Effects of asparaginase-associated pancreatitis in children with haematological tumours.

Background: Asparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and long-term complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies. Methods: We retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin's lymphoma at Shanghai Children's Medical Center from November 2013 to November 2023. Results: Of the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-re-exposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate- to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-re-exposed group. The second AAP episode's occurrence and severity had no relation to the first AAP episode's severity, and the second AAP episode was significantly less severe than the first (p<0.001). Conclusions: The second AAP episode's occurrence is unrelated to the first AAP episode's severity, and the second AAP episode's severity is significantly lower than that of the first. Further, asparaginase therapy could improve EFS in children with intermediate and high-risk ALL.

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms.

Efferocytosis is defined as the highly effective phagocytic removal of apoptotic cells (ACs) by professional or non-professional phagocytes. Tissue-resident professional phagocytes ("efferocytes"), such as macrophages, have high phagocytic capacity and are crucial to resolve inflammation and aid in homeostasis. Recently, numerous exciting discoveries have revealed divergent (and even diametrically opposite) findings regarding metabolic immune reprogramming associated with efferocytosis by macrophages. In this review, we highlight the key metabolites involved in the three phases of efferocytosis and immune reprogramming of macrophages under physiological and pathological conditions. The next decade is expected to yield further breakthroughs in the regulatory pathways and molecular mechanisms connecting immunological outcomes to metabolic cues as well as avenues for "personalized" therapeutic intervention.

Heme induced progesterone-resistant profiling and promotion of endometriosis in vitro and in vivo.

Endometriosis is an estrogen-dependent, progesterone-resistant gynecological disease with an unknown pathogenesis. Compared to women without endometriosis, women with endometriosis have a remarkably high heme level in the peritoneal fluid. To further investigate the pathomechanisms of heme in endometriosis, we aimed to identify the dysregulated expression of heme-trafficking proteins, such as PGRMC1/2 that are also receptors that mediate the non-genomic responses to progesterone, and heme-degrading enzymes between ectopic endometrial stromal cells and their normal counterparts. We found that heme could regulate progesterone receptor-related gene expression. Functional human endometrial stromal cell experiments showed that heme promotes cell proliferation and migration in a heme oxygenase-1-independent manner; moreover, blocking oxidative phosphorylation/ATP generation could abolish these effects of heme in vitro, whereas intraperitoneal hemopexin administration could alleviate heme-triggered ectopic lesions in vivo. Therefore, heme likely mediates the induction of progesterone resistance and simultaneously induces endometriosis via the mitochondrial oxidative phosphorylation pathway.

CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization.

Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.

IL-27 promotes decidualization via the STAT3-ESR/PGR regulatory axis.

Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activation of progesterone-mediated signaling pathway, the exact mechanisms have not been elucidated. Here, we demonstrated that both IL-27 and IL27RA were highly expressed in decidua than those in endometrium during secretory phase. Estrogen plus progesterone significantly upregulated the expression of IL-27 and IL-27RA in endometrium stromal cells (ESCs). In addition, inhibiting IL-27 signaling with IL-27 neutralization antibody (anti-IL-27) suppressed the expression of decidualization-related molecules, receptors of estrogen (gene coded by ESR) and progesterone (PGR) induced by cAMP or estrogen plus progesterone. Similar results were obtained from Il27ra-/- (knockout of Il27ra) female mice. Moreover, knockout of Il27ra did not affect the estrus cycle and folliculogenesis in mice but reduced implantation rate with the impairing decidualization. Mechanistically, IL-27 upregulated the expression of ESR1, ESR2 and PGR in ESCs and DSCs, as well as the phosphorylation level of STAT3. In the presence of estrogen plus progesterone, treatment with ESCs with anti-IL-27 inhibited the activation of STAT3. Also, the expression of ESR, PGR was decreased in Il27ra-/- mice. In conclusion, these findings demonstrate that IL-27 upregulated by estrogen and progestogen promotes decidualization possibly through a STAT3-dominant pathway.

An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages.

During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the relationship between efferocytosis-related metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here, we report positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum levels of IL-33 and sST2, along with IL-33 and ST2, efferocytosis and metabolism of dMΦs, from patients with normal pregnancies and unexplained recurrent pregnancy loss (RPL). We revealed disruption of the IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from patients with RPL. The dMΦs that engulfed many apoptotic cells secreted more sST2 and less TGF-ß, which polarized dMΦs toward the M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis-related metabolism of RPL dMΦs toward oxidative phosphorylation and exacerbated the disruption of the IL-33/ST2 signaling pathway. Metabolic disorders also lead to dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and secondary necrosis. We also screened the efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback axis of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation with mouse IL-33 reduced the embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for homeostasis of the microenvironment at the maternal-fetal interface.

[Robot-assisted laparoscopic radical prostatectomy helps improve postoperative urinary continence recovery in patients with prostate cancer].

OBJECTIVE: To observe the recovery of urinary continence through postoperative rehabilitation training after robot-assisted laparoscopic radical prostatectomy (RARP) versus that after traditional laparoscopic radical prostatectomy (LRP). METHODS: This study included 64 cases of urinary incontinence after surgically treated for PCa from May 2017 to February 2021, 32 by RARP and the other 32 by LRP as the controls. All the patients received standard urinary continence rehabilitation training and routine nursing care postoperatively, followed by comparison of the rate and time of urinary incontinence recovery and the patients' scores on the quality of life (QOL) and satisfaction with treatment between the two groups. RESULTS: There were no statistically significant differences in age, PSA level or pathological stage between the two groups of patients (P > 0.05). After standard urinary continence rehabilitation training, the patients in the RARP group, compared with those in the LRP control, showed a lower grade of urinary incontinence (χ2 = 6.483, P = 0.039), a shorter mean duration of urinary incontinence per day, an earlier recovery of urinary continence (χ2 = 4.73, P = 0.030 at 1－3 months; χ2 = 12.696, P < 0.001 at 4－6 months), a higher rate of overall recovery (χ2 = 13.396, P = 0.004), and higher scores on QOL and satisfaction with treatment. CONCLUSION: RARP can effectively improve the recovery from postoperative urinary incontinence in PCa patients.

The Clinical Characteristics of ARDS in Children With Hematological Neoplasms.

In order to explore the clinical characteristics of pediatric patients admitted to the pediatric intensive care unit (PICU) who suffered from hematological neoplasms complicated with acute respiratory distress syndrome (ARDS), we retrospectively analyzed 45 ARDS children with hematological neoplasms who were admitted to the PICU of Shanghai Children's Medical Center from January 1, 2014, to December 31, 2020. The 45 children were divided into a survival group and a non-survival group, a pulmonary ARDS group and an exogenous pulmonary ARDS group, and an agranulocytosis group and a non-agranulocytosis group, for statistical analysis. The main clinical manifestations were fever, cough, progressive dyspnea, and hypoxemia; 55.6% (25/45) of the children had multiple organ dysfunction syndrome (MODS). The overall mortality rate was 55.6% (25/45). The vasoactive inotropic score (VIS), pediatric critical illness scoring (PCIS), average fluid volume in the first 3 days and the first 7 days, and the incidence of MODS in the non-survival group were all significantly higher than those in the survival group (P < 0.05). However, total length of mechanical ventilation and length of hospital stay and PICU days in the non-survival group were significantly lower than those in the survival group (P < 0.05). The PCIS (OR = 0.832, P = 0.004) and the average fluid volume in the first 3 days (OR = 1.092, P = 0.025) were independent risk factors for predicting death. Children with exogenous pulmonary ARDS were more likely to have MODS than pulmonary ARDS (P < 0.05). The mean values of VIS, C-reactive protein (CRP), and procalcitonin (PCT) in children with exogenous pulmonary ARDS were also higher (P < 0.05). After multivariate analysis, PCT was independently related to exogenous pulmonary ARDS. The total length of hospital stay, peak inspiratory pressure (PIP), VIS, CRP, and PCT in the agranulocytosis group were significantly higher than those in the non-agranulocytosis group (P < 0.05). Last, CRP and PIP were independently related to agranulocytosis. In conclusion, children with hematological neoplasms complicated with ARDS had a high overall mortality and poor prognosis. Children complicated with MODS, positive fluid balance, and high VIS and PCIS scores were positively correlated with mortality. In particular, PCIS score and average fluid volume in the first 3 days were independent risk factors for predicting death. Children with exogenous pulmonary ARDS and children with agranulocytosis were in a severely infected status and more critically ill.

Effect of chromodomain helicase/ATPase DNA binding protein 1-like gene on the invasion and metastasis of tongue squamous cell carcinoma CAL27 cells.

OBJECTIVES: A study was conducted to investigate the molecular mechanism of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) influencing the invasion and metastasis of tongue squamous cell carcinoma and to provide a new target for clinical inhibition of invasion and metastasis of tongue squamous cell carcinoma. METHODS: Ualcan website was used to analyze the expression of CHD1L in normal epithelial tissue and primary head and neck squamous cell carcinoma and to analyze the effect of lymph node metastasis on the expression of CHD1L in tissues with head and neck squamous cell carcinoma. The relationship between CHD1L expression and the survival rate of patients with head and neck squamous cell carcinoma was tested by the GEPIA website. Western blot was used to quantify the levels of CHD1L protein in human tongue squamous cell carcinoma CAL27 and immortalized human skin keratinocyte cell HaCaT. After knocking down CAL27 in human tongue squamous cell carcinoma cells with an RNA interference plasmid, the cells were designated as SiCHD1L/CAL27 and Scr/CAL27. Western blot was utilized to detect the expression of CHD1L in each group of cells. The change in CAL27 cell proliferation ability was tested by EdU proliferation test after CHD1L knockdown. The change of cell migration ability of each group cells was tested through the wound healing assay. Western blot was used to detect epithelial-mesenchymal transition (EMT) marker E-cadherin and Vimentin protein expression levels. RESULTS: Ualcan database showed that the expression of CHD1L in primary head and neck squamous cell carcinoma tissues was higher than in normal epithelial tissues and in head and neck squamous cell carcinoma tissues with lymph node metastasis. GEPIA website analysis showed that the overall survival rate of patients with head and neck squamous cell carcinoma with high expression of CHD1L was significantly lower than that of patients with low expression. Western blot results showed that CHD1L expression in human tongue squamous carcinoma cells CAL27 was higher than that of human normal skin cells HaCaT. CHD1L expression in SiCHD1L/CAL27 cells was much lower than that in Scr/CAL27 cells. Results of EdU proliferation experiments showed the significant reduction in the cell proliferation ability of the SiCHD1L/CAL27 cells. Results of the wound healing experiments showed the reduction in the migration capacity of the SiCHD1L/CAL27 cells. The expression of E-cadherin increased, whereas that of Vimentin decreased, in SiCHD1L/CAL27 cells. CONCLUSIONS: CHD1L promoted the EMT, proliferation, migration, and invasion ability of tongue squamous cell carcinoma cells.

[Effects of RAB1A on the proliferation, invasion, and metastasis of tongue squamous cell carcinoma cells].

OBJECTIVE: This study aimed to investigate the molecular mechanism of RAB1A in the proliferation, invasion, and metastasis of human tongue squamous cell carcinoma. METHODS: Western blot was used to detect the expression of RAB1A protein in human normal tongue epithelial cells (Hacat) and tongue squamous cell carcinoma Tca8113. The changes in RAB1A after plasmid transfection were also studied. The Tca8113 cells were named SiRAB1A/Tca8113 after RAB1A plasmid transfection. The expression of the epithelial-mesenchymal transition (EMT)-related markers of SiRAB1A/Tca8113 cells was also detected. CCK-8 assay was used to detect the proliferation of SiRAB1A/Tca8113 cells. Transwell and wound healing assays were used to detect the invasive and metastatic abilities of SiRAB1A/Tca8113 cells, respectively. RESULTS: Western blot results showed that the expression of RAB1A in tongue squamous cell carcinoma cells was significantly higher than that in Hacat. RAB1A decreased significantly after SiRAB1A plasmid transfection. CCK-8 proliferation assay showed that the proliferation of SiRAB1A/Tca8113 cells also decreased significantly. Transwell and wound healing assays demonstrated that the invasive and metastatic abilities of SiRAB1A/Tca8113 cells decreased significantly, respectively. In addition, Western blot results demonstrated that RAB1A deletion significantly increased the expression of E-cadherin and inhibited the expression of Vimentin. CONCLUSIONS: RAB1A could promote the proliferation, invasion, and metastasis of tongue squamous cell carcinoma cells.

Preservation of level IIb lymph nodes during supraomohyoid neck dissection for clinically node-negative oral squamous cell carcinoma.

PURPOSE: To identify the significance of level IIb neck dissection for patients with clinically node-negative oral squamous cell carcinoma (OSCC). METHODS: A retrospective study was conducted with 203 patients with OSCC with no palpable lymph nodes in neck admitted to the Department of Oral Maxillofacial-Head and Neck Oncology from January 2012 through December 2014. After the diagnostic evaluations, all patients underwent wide local dissection and periodic supraomohyoid neck dissection (SOHND). In total, 115 patients underwent SOHND with IIb lymph node dissection, and 88 patients underwent elective SOHND without IIb lymph node dissection. The incidence of level IIb lymph node metastasis was evaluated by pathological and immunohistological analyses. The results were analyzed with independent sample t-tests. The incidence of complications (mainly scapular syndrome) and IIb lymph node metastasis rate (mainly for the preserving IIb group) were analyzed. RESULTS: In total, 7 (6.09%) of the 115 patients who underwent SOHND had level IIb lymph nodes involvement. After 3 years of follow-up, 83 (72.17%) patients who underwent SOHND had different degrees of scapular syndrome, and 27 (32.53%) patients who underwent SOHND improved through rehabilitation training but did not fully recover. Four (4.55%) patients who underwent elective SOHND (preserving IIb) developed scapular syndrome and recovered through rehabilitation after surgery. The 3-year overall survival rate of the 115 patients was 86.09%, and the 3-year overall survival rate of the 88 patients who underwent elective SOHND (preserving IIb) was 84.09%. There were no significant differences between the two groups (P > 0.05). CONCLUSION: Patients with clinically N0 OSCC have a low rate of level IIb lymph node metastasis. Level IIb lymph nodes resection are not necessary during SOHND, which thereby protects the accessory nerve and its branches from damage and improves patient quality of life.

[Clinical effect of the SCMC APL-2010 regimen in treatment of acute promyelocytic leukemia in children: an analysis of 44 cases].

OBJECTIVE: To study the clinical effect of the SCMC APL-2010 regimen in the treatment of acute promyelocytic leukemia (APL) in children. METHODS: A retrospective analysis was performed for the clinical data of 44 children with APL who received treatment with the SCMC APL-2010 regimen between April 2010 and July 2016. The Kaplan-Meier survival analysis was used to evaluate event-free survival (EFS) rate and overall survival (OS) rate. RESULTS: Of the 44 children with APL, 42 (95%) achieved a complete remission (CR) after one course of treatment and 1 achieved CR after two courses of treatment, with an overall CR rate of 98%. The 9-year EFS and OS rates were 96%±3% and 97.7%±2.2% respectively. As for adverse events, 41 (93%) had infection, 29 (66%) had granulocyte reduction, 12 (27%, 1 died) had differentiation syndrome, 16 (36%) had liver dysfunction, 12 (27%) had adverse gastrointestinal reactions, and 7 (16%) had QT prolongation, 1 (2%) had orchitis, and no secondary neoplasm was observed. CONCLUSIONS: Children with APL receiving the SCMC APL-2010 regimen have a good prognosis and can achieve a long-term survival, while treatment-related infection is commonly seen.

Genistein Decreases APP/tau Phosphorylation and Ameliorates Aß Overproduction Through Inhibiting CIP2A.

BACKGROUND: Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease-related phosphorylation of tau/APP and tau pathology/Aß overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. Whether Genistein can ameliorate AD pathology through targeting CIP2A needs further investigation. METHODS: The inhibitory effects of Genistein on tau/APP phosphorylation and Aß overproduction in AD cell models have been explored. HEK293-T cells were co-transfected with CIP2A and APP plasmids, or CIP2A and tau plasmids, with Genistein incubation at 0, 30, 60 or 120 µM for 48 h, cell viability and PP2A activities were measured. HEK293-T cells with CIP2A/APP overexpression treated with Genistein at 30 µM for 48 h were collected and lyzed for Western blotting detection of CIP2A, PP2Ac, APP-T668, total APP, PS1, BACE1, sAPPα and sAPPß. Aß40 and Aß42 levels in cell supernatant, soluble fraction (RIPA) and insoluble fraction (formic acid soluble) of cell lysates were measured by ELISA. HEK293-T cells with CIP2A/tau overexpression treated with Genistein at 30 µM for 48 h were collected for Western blotting detection of CIP2A, PP2Ac, tau-S396, tau-S404 and total tau. RESULTS: Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP, CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aß production. Meantime, Genistein ameliorated tau hyperphosphorylation through repressing the inhibitory effect of CIP2A on PP2A. CONCLUSION: CIP2A is a target of Genistein in AD therapy. Genistein reduces APP/tau hyperphosphorylation and Aß production through inhibiting the effect of CIP2A on PP2A.

Elevated heme impairs macrophage phagocytosis in endometriosis.

Endometriosis (EMS) is a chronic inflammatory disease characterized by the presence of extrauterine endometrial tissues. It has been previously reported that the refluxed blood containing viable endometrial tissues and the defective elimination of peritoneal macrophages in the pelvic cavity may involve in EMS pathogenesis. However, the mechanism by which macrophages exhibit attenuated phagocytic capability in EMS remains undetermined. Herein, we found that heme, the byproduct of lysed erythrocytes, accumulated abnormally in the peritoneal fluid (PF) of patients with EMS (14.22 µmol/L, 95% confidence interval (CI): 12.54-16.71), compared with the EMS-free group (9.517 µmol/L, 95% CI: 8.891-10.1053). This abnormal accumulation was not associated with the color of PF, phase of the menstrual cycle or severity of the disease. The reduced phagocytic ability of peritoneal macrophages (pMφs) was observed in the EMS group. Consistently, a high-concentration (30 µmol/L) heme treatment impaired EMS-pMφs phagocytosis more than a low-concentration (10 µmol/L) heme treatment. A similar phenomenon was observed in the EMS-free control pMφs (Ctrl-pMφs) and the CD14+ peripheral monocytes (CD14+ Mos). These results indicated that a high heme concentration exhibits a negative effect on macrophage phagocytosis, which supplements the mechanism of impaired scavenger function of pMφs in EMS.

Insights of efferocytosis in normal and pathological pregnancy.

Efferocytosis, which is known as the phagocytic clearance of dying cells by professional as well as non-professional phagocytes, including a great number of intracellular/extracellular factors and signals, is interrelated with the immune system, contributing to local and systemic homeostasis, especially in tissues with high constitutive rates of apoptosis. Accumulating studies have indicated that immune dysregulation is associated with the pathogenesis of the female reproductive system, which causes preeclampsia (PE), recurrent spontaneous abortion (RSA), ruptured ectopic pregnancy, and so on. And some studies have revealed the pleiotropic and essential role of efferocytosis in these obstetrical disorders. More specifically, the occurrence and development of these diseases were in connection with some efferocytosis-related factors and signals, such as C1q, MBL, and IL-33/ST2. In this review, we systematically review the diverse impacts of efferocytosis in immune system and discuss its relevance to normal and pathological pregnancy. These findings may instruct future basic researches as well as clinical applications of efferocytosis-related factors and signals as latent predictors or therapeutic targets on the obstetrical disorders.

CIP2A-promoted astrogliosis induces AD-like synaptic degeneration and cognitive deficits.

Reactive astrogliosis and early synaptic degeneration are 2 characteristic hallmarks in Alzheimer's disease (AD) brains, but a direct link between the 2 events has not been established. Here, we show that cancerous inhibitor of PP2A (CIP2A), a cancerous protein with high expression level in astrocytes, is upregulated in patients with AD and 3xTg-AD transgenic mice. Overexpression of CIP2A in astrocytes through adeno-associated virus infection both in cultured cells and in mice brains results in activation of astrocytes, increased production of cytokines and Aß, and synaptic degeneration indicated by decreased levels of synaptic proteins, spine loss, and impairment in long-term potentiation. As a result of synaptic degeneration, CIP2A overexpression in astrocytes in vivo induces significant deficits in visual episodic memory detected by novel objective recognition test and spatial memory detected by Morris water maze. We conclude that CIP2A-promoted astrogliosis induces synaptic degeneration and cognitive deficits in AD.

IL-33/ST2 axis affects the polarization and efferocytosis of decidual macrophages in early pregnancy.

PROBLEM: To explore whether IL-33/ST2 axis modulates the polarization and efferocytosis of decidual macrophages (dMφs). METHOD OF STUDY: The phenotype characteristics of dMφs from both normal pregnant women and recurrent spontaneous abortion (RSA) patients were determined by real-time polymerase chain reaction (RT-PCR) and flow cytometry (FCM). Then, the efferocytosis and expression of IL-33 and its receptor (ST2) in dMφs were analyzed by FCM. Finally, the effects of sST2, a decoy receptor for IL-33 that inhibits the IL-33/ST2 signaling pathway, on the polarization and efferocytosis of dMφs and human macrophage cell line U937 were investigated. RESULTS: Compared with normal pregnancy, dMφs from RSA patients presented a M1 phenotype with high secretion of IL-33, whereas the expression of ST2 decreased. However, dMφs from RSA patients possessed a more powerful efferocytosis ability to clear the apoptotic decidual stromal cells (DSCs) compared with dMφs from normal pregnancy patients. Treatment with recombinant human sST2 led to the up-regulation of M1 bias and efferocytosis ability of both normal dMφs and U937. CONCLUSION: This study indicates that IL-33 secreted by dMφs promotes M2 bias at the feto-maternal interface, and as a result, RSA might attribute to the disturbance of IL-33/ST2 axis and the enhancement of efferocytosis of dMφs subsequently.

IL­33 restricts invasion and adhesion of trophoblast cell line JEG3 by downregulation of integrin α4ß1 and CD62L.

Interleukin-33 (IL-33) promotes migration of cancer cells through downregulating the expression of E-cadherin. Previous studies have demonstrated that IL­33 stimulates the proliferation of trophoblasts. However, the effect of IL­33 on the adhesion and invasion of trophoblasts has not been investigated in detail. In the present study, the expression of IL­33 and its receptor, IL­1 receptor­like 1 (ST2), was examined in villi from women during early pregnancy using immunohistochemistry. ST2 expression on human trophoblast and choriocarcinoma cell lines JAR, BeWo, JEG3 and HTR8 was confirmed by flow cytometry (FCM) assay. The effect of recombinant human IL­33 (rhIL­33) on adhesion, invasion and associated molecules was analyzed by cell adhesion, Matrigel invasion and FCM assays. The current study identified that human trophoblasts expressed IL­33 and ST2. RhIL­33 inhibited trophoblast invasion and adhesion, and decreased adhesion and invasion­associated molecules such as integrin α4ß1 and CD62L. Therefore, these results suggest that IL­33 may serve an important role in limiting invasion and implantation of trophoblasts by adhesion and invasion­associated molecules, contributing to the formation of the placenta and maintenance of normal pregnancy during early pregnancy.

IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signaling.

Interleukin (IL)-33, a newly described member of the IL-1 family, has been reported to facilitate primary tumor progression and metastatic dissemination. However, its biological function on decidual stromal cells (DSCs) remains unclear. In this study, we tested the hypothesis whether IL-33 promotes proliferation and invasion of DSCs, and the possible mechanism. IL-33 and its orphan receptor ST2 was found to be co-expressed by DSCs in human first-trimester pregnancy. Addition of IL-33, enhanced the proliferation and invasion of DSCs in a dosage-dependent manner, concomitantly with increasing expression of proliferation relative gene (PCNA, survivin) and invasion relative gene (titin, MMP2). Blocking IL-33/ST2 signaling by soluble sST2 apparently abolished the stimulatory effect on the proliferation, invasiveness and related gene expression in DSCs. We also demonstrated that chemokines CCL2/CCR2 was significantly increased with IL-33 administration. Moreover, inhibition of CCL2/CCR2 activation using CCL2 neutralizing antibody or CCR2 blocker prevented IL-33-stimulated proliferation and invasiveness capacity of DSCs. Increasing phosphorylation of nuclear factor NF-κB p65 and extracellular signal-regulated kinases ERK1/2 after treatment with IL-33 was confirmed by western blotting. And the IL-33-induced CCL2/CCR2 expression was abrogated by treatment with the NF-κB inhibitor BAY 11-7082 or ERK1/2 inhibitor U0126. Finally, we showed that decreased IL-33/ST2 expression was observed in DSCs from spontaneous abortion compared with normal pregnancy at both gene and protein levels. This study provides evidence for the molecular mechanism of IL-33 in promoting proliferation and invasiveness of DSCs by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signal pathways and thus contributes insight to the potential of IL-33 involved in successful pregnancy via inducing DSCs mitosis and invasion.

[Long-term follow-up of childhood low-risk ALL patients treated with SCMC-ALL-2005 protocol].

OBJECTIVE: To evaluate the long-term efficacy of SCMC-ALL-2005 protocol in treatment of low-risk childhood acute lymphoblastic leukemia (ALL). METHODS: From May 1, 2005 to April 30, 2009, 387 patients enrolled into SCMC-ALL-2005 protocol. Based on the characteristics of cell morphology, immunology, cytogenetics and molecular biology and treatment response, 158 patients were fit into the low-risk treatment group. All the cases were registered in pediatric oncology network database (POND). The clinical characteristics and outcome were analyzed. RESULTS: Until December 31, 2012, the 5-year event free survival (EFS) and overall survival (OS) is (77.76±3.37)% and (89.55±2.83)%, respectively. Median follow-up time is 5.33 y (3.75-7.70 y). Five patients (3.16%) died of complication, all of them were severe infections. Twenty-seven patients (17.09%) relapsed, including 13 bone marrow relapse (8.23%), 5 testis relapse (5.32% of boys, 2 of unilateral and 3 bilateral), 6 central nerve system relapse (CNS, 3.80%), 1 relapse in both bone marrow and CNS, 1 relapse in both bone marrow and testis, and 1 right ovary and fallopian tube relapse. Relapse is related to positive minimal residual disease. Two cases (1.27%) occurred second tumors, 4 patients (2.53%) gave up treatment in complete remission without special reasons. CONCLUSION: The EFS and life quality of SCMC-ALL-2005 protocol in the treatment of childhood low-risk ALL is satisfactory. The treatment-related mortality rate is lower, and the long-term EFS is higher than that of XH-99 protocol.