. However, the prognosis of HER2-positive gastric cancer is poor. Inetetamab, a novel anti-HER2 targeting drug independently developed in China, exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab, which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy. In this case, the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer. CASE SUMMARY: A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension, poor appetite, and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery, followed by tegafur monotherapy for six months. The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma. He received 17 cycles of a combination of inetetamab, an innovative domestically developed anti-HER2 monoclonal antibody, and tegafur chemotherapy as the second-line treatment (inetetamab 200 mg on day 1, every 3 wk combined with tegafur twice daily on days 1-14, every 3 wk). Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months. He tolerated the treatment well without exhibiting any grade 3-4 adverse events. CONCLUSION: Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.

A MOF-derived flower-shaped CeCo-oxide as a multifunctional material for high-performance lithium-ion batteries and supercapacitors.

Precursor method is a well-known technology for preparing certain functional materials. In this work, a novel 3d-4f bimetallic organic framework, denoted as 45MCeCo (45 M representing 4,5-imidazole dicarboxylic acid), was successfully synthesized via a hydrothermal technique. The compound thus obtained has the molecular formula of C10H11CeCoN4O12. By meticulously controlling the amounts of the experimental materials, it was feasible to prepare flower-like crystals possessing identical single crystal structures and significantly larger specific surface areas. As a precursor for electrode materials, this structure underwent calcination at different temperatures to prepare Co3O4/CeO2 composites with in situ composite heterostructures. Post-electrochemical tests revealed that CeO2 remains unreactive across all potentials, thereby contributing to the stabilization of the electrode material structure. In contrast, Co3O4 participated in redox reactions to provide a specific capacity to the sample. In addition, when comparing the performance of the electrode material under different calcination conditions, it became evident that the material exhibited optimal electrochemical performance when subjected to a temperature of 700 °C for 2 h.

Telocyte-Derived Exosomes Provide an Important Source of Wnts That Inhibits Fibrosis and Supports Regeneration and Repair of Endometrium.

Intrauterine adhesions (IUAs) often occurred after common obstetrical and gynecological procedures or infections in women of reproductive age. It was characterized by the formation of endometrial fibrosis and prevention of endometrial regeneration, usually with devastating fertility consequences and poor treatment outcomes so far. Telocytes (TCs), as a novel interstitial cell type, present in female uterus with in vitro therapeutic potential in decidualization-defective gynecologic diseases. This study aims to further investigate the role of TC-derived Wnt ligands carried by exosomes (Exo) in reversal of fibrosis and enhancement of regeneration repair in endometrium. IUA cellular and animal models were established from endometrial stromal cells (ESCs) and mice, followed with treatment of TC-conditioned medium (TCM) or TC-derived Exo. In cellular model, fibrosis markers (collagen type 1 alpha 1 [COL1A1], fibronectin [FN], and α-smooth muscle actin [α-SMA]), angiogenesis (vascular endothelial growth factor [VEGF]), and pathway protein (ß-catenin) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting (WB), and immunofluorescence. Results showed that, TCs (either TCM or TC-derived Exo) provide a source of Wnts that inhibit cellular fibrosis, as evidenced by significantly elevated VEGF and ß-catenin with decreased fibrotic markers, whereas TCs lost salvage on fibrosis after being blocked with Wnt/ß-catenin inhibitors (XAV939 or ETC-159). Further in mouse model, regeneration repair (endometrial thickness, number of glands, and fibrosis area ratio), fibrosis markers (fibronectin [FN]), mesenchymal-epithelial transition (MET) (E-cadherin, N-cadherin), and angiogenesis (VEGF, microvessel density [MVD]) were studied by hematoxylin-eosin (HE), Masson staining, and immunohistochemistry. Results demonstrated that TC-Exo treatment effectively promotes regeneration repair of endometrium by relieving fibrosis, enhancing MET, and angiogenesis. These results confirmed new evidence for therapeutic perspective of TC-derived Exo in IUAs.

A review of physiological functions of orexin: From instinctive responses to subjective cognition.

Orexin, also known as hypocretin, is an excitatory neuropeptide secreted by the hypothalamus. Orexin is divided into orexin-A (OXA) and orexin-B (OXB), which are derived from a common precursor secreted by hypothalamic neurons. Orexin acts on orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R). Orexin neurons, as well as receptors, are widely distributed in various regions of the brain as well as in the peripheral system and have a wider range of functions. This paper reviews the latest research results of orexin in the aspects of food intake, sleep, addiction, depression and anxiety. Because orexin has certain physiological functions in many systems, we further explored the possibility of orexin as a new target for the treatment of bulimia, anorexia nervosa, insomnia, lethargy, anxiety and depression. It is precisely because orexin has physiological functions in multiple systems that orexin, as a new target for the treatment of the above diseases, has potential contradictions. For example, it promotes the function of 1 system and may inhibit the function of another system. How to study a new drug, which can not only treat the diseases of this system, but also do not affect other system functions, is what we need to focus on.

Metal-Catalyst-Free One-Pot Aqueous Synthesis of trans-1,2-Diols from Electron-Deficient α,ß-Unsaturated Amides via Epoxidation Using Oxone as a Dual Role Reagent.

In organic synthesis, incorporating two functional groups into the carbon-carbon double bond of α,ß-unsaturated amides is challenging due to the electron-deficient nature of the olefin moiety. Although a few examples of dihydroxylation of α,ß-unsaturated amides have been demonstrated, producing cis-1,2-diols using either highly toxic OsO4 or other specialized metal reagents in organic solvents, they are limited to several specific amides. We describe herein a general and one-pot direct synthesis of trans-1,2-diols from electron-deficient α,ß-unsaturated amides through dihydroxylation using oxone as a dual-role reagent in water. This reaction does not require any metal catalyst and produces non-hazardous and nontoxic K2 SO4 as the sole byproduct. Moreover, epoxidation products could also be selectively formed by adjusting the reaction conditions. By the strategy, the intermediates of Mcl-1 inhibitor and antiallergic bioactive molecule can be synthesized in one pot. The gram-scale synthesis of trans-1,2-diol which is isolated and purified by recrystallization further shows the potential applications of this new reaction in organic synthesis.

Anti-tumour effect of Huangqin Decoction on colorectal cancer mice through microbial butyrate mediated PI3K/Akt pathway suppression.

Introduction. Huangqin Decoction (HQD), a Chinese herbal formula, is widely used for various diseases, including colorectal cancer (CRC).Hypothesis/Gap Statement. We proposed that microbial butyrate mediated PI3K/Akt pathway suppression might involve the anti-cancer effect of HQD.Aim. This study aimed to evaluate the potential mechanism of HQD against CRC.Methodology. An azoxymethane plus dextran sulphate sodium induced CRC mouse model was used, and the intestinal flora and faecal short-chain fatty acid changes were detected, respectively, after HQD administration with 16S rRNA sequencing and gas chromatography coupled with mass spectrometry. Disease activity index, colon length and levels of inflammatory cytokines were measured to evaluate the effect of HQD on intestinal inflammation. Tumour size, number and histopathology were assessed to reflect the impact of HQD on tumour burden. Apoptosis and PI3K/Akt pathway activity were measured by TUNEL staining and Western-blotting. In vitro, the effects of sodium butyrate (NaB) on the viability of CRC cell lines were detected by the Cell-counting Kit-8. The apoptotic cells were determined by TUNEL staining. Cell migration and invasion were assessed by wound healing assay and Transwell assay, respectively. Western-blotting and immunofluorescent staining were used to test the activity of PI3K/Akt pathway.Results. Animal study showed that HQD could improve the gut dysbiosis, increase the abundance of Clostridium and the level of faecal butyric acid. Then, we found that HQD could attenuate colitis, reduce tumour burden, promote cell apoptosis and suppress PI3K/Akt pathway activity in CRC mice. In vitro experiment revealed that NaB treatment could inhibit cell growth, migration and invasion in CRC cell lines. Additionally, NaB enhanced cellular apoptosis, and reduced phosphorylated PI3K and Akt expressions. Interestingly, addition of 740Y-P, an agonist of PI3K, reversed the NaB effects on CRC cells.Conclusion. Overall, in this study, we revealed that HQD could induce apoptosis through microbial butyrate mediated PI3K/Akt inhibition and perform anti-CRC activity.

ANP promotes HTR-8/SVneo cell invasion by upregulating protein kinase N 3 via autophagy inhibition.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese.

BACKGROUND: Genetic knowledge of gestational diabetes mellitus (GDM) in Chinese women is quite limited. This study aimed to identify the risk factors and mechanism of GDM at the genetic level in a Chinese population. METHODS: We conducted a genome-wide association study (GWAS) based on single nucleotide polymorphism (SNP) array genotyping (ASA-CHIA Bead chip, Illumina) and a case-cohort study design. Variants including SNPs, copy number variants (CNVs), and insertions-deletions (InDels) were called from genotyping data. A total of 2232 pregnant women were enrolled in their first/second trimester between February 2018 and December 2020 from Anqing Municipal Hospital in Anhui Province, China. The GWAS included 193 GDM patients and 819 subjects without a diabetes diagnosis, and risk ratios (RRs) and their 95% confidence intervals (CIs) were estimated by a regression-based method conditional on the population structure. The calling and quality control of genotyping data were performed following published guidelines. CNVs were merged into CNV regions (CNVR) to simplify analyses. To interpret the GWAS results, gene mapping and overexpression analyses (ORAs) were further performed to prioritize the candidate genes and related biological mechanisms. RESULTS: We identified 14 CNVRs (false discovery rate corrected P values < 0.05) and two suggestively significant SNPs (P value < 0.00001) associated with GDM, and a total of 19 candidate genes were mapped. Ten genes were significantly enriched in gene sets related to lipase (triglyceride lipase and lipoprotein lipase) activity (LIPF, LIPK, LIPN, and LIPJ genes), oxidoreductase activity (TPH1 and TPH2 genes), and cellular components beta-catenin destruction complex (APC and GSK3B genes), Wnt signalosome (APC and GSK3B genes), and lateral element in the Gene Ontology resource (BRCA1 and SYCP2 genes) by two ORA methods (adjusted P values < 0.05). CONCLUSIONS: Genes related to lipolysis, redox reaction, and proliferation of islet ß-cells are associated with GDM in Chinese women. Energy metabolism, particularly lipolysis, may play an important role in GDM aetiology and pathology, which needs further molecular studies to verify.

Central GLP-1 Resistance Induced by Severe Traumatic Brain Injury Was Associated with Persistent Hyperglycemia in Humans.

INTRODUCTION: Whether central glucagon-like peptide 1 (GLP-1)/GLP-1 receptor system mediated peripheral glucose homeostasis in patients with traumatic brain injury (TBI) is not clear. We aim to determine if plasma GLP-1 level could distinguish the non-survivors from the survivors during the first 14 days after TBI that could prognose 6 months mortality. METHODS: Metabolic, inflammatory, and hematologic profiles were examined in 73 patients with TBI in neurological intensive care unit. Factors that discriminate non-survivors from survivors were determined by two-way ANOVA. Biomarkers associated with mortality were determined by binary logistic regression and Cox proportional hazard regression. RESULTS: The non-survivors had higher infectious SOFA scores (p < 0.001), lower first 3 days' body temperature (p = 0.017), greater chance of cerebral hernia (p = 0.048), and decompressive craniectomy (p = 0.001) than the survivors. Higher 14-day plasma GLP-1 (p < 0.0001), glucose (p = 0.002), and IL-6 (p = 0.005) levels, in contrast with lower insulin level at days 4-7 (p = 0.020) were found in non-survivors than in survivors. Except the survivors who had an increased 14-day platelet number (p < 0.001), the two groups did not differ in hematological profile and intestinal barrier function. Although GLP-1 correlated closely with IL-6 in both the groups, it correlated with neither insulin nor glucose in each group. GLP-1 on days 8-10 and IL-6 on days 1-3 were positively, while insulin on days 4-7 was negatively associated with mortality. CONCLUSION: Persistent higher GLP-1 level in non-survivors over the survivors may present more severe central resistance to endogenous GLP-1 in non-survivors, which may be associated with progressive hyperglycemia with increased mortality in TBI.

Involvement of MMP-9 in collagen degradation of sea bass (Lateolabrax japonicus): Cloning, expression, and characterization.

Disintegration of intramuscular connective tissue is responsible for postmortem tenderization of fish muscles during chilled storage. Matrix metalloproteinase-9 (MMP-9) was reported to be involved in this process, whereas the mechanism has not been revealed. In the present study, purified type I and V collagens from the connective tissues of sea bass (Lateolabrax japonicus) muscles were first prepared. These two kinds of collagens comprise three polypeptide chains (α), forming a typical triple-helical domain as determined by circular dichroism. The complete coding region of MMP-9 containing an open reading frame of 2070 bp encoding 689 amino acid residues was then cloned. The recombinant MMP-9 catalytic domain (rcMMP-9) was expressed in Escherichia coli and exhibited high hydrolyzing activity toward gelatin. Besides, rcMMP-9 was effective in degrading type V collagen rather than type I collagen at 4°C. The enzymatic activity of rcMMP-9 was highly pH-dependent, and its enzymatic activity under neutral and basic conditions was higher than that under acidic conditions. Metal ion Ca2+ was necessary for the maintenance of rcMMP-9 activity, whereas Zn2+ inhibited its activity. Our present study indicated that MMP-9 is responsible for the disintegration of intramuscular connective tissues by cleaving type V collagen during postmortem tenderization of fish muscle. PRACTICAL APPLICATION: Elucidation the involvement of MMP-9 in collagen degradation will deliver a reference for the prevention of muscular protein decomposition during chilled storage of fish fillets.

Prognostic Significance of Plasma Insulin Level for Deep Venous Thrombosis in Patients with Severe Traumatic Brain Injury in Critical Care.

BACKGROUND: Whether insulin resistance underlies deep venous thrombosis (DVT) development in patients with severe traumatic brain injury (TBI) is unclear. In this study, the association between plasma insulin levels and DVT was analyzed in patients with severe TBI. METHODS: A prospective observational study of 73 patients measured insulin, glucose, glucagon-like peptide 1 (GLP-1), inflammatory factors, and hematological profiles within four preset times during the first 14 days after TBI. Ultrasonic surveillance of DVT was tracked. Two-way analysis of variance was used to determine the factors that discriminated between patients with and without DVT or with and without insulin therapy. Partial correlations of insulin level with all the variables were conducted separately in patients with DVT or patients without DVT. Factors associated with DVT were analyzed by multivariable logistic regression. Neurological outcomes 6 months after TBI were assessed. RESULTS: Among patients with a mean (± standard deviation) age of 53 (± 16 years), DVT developed in 20 patients (27%) on median 10.4 days (range 4-22), with higher Acute Physiology and Chronic Health Evaluation II scores but similar Sequential Organ Failure Assessment scores and TBI severity. Patients with DVT were more likely to receive insulin therapy than patients without DVT (60% vs. 28%; P = 0.012); hence, they had higher 14-day insulin levels. However, insulin levels were comparable between patients with DVT and patients without DVT in the subgroups of patients with insulin therapy (n = 27) and patients without insulin therapy (n = 46). The platelet profile significantly discriminated between patients with and without DVT. Surprisingly, none of the coagulation profiles, blood cell counts, or inflammatory mediators differed between the two groups. Patients with insulin therapy had significantly higher insulin (P = 0.006), glucose (P < 0.001), and GLP-1 (P = 0.01) levels and were more likely to develop DVT (60% vs. 15%; P < 0.001) along with concomitant platelet depletion. Insulin levels correlated with glucose, GLP-1 levels, and platelet count exclusively in patients without DVT. Conversely, in patients with DVT, insulin correlated negatively with GLP-1 levels (P = 0.016). Age (P = 0.01) and elevated insulin levels at days 4-7 (P = 0.04) were independently associated with DVT. Patients with insulin therapy also showed worse Glasgow Outcome Scale scores (P = 0.001). CONCLUSIONS: Elevated insulin levels in the first 14 days after TBI may indicate insulin resistance, which is associated with platelet hyperactivity, and thus increasing the risk of DVT.

SCC-UEFAS, an urban-ecological-feature based assessment system for sponge city construction.

An effective sponge city construction evaluation system plays a crucial role in evaluating sponge city construction schemes. The construction of a sponge city evaluation system still faces challenges related to incomplete index selection and unscientific weight division. Limited studies have focused on the comprehensive assessment of sponge city construction in the early stages. This study constructed a scientific assessment indicator system and a quantitative indicator weight at all levels by literature review and statistical analysis methods from an objective perspective. To demonstrate how to utilize our evaluation methods, three construction schemes randomly generated by MATLAB were evaluated under evaluation states of constant weight and variable weight, respectively. Scheme 3 had the highest score of 0.638 under the constant weight assessment, but it cannot practically be the final construction scheme due to the imbalance between indicators. Compared to the constant weight assessment, a variable weight assessment can effectively balance the states of the evaluation index with changes in the decision variable. Among the three schemes, Scheme 2 is the best choice with a value of 0.0355 under variable weight evaluation due to punishment and incentives in the variable weight method. The concept of "punishing" a disadvantageous indicator and "motivating" an advantageous indicator increases the relative advantages of the indices, ultimately affecting the assessment results of schemes and leading to a more balanced state. This study provides reasonable analysis and decision-making mechanisms to support decision-making and guide the scientific selection of a construction scheme.

Differential distribution and prognostic value of CD4+ T cell subsets before and after radioactive iodine therapy in differentiated thyroid cancer with varied curative outcomes.

Differentiated thyroid cancer is the most frequently diagnosed endocrine tumor. While differentiated thyroid cancers often respond to initial treatment, little is known about the differences in circulating immune cells amongst patients who respond differently. A prospective study of 39 patients with differentiated thyroid cancer was conducted. Serum thyroglobulin levels and thyroid and immunological functions were tested before and after radioactive iodine treatment (RAIT). Efficacy assessments were performed 6 to 12 months after radioactive iodine treatment. Most patients showed an excellent response to radioactive iodine treatment. Before radioactive iodine treatment, the excellent response group had considerably fewer circulating CD4+ T cell subsets than the non-excellent response group. Both the excellent response and non-excellent response groups had considerably lower circulating CD4+ T lymphocyte subsets 30 days after radioactive iodine treatment, but those of the excellent response group were still lower than those of the non-excellent response group. All circulating CD4+ T cell subsets in the excellent response group rose by varying degrees by the 90th day, but only Treg cell amounts increased in the non-excellent response group. Interestingly, in the non-excellent response group, we noticed a steady drop in Th1 cells. However, the bulk of circulating CD4+ T cell subsets between the two groups did not differ appreciably by the 90th day. Finally, we discovered that CD4+ T cell subsets had strong predictive potential, and we thus developed high-predictive-performance models that deliver more dependable prognostic information. In conclusion, in individuals with differentiated thyroid cancer, there is great variation in circulating immune cells, resulting in distinct treatment outcomes. Low absolute CD4+ T cell counts is linked to improved clinical outcomes as well as stronger adaptive and resilience capacities.

[Enrichment Factors of Soil-Se in the Farmland in Shizuishan City, Ningxia].

Shizuishan is a typical exhausted resources-based city in the northern area of the Ningxia Hui autonomous region in China. In order to develop the planting industry of selenium (Se)-rich agricultural products and promote green and sustainable urban development and transformation, investigations on the quality of Se-rich land were carried out in Shizuishan City, where 7399 surface soil (0-20 cm) samples of farmlands, 30 atmospheric precipitation samples, and nine parent rocks were collected. By means of semi variogram model construction by GS+, Kriging interpolation in ArcGIS and statistics via SPSS, such as correlation analysis and mean-value analysis, the content, spatial distribution, and enrichment factors of Se-soil were analyzed. Further, the enrichment characteristics of soil Se in alkaline conditions were summarized. The results indicated that ω(Se) in surface soil was (0.26±0.12) mg·kg-1, and its spatial distribution was highly auto-correlated. The variation in Se content was related to natural factors. Along Helan Mountain, the content of Se in the surface soil was comparatively higher than that where coal mines were located. The parent rock was the principal factor that controlled the enrichment of soil Se. The physical and chemical properties of soil such as organic material, pH, and iron and manganese oxides had crucial effects on the enrichment of soil Se in a surficial environment. Compared to a strong alkaline environment, alkaline conditions were beneficial for the enrichment of Se in the surface soil.

[Effect of Netrin-1 on VEGFA Expression in T-ALL Cells and Its Related Mechanism].

AbstractObjective: To investigate the effect of the axon guidance factor Netrin-1 on the expression of VEGFA in T cell acute lymphoblastic leukemia(T-ALL) and its related mechanism. METHODS: ELISA assays were applied to detect the levels of Netrin-1 and VEGFA in the bone marrow (BM) samples from children in the T-ALL and control group. The level of Netrin-1 and VEGFA were compared between control children and patients, and the liner correlation between Netrin-1 and VEGFA was analyzed. The T-ALL cells Jurkat and Molt-4 were culture in vitro, and the cells were treated with different concentration of Netrin-1 (0, 25, 50, 100 ng/ml) for 24 h, quantitative RT-PCR (qRT-PCR) and Western blot were used to detect the VEGFA expression in Jurkat, Molt-4 cells. The expression of Netrin-1 receptors in T-ALL cells was detected by qRT-PCR and the interaction between Netrin-1 and receptor in each cells was detected by co-IP. Furthermore, Western blot was used to detect the phosphorylation level of key prateins of AKT signal transduction pathway including Akt and mTOR in T-ALL cells treated with Netrin-1 (100 ng/ml). The expression of VEGFA and phosphorylation of AKT pathway transducers were detected by Western blot, after T-ALL cells treated with Netrin-1 (100 ng/ml) combined with inhibitors specific to Akt or mTOR. RESULTS: The expression level of Netrin-1 and VEGFA in T-ALL patients BM samples were both signi-ficantly higher than that of control group. And the expression level of Netrin-1 was positively correlated with that of VEGFA（r2=0974). With the increase of Netrin-1 concentration, the expression level of VEGFA also increased(P<0.05）. Netrin-1 interacted with its receptor, integrin-ß4 at the Netrin-1 concentration of 100 ng/ml. Further, the treatment of Netrin-1 could increase the phosphorylation of Akt and mTOR, which were the key transducers of AKT pathway. After treatment of T-ALL cells with Netrin-1 (100 ng/mL) and Akt inhibitor, the expression of VEGFA and phosphorylation of Akt or mTOR decreased. When the cells were treated with Netrin-1(100 ng/ml) and mTOR inbititor, the phosphorylation level of mTOR and the expression of VEGFA decreased, the phosphorylation level of Akt increased. CONCLUSION: The expression of Netrin-1 and VEGFA in bone marrow of childred with T-ALL were abnormal, and there was a linear relationship between them. Netrin-1 can interact with its receptor, integrin-ß4 and activate AKT transduction pathway to elevate the expression of VEGFA in T-ALL cells.

Dynamic Immune Function Changes Before and After the First Radioactive Iodine Therapy After Total Resection of Differentiated Thyroid Carcinoma.

The effects of total thyroidectomy or radioactive iodine therapy on immune activation and suppression of the tumor microenvironment remain unknown. We aimed to investigate the effects of these treatments on the immune function in patients with differentiated thyroid carcinoma (DTC). Our cohort included 45 patients with DTC treated with total thyroidectomy and radioactive iodine therapy (RAIT). Immune function tests were performed by flow cytometry at 0, 30, and 90 days post-RAIT. Both the percentage and absolute number of circulating regulatory T cells were significantly lower in the postoperative DTC compared to the healthy controls. Notably, the absolute number of multiple lymphocyte subgroups significantly decreased at 30 days post-RAIT compared to those pre-RAIT. The absolute counts of these lymphocytes were recovered at 90 days post-RAIT, but not at pre-RAIT levels. Additionally, the Th17 cell percentage before RAIT was positively correlated with thyroglobulin (Tg) levels after RAIT. The tumor burden might contribute to increased levels of circulating Tregs. In conclusion, RAIT caused transient radiation damage in patients with DTC and the percentage of Th17 cells before RAIT could be a significant predictor of poor prognosis in patients with DTC.

Absolute reduction in peripheral regulatory T cells in patients with Graves' disease and post-treatment recovery.

OBJECTIVE: Graves' disease (GD) is one of the most common autoimmune conditions, but the mechanisms underlying the associated induction of autoimmunity are not known. We explored the role of peripheral lymphocyte subpopulations in disease pathogenesis. METHODS: In total, 32 patients and 40 age- and sex-matched healthy controls were recruited in this study. Peripheral levels of T, B, NK, CD4+ T, CD8+ T, Th1, Th2, Th17, and Treg cells were measured using flow cytometry. For all patients, we compared all lymphocyte subpopulations between GD patients and healthy controls. Changes in patient lymphocyte subsets were compared before and after treatment. RESULTS: The absolute numbers of circulating Th17 cells (0.45 ± 1.16, p > 0.05) between GD patients and healthy controls were not significantly different. However, the percentage of Th17 cells was significantly increased (0.25 ± 0.11, p < 0.05). The absolute numbers and percentages of circulating Tregs in GD patients were significantly decreased compared with those in healthy participants (11.61 ± 2.75, p < 0.05). There was a significant difference in Treg absolute numbers between the untreated and drug-treated groups. Furthermore, we found that the Treg percentage in untreated patients (mean=4.78) was not significantly different from that in the drug-treated group (mean=4.81). In addition, circulating Treg absolute numbers in GD patients with exophthalmos were significantly lower than those in GD patients without exophthalmos (9.96 ± 4.16, p < 0.05). A similar trend was observed in GD patients with weight loss (11.97 ± 3.28, p < 0.05). CONCLUSION: GD pathogenesis was associated with a lower Treg population and an increased Th17/Treg ratio (T helper cell 17/ regulatory T cells). Th17 cells in this study were not related to the disease. Furthermore, anti-thyroid drug therapy improved immune-mediated system disorders. Finally, we found lower absolute numbers of circulating Tregs in GD patients with certain positive signs, such as exophthalmos and/or weight loss. Thus, immune changes are correlated with partial clinical manifestations.

Programmed intermittent epidural bolus in parturients: A meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate the efficacy and safety of programmed intermittent epidural bolus (PIEB) in parturients. METHODS: The PubMed, Embase, and the Cochrane Library (from inception to July 2021) were searched for identification of randomized placebo-controlled trials in which PIEB was applied in parturients. The outcomes were the effect of analgesia, satisfaction score, mode of delivery, duration of labor, neonatal condition, and adverse events. The pooled odds ratios (OR), weighted mean difference (WMD), and 95% confidence intervals (CIs) were calculated using random- and fixed-effects models. RESULTS: PIEB was found to be associated with decreased total consumption of ropivacaine (WMD = -15.83, 95% CI: -19.06 to -12.60, P < .00001; I2 = 61%; P for heterogeneity = .04), total consumption of sufentanil (WMD = -4.93, 95% CI: -6.87 to 2.98, P < .00001; I2 = 68%; P for heterogeneity = .05), numbers of patients who require patient-controlled epidural analgesia bolus (OR = 0.27, 95% CI: 0.14-0.51, P < .0001; I2 = 65%; P for heterogeneity = .01), the number of attempts (WMD = -4.12, 95% CI: -7.21 to -1.04, P = .009; I2 = 100%; P for heterogeneity < .00001), rate of breakthrough pain (OR = 0.47, 95% CI: 0.28-0.80, P = .005; I2 = 47%; P for heterogeneity = .09). Eight studies focus on the duration of analgesia. After by meta-analysis, we found that the pain visual analogue scale (VAS) score at 30 minutes, 2 hours, 4 hours, and 5 hours in PIEB group was significantly lower when compared with control group, (WMD = -0.15, 95% CI: -0.26 to -0.04, P = .006; I2 = 0%; P for heterogeneity = .64), (WMD = -0.79, 95% CI: -1.32 to 0.25, P = .004; I2 = 97%; P for heterogeneity < .00001), (WMD = -1.00, 95% CI: -1.08 to -0.91, P < .00001; I2 = 0%; P for heterogeneity = .67), (WMD = -1.81, 95% CI: -3.23 to -0.39, P = .01; I2 = 98%; P for heterogeneity < .00001), respectively. Nineteen studies discussed the mode of delivery between 2 groups. The results suggest that the rate of normal delivery is significantly higher in PIEB group compared with control group (OR = 1.37, 95% CI: 1.08-1.75, P = .01). The time of first and second stage of labor are significantly shorter in PIEB group compared with control group, the result is (WMD = -10.52, 95% CI: -14.74 to 4.76, P < .00001; I2 = 0%; P for heterogeneity = .86), (WMD = -1.48, 95% CI: -2.26 to -0.69, P = .0002; I2 = 35%; P for heterogeneity = .10), respectively. Thirteen studies concerned the satisfaction score of patients. The satisfaction score of patients in the PIEB group was significantly higher when compared with control group (WMD = 0.91, 95% CI: 0.42-1.39, P = .0003; I2 = 98%; P for heterogeneity < .00001). The Apgar score at 1, 5 minutes in PIEB group are significantly higher (WMD = 0.07, 95% CI: 0.02-0.13 P = .007; I2 = 55%; P for heterogeneity = .04), (WMD = -0.08, 95% CI: -0.12 to -0.05, P < .00001; I2 = 21%; P for heterogeneity = .27), respectively. CONCLUSIONS: PIEB is a good alternative for labor analgesia with better analgesic effect, maternal and infant outcome.