Thrombopoietin receptor agonists regulate myeloid-derived suppressor cell-mediated immunomodulatory effects in ITP.

TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.

Impact of Gestational Exposure to Individual and Combined Per- and Polyfluoroalkyl Substances on a Placental Structure and Efficiency: Findings from the Ma'anshan Birth Cohort.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is inevitable among pregnant women. Nevertheless, there is a scarcity of research investigating the connections between prenatal PFAS exposure and the placental structure and efficiency. Based on 712 maternal-fetal dyads in the Ma'anshan Birth Cohort, we analyzed associations between individual and mixed PFAS exposure and placental measures. We repeatedly measured 12 PFAS in the maternal serum during pregnancy. Placental weight, scaling exponent, chorionic disc area, and disc eccentricity were used as the outcome variables. Upon adjusting for confounders and implementing corrections for multiple comparisons, we identified positive associations between branched perfluorohexane sulfonate (br-PFHxS) and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) with placental weight. Additionally, a positive association was observed between br-PFHxS and the scaling exponent, where a higher scaling exponent signified reduced placental efficiency. Based on neonatal sex stratification, female infants were found to be more susceptible to the adverse effects of PFAS exposure. Mixed exposure modeling revealed that mixed PFAS exposure was positively associated with placental weight and scaling exponent, particularly during the second and third trimesters. Furthermore, br-PFHxS and 6:2 Cl-PFESA played major roles in the placental measures. This study provides the first epidemiological evidence of the relationship between prenatal PFAS exposure and placental measures.

Trimester-specific effect of maternal co-exposure to organophosphate esters and phthalates on preschooler cognitive development: The moderating role of gestational vitamin D status.

Organophosphate esters (OPEs) and phthalate acid esters (PAEs) are prevalent endocrine-disrupting chemicals (EDCs). Humans are often exposed to OPEs and PAEs simultaneously through multiple routes. Given that fetal stage is a critical period for neurodevelopment, it is necessary to know whether gestational co-exposure to OPEs and PAEs affects fetal neurodevelopment. However, accessible epidemiological studies are limited. The present study included 2, 120 pregnant women from the Ma'anshan Birth Cohort (MABC) study. The concentrations of tris (2-chloroethyl) phosphate (TCEP), 6 OPE metabolites and 7 PAE metabolites were measured in the first, second and third trimester using ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS). Cognitive development of preschooler was assessed based on the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) of the Chinese version. Generalized estimating equations (GEEs), restricted cubic spline (RCS) and generalized additive models (GAMs) were employed to explore the associations between individual OPE exposure and preschooler cognitive development. The quantile-based g-computation (QGC) method was used to estimate the joint effect of PAEs and OPEs exposure on cognitive development. GEEs revealed significant adverse associations between diphenyl phosphate (DPHP) (ß: -0.58, 95% CI: -1.14, -0.01), bis (2-butoxyethyl) phosphate(BBOEP) (ß: -0.44, 95% CI: -0.85, -0.02), bis(1-chloro-2-propyl) phosphate (BCIPP) (ß: -0.81, 95%CI: -1.43, -0.20) and full-scale intelligence quotient (FSIQ) in the first trimester; additionally, TCEP and bis(2-ethylhexyl) phosphate (BEHP) in the second trimester, as well as DPHP in the third trimester, were negatively associated with cognitive development. Through the QGC analyses, mixture exposure in the first trimester was negatively associated with FSIQ scores (ß: -1.70, 95% CI: -3.06, -0.34), mono-butyl phthalate (MBP), BCIPP, and DPHP might be the dominant contributors after controlling for other OPEs and PAEs congeners. Additionally, the effect of OPEs and PAEs mixture on cognitive development might be driven by vitamin D deficiency.

[Effect and mechanism of Linggui Zhugan Decoction in regulating Sig1R on Angâ ¡-induced cardiomyocyte hypertrophy].

This study aims to explore the mechanism of Linggui Zhugan Decoction(LGZGD) in inhibiting Angiotensin Ⅱ(AngⅡ)-induced cardiomyocyte hypertrophy by regulating sigma-1 receptor(Sig1R). The model of H9c2 cardiomyocyte hypertrophy induced by AngⅡ in vitro was established by preparing LGZGD-containing serum and blank serum. H9c2 cells were divided into normal group, AngⅡ model group, 20% normal rat serum group(20% NSC), and 20% LGZGD-containing serum group. After the cells were incubated with AngⅡ(1 µmol·L~(-1)) or AngⅡ with serum for 72 h, the surface area of cardiomyocytes was detected by phalloidine staining, and the activities of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase were detected by micromethod. The mitochondrial Ca~(2+) levels were detected by flow cytometry, and the expression levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP), Sig1R, and inositol 1,4,5-triphosphate receptor type 2(IP_3R_2) were detected by Western blot. The expression of Sig1R was down-regulated by transfecting specific siRNA for investigating the efficacy of LGZGD-containing serum on cardiomyocyte surface area, Na~+-K~+-ATPase activity, Ca~(2+)-Mg~(2+)-ATPase activity, mitochondrial Ca~(2+), as well as ANP, BNP, and IP_3R_2 protein expressions. The results showed that compared with the normal group, AngⅡ could significantly increase the surface area of cardiomyocytes and the expression of ANP and BNP(P<0.01), and it could decrease the activities of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase, the concentration of mitochondrial Ca~(2+), and the expression of Sig1R(P<0.01). In addition, IP_3R_2 protein expression was significantly increased(P<0.01). LGZGD-containing serum could significantly decrease the surface area of cardiomyocytes and the expression of ANP and BNP(P<0.05, P<0.01), and it could increase the activities of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase, the concentration of mitochondrial Ca~(2+ )(P<0.01), and the expression of Sig1R(P<0.05). In addition, IP_3R_2 protein expression was significantly decreased(P<0.05). However, after Sig1R was down-regulated, the effects of LGZGD-containing serum were reversed(P<0.01). These results indicated that the LGZGD-containing serum could inhibit cardiomyocyte hypertrophy induced by AngⅡ, and its pharmacological effect was related to regulating Sig1R, promoting mitochondrial Ca~(2+ )inflow, restoring ATP synthesis, and protecting mitochondrial function.

Placental inflammatory cytokines mRNA expression and preschool children's cognitive performance: a birth cohort study in China.

BACKGROUND: The immunologic milieu at the maternal-fetal interface has profound effects on propelling the development of the fetal brain. However, accessible epidemiological studies concerning the association between placental inflammatory cytokines and the intellectual development of offspring in humans are limited. Therefore, we explored the possible link between mRNA expression of inflammatory cytokines in placenta and preschoolers' cognitive performance. METHODS: Study subjects were obtained from the Ma'anshan birth cohort (MABC). Placental samples were collected after delivery, and real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to measure the mRNA expression levels of IL-8, IL-1ß, IL-6, TNF-α, CRP, IFN-γ, IL-10, and IL-4. Children's intellectual development was assessed at preschool age by using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Multiple linear regression and restricted cubic spline models were used for statistical analysis. RESULTS: A total of 1665 pairs of mother and child were included in the analysis. After adjusting for confounders and after correction for multiple comparisons, we observed that mRNA expression of IL-8 (ß = - 0.53; 95% CI, - 0.92 to - 0.15), IL-6 (ß = - 0.58; 95% CI, - 0.97 to - 0.19), TNF-α (ß = - 0.37; 95% CI, - 0.71 to - 0.02), and IFN-γ (ß = - 0.31; 95% CI, - 0.61 to - 0.03) in the placenta was negatively associated with preschoolers' full scale intelligence quotient (FSIQ). Both higher IL-8 and IL-6 were associated with lower children's low fluid reasoning index (FRI), and higher IFN-γ was associated with lower children's working memory index (WMI). After further adjusting for confounders and children's age at cognitive testing, the integrated index of six pro-inflammatory cytokines (index 2) was found to be significantly and negatively correlated with both the FSIQ and each sub-dimension (verbal comprehension index (VCI), visual spatial index (VSI), FRI, WMI, processing speed index (PSI)). Sex-stratified analyses showed that the association of IL-8, IFN-γ, and index 2 with children's cognitive development was mainly concentrated in boys. CONCLUSIONS: Evidence of an association between low cognitive performance and high expression of placental inflammatory cytokines (IL-8, IL-6, TNF-α, and IFN-γ) was found, highlighting the potential importance of intrauterine placental immune status in dissecting offspring cognitive development.

Identification and prediction model of placenta-brain axis genes associated with neurodevelopmental delay in moderate and late preterm children.

BACKGROUND: Moderate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and neurobehavioral developmental delays in children and the underlying biological mechanisms need to be further revealed. The "placenta-brain axis" (PBA) provides a new perspective for gene regulation and risk prediction of neurodevelopmental delays in MLPT children. METHODS: The authors performed multivariate logistic regression models between MLPT and children's neurodevelopmental outcomes, using data from 129 MLPT infants and 3136 full-term controls from the Ma'anshan Birth Cohort (MABC). Furthermore, the authors identified the abnormally regulated PBA-related genes in MLPT placenta by bioinformatics analysis of RNA-seq data and RT-qPCR verification on independent samples. Finally, the authors established the prediction model of neurodevelopmental delay in children with MLPT using multiple machine learning models. RESULTS: The authors found an increased risk of neurodevelopmental delay in children with MLPT at 6 months, 18 months, and 48 months, especially in boys. Further verification showed that APOE and CST3 genes were significantly correlated with the developmental levels of gross-motor domain, fine-motor domain, and personal social domain in 6-month-old male MLPT children. CONCLUSIONS: These findings suggested that there was a sex-specific association between MLPT and neurodevelopmental delays. Moreover, APOE and CST3 were identified as placental biomarkers. The results provided guidance for the etiology investigation, risk prediction, and early intervention of neurodevelopmental delays in children with MLPT.

Association between prenatal metals exposure and blood pressure in 5-6 years children: A birth cohort study.

BACKGROUND: The trajectory of blood pressure (BP) from childhood to early middle age suggested that individuals with elevated BP in early childhood were more likely to be affected by cardiovascular disease in adulthood. Exposure to metals may affect BP in children, and pregnancy is a sensitive time for metal exposure. This study assessed the relationship between different stages of prenatal exposure to metals or metal mixtures and BP in children aged 5-6 years. METHODS: The study included 2535, 2680, 2534 mother-child pairs in three trimesters, from the Ma'anshan birth cohort study (MABC). We collected maternal blood samples during pregnancy and measured the serum levels of four metals (arsenic, selenium, cadmium, and mercury). BP was measured in children aged 5-6 years. A linear regression model and Bayesian kernel machine regression (BKMR) were used to explore associations between prenatal exposure to metals at different stages and multiple metal exposure with BP in children aged 5-6 years. RESULTS: Associations were observed between the arsenic in the third trimester and children's diastolic blood pressure (DBP) (ß = 0.88, 95% CI: 0.44, 1.33), systolic blood pressure (SBP) (ß = 0.72, 95% CI: 0.19, 1.24) and mean arterial pressure (MAP) (ß = 0.83, 95% CI: 0.42, 1.23), as well as between the mercury and children's DBP (ß = 0.65, 95% CI: 0.13, 1.16) and MAP (ß = 0.60, 95% CI: 0.14, 1.07). The BKMR analysis showed that multiple metals had a significant positive joint effect on children's DBP, SBP and MAP. A potential interaction between arsenic and mercury was observed (ß = -0.85, 95% CI: -1.62, -0.08). CONCLUSIONS: Exposure to arsenic and mercury during pregnancy was associated with altered BP in children. The third trimester may represent an important window of opportunity to reduce the effects of metal exposure on children's blood pressure and long-term health.

Early sleep duration trajectories and children's cognitive development: a prospective cohort study.

We aimed to investigate the association between sleep duration trajectories and cognitive performance in preschool-aged Chinese children. We included 2131 children from the Ma'anshan birth cohort (MABC) study. Sleep duration trajectories from 6 to 48 months of age were determined using the group-based trajectory modeling (GBTM). Children's intellectual development was assessed using the Wechsler Preschool and Primary Scale of Intelligence. Compared to those with a medium total sleep duration trajectory, children with a short total sleep duration trajectory had poorer cognitive performance on the Visual Spatial Index (VSI) (ß = -3.65; 95% CI = -6.77 to -0.53), which was associated with an increased risk of a low full-scale intelligence quotient (FSIQ) (OR = 1.60; 95% CI = 1.02 to 2.51). The short total sleep duration trajectory was associated with a low VSI compared with both the medium total sleep duration trajectory and the long total sleep duration trajectory. Compared to children with normal nighttime sleep duration and normal daytime sleep duration trajectories, children with short nighttime sleep and long daytime sleep duration trajectories, normal nighttime sleep and long daytime sleep duration trajectories, and short nighttime sleep and normal daytime sleep duration trajectories all had lower cognitive performance. The restricted cubic spline (RCS) also showed that children with and appropriate total sleep duration, an adequate nighttime sleep duration, and a moderate daytime sleep duration had higher FSIQ. CONCLUSIONS: The results of this study emphasize that a medium total sleep duration, adequate sleep at nighttime, and appropriate sleep in the daytime appear to be more beneficial for children's cognitive development. WHAT IS KNOWN: • Sleep duration in infancy is strongly associated with neurocognitive development. WHAT IS NEW: • Medium and long total sleep duration trajectories are beneficial for children's cognitive performance compared to the short total sleep duration trajectory. • A medium total sleep duration, adequate sleep at nighttime and appropriate sleep in the daytime appear to be more beneficial for children's cognitive development.

The Addition of Hypomethylating Agents to Low-Intensity Induction Chemotherapy Does Not Improve Outcomes in Elderly Acute Myeloid Leukemia Patients: A Single-Center Retrospective Study.

Background and Objectives: This study aimed to evaluate whether the addition of hypomethylating agents (HMA) to low-intensity chemotherapy can enhance the clinical efficacy of induction treatment for elderly acute myeloid leukemia (AML) patients who are unsuitable for standard induction therapy. Materials and Methods: This study retrospectively analyzed 117 patients over 60 years old who were initially diagnosed with AML and received low-intensity induction treatment in the Department of Hematology in Anhui provincial hospital from January 2015 to December 2020. Twenty-three patients were excluded, and the remaining 94 patients were divided into two groups according to the selection of induction regimens. Results: Forty-four patients received HMA combined with low-intensity chemotherapy, and the other 50 patients received only low-intensity induction chemotherapy. Forty-three patients (45.7%) obtained complete remission (CR) after the initial induction treatment. The CR rate in the HMA plus low-intensity chemotherapy group was 34.1% (15/44), and in the single low-intensity chemotherapy group was 56.0% (28/50) (p = 0.04). The 30 days cumulative early death rates were 9.1% (95% CI: 3.5-22.4%) in the HMA plus low-intensity chemotherapy group and 6.0% (95% CI: 2.0-17.5%) in the single low-intensity chemotherapy group, respectively (p = 0.59), and the one-year cumulative relapse rates were 21.1% (95% Cl: 9.8-41.9%) and 33.3% (95% Cl: 20.3-51.5%), respectively (p = 0.80). The one-year overall survival (OS) rates for patients in the HMA plus low-intensity chemotherapy group and the single low-intensity chemotherapy group were 37.3% (95% Cl: 23.1-51.5%) and 55.4% (95% Cl: 40.5-67.9%), respectively (p = 0.098), and the one-year event-free survival (EFS) rates were 8.5% (95% Cl: 2.2-20.6%) and 20.6% (95% Cl: 9.1-35.3%), respectively (p = 0.058). Conclusions: This study showed that the addition of HMA to low-intensity induction chemotherapy does not improve prognosis in elderly AML patients who are unsuitable for standard induction chemotherapy.

Clinical outcome of cord blood transplantation for nine children with juvenile myelomonocytic leukemia receiving fludarabine-busulfan-cyclophosphamide-based conditioning.

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy in young children and can only be cured through the allogeneic stem cell transplantation. PROCEDURE: We have retrospectively analyzed the outcomes of nine children with JMML after unrelated cord blood transplantation (UCBT). RESULTS: Eight patients who have received a myeloablative conditioning regimen of fludarabine (FLU), busulfan (BU), and cyclophosphamide (CY) have gotten engraftment. None of the nine patients has relapsed following initial UCBT. Six patients are still alive and in complete remission after UCBT with a median observation time of 43 months (range: 10-80 months). CONCLUSIONS: This study shows that UCBT with FLU-BU-CY conditioning regimen can represent a suitable option for children with JMML.

Cytokine release syndrome and relevant factors of CD19 targeted chimeric antigen receptor T cell therapy in relapsed/refractory B cell hematological malignancies.

OBJECTIVES AND METHODS: We reviewed the outcomes of 77 episodes of CD19 CAR-T therapy in 67 patients with B cell hematological malignancies from October 2016 to January 2020. Factors related to the grade of cytokine release syndrome (CRS) were explored by multivariate analysis, nonparametric test was conducted to explore the correlation between CRS and response. Kaplan-Meier curves were used to indicate survival profiles, and the correlation between CRS and survival was determined by the log-rank test. RESULTS: The rate of complete remission (CR) was 74.0% (57/77). CRS of any grade occurred in 68 of 77 episodes (grade 1: 32.5%, grade 2: 24.7%, grade 3: 22.1%, grade 4: 6.5%, grade 5: 2.6%). Patients with a history of transplantation had less severe CRS, and dose escalation-based infusion reduced the severity of CRS. Severe CRS was related to a higher CR rate but had no significant impact on event-free survival (EFS), relapse-free survival (RFS), or overall survival (OS). CONCLUSION: As a common adverse reaction of CAR-T therapy, the severity of CRS can be alleviated by dose escalation infusion, a history of transplantation was correlated with less severe CRS. Severe CRS was related to better response but was unrelated to long-term survival.

[Effect of Linggui Zhugan Decoction-containing serum on mitochondrial oxidative stress in cardiomyocytes: an exploration based on Nrf2/BNIP3 signaling pathway].

This study aimed to explore the effect of Linggui Zhugan Decoction(LGZGD)-containing serum on mitochondrial oxidative stress in cardiomyocytes based on the NF-E2-related factor2(Nrf2)/Bcl-2/adenovirus E1 B 19 kDa interacting protein(BNIP3) signaling pathway. After the preparation of LGZGD-containing serum and blank serum, H9 c2 cardiomyocytes were exposed to H_2O_2 for inducing oxidative stress in vitro. The H9 c2 cells were divided into four groups, namely normal control group, H_2O_2 model group, 20% blank serum group, and 20% LGZGD-containing serum group. After the cells were pre-treated with different types of serum for 12 h and cultured with 100 µmol·L~(-1 )H_2O_2 for 6 h, the reactive oxygen species(ROS) level in each group was detected by DCFH-DA, and the openness of mitochondrial permeability transition pore(mPTP) was measured using a calcein AM fluorescent probe. The expression levels of cytoplasmic cytochrome C(CytC), mitochondrial CytC, cytoplasmic and nuclear Nrf2, and BNIP3 were detected by Western blot. Nrf2-silenced H9 c2 cells were prepared by transfecting them with siRNA-Nrf2 for investigating the efficacy of LGZGD-containing serum in regulating ROS, mPTP, cytoplasmic and mitochondrial CytC, and BNIP3. The results showed that compared with the normal control group, H_2O_2 significantly increased the ROS content and mPTP openness(P<0.01), and the expression of Nrf2, BNIP3, and cytoplasmic CytC(P<0.01), and decreased the expression of mitochondrial CytC(P<0.01), without causing obvious change in cytoplasmic Nrf2. LGZGD-containing serum significantly lowered ROS content(P<0.01), inhibited mPTP openness(P<0.01), down-regulated the expression of cytoplasmic CytC and BNIP3(P<0.01), up-regulated mitochondrial CytC expression(P<0.01), and promoted Nrf2 nuclear translocation(P<0.05). However, after Nrf2 silencing, the reduced ROS production, diminished BNIP3 expression, and inhibited mPTP openness and CytC release induced by LGZGD-containing serum were reversed(P<0.01). These results have suggested that LGZGD-containing serum is able to alleviate the mitochondrial oxidative stress injury of cardiomyocytes by regulating the Nrf2/BNIP3 signaling pathway.

[Mechanism of atractylenolide â ¢ in alleviating H9c2 cell apoptosis through ROS/GRP78/caspase-12 signaling pathway based on molecular docking].

This study aims to investigate the effect of atractylenolide Ⅲ(ATL-Ⅲ) on hydrogen peroxide(H_2O_2)-induced endoplasmic reticulum stress and apoptosis of H9 c2 cells via the ROS/GRP78/caspase-12 signaling pathway.The binding activity of ATL-Ⅲ to GRP78 was determined by molecular docking.The result showed that ATL-Ⅲ had a good binding activity to GRP78, and the binding activity of ATL-Ⅲ was stronger than that of its specific inhibitor.The endoplasmic reticulum stress model of H9 c2 was established by H_2O_2(100 µmol·L~(-1)) treatment.Five groups were designed: blank control group, model group, and ATL-Ⅲ(15, 30, and 60 µmol·L~(-1)) groups.Apoptosis was detected by Hoechst/PI double staining and flow cytometry.The levels of superoxide dismutase(SOD), malondialdehyde(MDA), and lactate dehydrogenase(LDH) were measured by colorimetry.The levels of reactive oxygen species(ROS) and calcium(Ca~(2+)) in cytoplasm were determined by the fluorescence probe DCFH-DA and the calcium fluorescence probe Flou-4, respectively.The protein levels of GRP78, caspase-12, and caspase-3 were determined by Western blot, and the mRNA levels of GRP78 and caspase-12 by RT-qPCR.N-acetyl-L-cysteine(NAC) and 4-phenylbutyric acid(4-PBA) were respectively used to inhibit ROS and GRP78, and then the mechanism of ATL-Ⅲ in protecting the cells from endoplasmic reticulum stress induced by H_2O_2 were deduced.ATL-Ⅲ(15, 30, and 60 µmol·L~(-1)) decreased the apoptosis rate and ROS, MDA, and LDH levels(P<0.01), increased the SOD activity(P<0.01), and down-regulated the protein levels of GRP78, caspase-12, and caspase-3 and the mRNA levels of GRP78 and caspase-12(P<0.05).The addition of NAC decreased the apoptosis rate and ROS, MDA, GRP78, caspase-12, and caspase-3 levels(P<0.01), while it elevated the SOD level(P<0.01).The addition of 4-PBA also decreased the apoptosis rate and the levels of GRP78, caspase-12, caspase-3, and Ca~(2+)(P<0.01).The effect of inhibitors were consistent with that of ATL-Ⅲ.In conclusion, ATL-Ⅲ can protect H9 c2 cardiomyocytes by regulating ROS/GRP78/caspase-12 signaling pathway to inhibit H_2O_2-induced endoplasmic reticulum stress and apoptosis.

Umbilical cord blood transplantation can overcome the poor prognosis of KMT2A-MLLT3 acute myeloid leukemia and can lead to good GVHD-free/relapse-free survival.

This is a retrospective study comparing the effectiveness of umbilical cord blood transplantation (UCBT) and chemotherapy for patients in the first complete remission period for acute myeloid leukemia with KMT2A-MLLT3 rearrangements. A total of 22 patients were included, all of whom achieved first complete remission (CR1) through 1-2 rounds of induction chemotherapy, excluding patients with an early relapse. Twelve patients were treated with UCBT, and 10 patients were treated with chemotherapy after 2 to 4 courses of consolidation therapy. The 3-year overall survival (OS) of the UCBT group was 71.3% (95% CI, 34.4-89.8%), and that of the chemotherapy group was 10% (95% CI, 5.89-37.3%). The OS of the UCBT group was significantly higher than that of the chemotherapy group (P = 0.003). The disease-free survival (DFS) of the UCBT group was 60.8% (95% CI, 25.0-83.6%), which was significantly higher than the 10% (95% CI, 5.72-35.8%) of the chemotherapy group (P = 0.003). The relapse rate of the UCBT group was 23.6% (95% CI, 0-46.8%), and that of the chemotherapy group was 85.4% (95% CI, 35.8-98.4%), which was significantly higher than that of the UCBT group (P < 0.001). The non-relapse mortality (NRM) rate in the UCBT group was 19.8% (95% CI, 0-41.3%), and that in the chemotherapy group was 0.0%. The NRM rate in the UCBT group was higher than that in the chemotherapy group, but there was no significant difference between the two groups (P = 0.272). Two patients in the UCBT group relapsed, two died of acute and chronic GVHD, and one patient developed chronic GVHD 140 days after UCBT and is still alive, so the GVHD-free/relapse-free survival (GRFS) was 50% (95% CI, 17.2-76.1%). AML patients with KMT2A-MLLT3 rearrangements who receive chemotherapy as their consolidation therapy after CR1 have a very poor prognosis. UCBT can overcome the poor prognosis and significantly improve survival, and the GRFS for these patients is very good. We suggest that UCBT is a better choice than chemotherapy for KMT2A-MLLT3 patients.

Outcomes of Adolescents and Young Adults Compared with Children with Acute Leukemia after Single-Unit Unrelated Cord Blood Transplantation Using Myeloablative Conditioning without Antithymocyte Globulin.

BACKGROUND: Although the use of cord blood transplantation (CBT) is becoming more frequent in acute leukemia, considering the relationship between the low stem cell dose and graft failure, whether use of CBT for adolescents and young adults (AYAs) is appropriate remains uncertain. METHODS: A retrospective registry-based analysis of clinical outcomes and immune reconstitution was conducted for 105 AYAs and 187 children with acute leukemia who underwent single-unit CBT using myeloablative conditioning (MAC) without antithymocyte globulin (ATG). RESULTS: Outcomes were similar between AYAs and children, except for nonrelapse mortality (NRM) and recovery rates of neutrophils and platelets. The 30-day cumulative incidence of neutrophil engraftment was similar between AYAs and children, but children had faster rates of neutrophil and platelet recovery than AYAs. The median time to neutrophil engraftment was earlier in children than in AYAs (AYAs, 19 days, 95% confidence interval [CI] 17.3-21.7; children, 16 days, 95% CI 13.1-19.5, p = 0.00003). The incidence of platelet recovery on day 120 was higher in children than in AYAs (AYAs, 80%, 95% CI 71-81%; children, 88%, 95% CI 82-92%, p = 0.037). CD34+ cell dose was the only independent factor influencing both neutrophil and platelet recovery. The cumulative incidence of NRM at 2 years was higher among AYAs than among children (AYAs, 27.5%, 95% CI 20-37%; children, 15%, 95% CI 10-21%, p = 0.008). Conditioning regimen was an independent factor influencing NRM. With respect to immune reconstitution, natural killer cell counts quickly recovered to normal levels 1-month post-CBT in both children and AYAs. CD8+ T-cell counts were higher in children than in AYAs at 1 and 3 months post-CBT. CD4+ T-cell counts were similar in both children and AYAs after CBT. CONCLUSION: AYAs with acute leukemia have outcomes of single-unit CBT using MAC without ATG that are as good as those of children. Thus, single-unit CBT using modified MAC without ATG is an acceptable choice for both AYAs and children who do not have a suitable donor.

Effects and long-term follow-up of using umbilical cord blood-derived mesenchymal stromal cells in pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis after unrelated cord blood transplantation.

This is a retrospective study to evaluate the efficacy and safety of umbilical cord blood-derived mesenchymal stromal cells (MSCs) for the treatment of pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis (BKV-HC) after unrelated cord blood transplantation (UCBT). Thirteen pediatric patients with severe BKV-HC from December 2013 to December 2015 were treated with MSCs. The number of MSCs transfused in each session was 1 × 106 /kg once a week until the symptoms improved. The median follow-up time was 1432 (89-2080) days. The median frequency of MSC infusion was 2 (1-3), with eight cured cases and five effective cases; the total efficacy rate was 100%. The copy number of urine BKV DNA was 4.43 (0.36-56.9) ×108 /mL before MSC infusion and 2.67 (0-56.3) ×108 /mL after MSC infusion; the difference was not significant (P = .219). There were no significant differences in the overall survival, disease-free survival, and the incidence of relapse and acute and chronic graft-versus-host disease between the MSC infusion group and non-MSC infusion group. There was also no significant difference in the cytomegalovirus, Epstein-Barr virus (EBV), and fungal and bacterial infection rates between the two groups. Although umbilical cord blood-derived MSCs do not reduce the number of BKV DNA copies in the urine, the cells have a high efficacy rate and minimal side effects in treating severe BKV-HC after UCBT among pediatric patients. MSCs do not affect the rates of relapse, long-term infection, or survival of patients with leukemia.

Decitabine prior to salvaged cord blood transplantation for acute myeloid leukaemia/myelodysplastic syndrome not in remission.

WHAT IS KNOWN AND OBJECTIVE: Many refractory/relapsed haematological malignancies, in non-remission state, still have poor prognosis even after allogeneic haematopoietic stem cell transplantation. Recently, decitabine or umbilical cord blood transplantation (UCBT) seemed to be effective in these patients. However, few studies have added decitabine to myeloablative conditioning regimens for UCBT in patients with haematological malignancies not in remission. Therefore, the objective was to evaluate the clinical outcomes of patients with refractory/relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) using decitabine as part of a myeloablative conditioning regimen prior to salvaged unrelated UCBT at our centre. METHODS: We enrolled 20 consecutive patients with refractory/relapsed AML/MDS between 2013 and 2018. All patients were in non-remission state before transplantation. All transplants were performed with decitabine as part of the myeloablative conditioning regimen, which was decitabine + fludarabine/busulfan/cyclophosphamide. RESULTS AND DISCUSSION: All patients achieved neutrophil and platelet engraftment. Incidence of grade III/IV acute graft-vs-host disease (GVHD) was 20.0%, which was also decreased compared to non-decitabine group (P = .025). The median follow-up time after UCBT was 29 months (range 14-64 months). The 2-year probability of GVHD-free relapse-free survival (GRFS) was higher in the decitabine group. Univariate showed that the decitabine group was associated with a higher GRFS than the non-decitabine group. The estimated probability of overall survival and relapse was 55% and 20.0%, respectively. WHAT IS NEW AND CONCLUSIONS: Our results suggest that addition of decitabine as part of the myeloablative conditioning regimen prior to UCBT for refractory/relapsed AML/MDS in patients who are not in remission is safe and might be an effective treatment option.

Status of dental caries and associated factors in Tibetan adults: findings from the fourth China National Oral Health Survey.

BACKGROUND: Tibet, a region where average elevation is above 3500 m and socio-economic development is relatively lower, was not included in National Oral Health Survey over decades. The cross-sectional study aimed to investigate the status of dental caries and associated factors in Tibetan adults. METHODS: Participants aged 35-44, 55-64 and 65-74 years were selected. Decayed, missing, and filled tooth (DMFT), decayed and filled root (DF-Root) and root canal index (RCI) were used to evaluate dental caries. Questionnaire survey on demographic information, socioeconomic status, dietary habits, and oral health knowledge and behavior was conducted. Mann-Whitney U test, logistic regression were used for the statistical analyses. RESULTS: A total of 446 participants were enrolled in the survey. Of these: 222 (49.8%) were females, 224 (50.2%) were males; 149 (33.4%), 151 (33.9%), 146 (32.7%) were aged 35-44, 55-64 and 65-74 years respectively. The mean DMFT (SD) was 7.62 (4.84), 12.46 (8.16), and 21.38 (8.93). The filling rate was very low in all age groups (1.77%, 0.98%, 0.45%). The mean DF-Root (SD) was 0.50 (1.04), 1.04 (2.02), 1.32 (2.14), respectively. Root caries index was 42.27, 44.78 and 57.60%. Older age (65-74 age group) was positively associated with crown caries (odds ratio = 31.20, 95% confidence interval: 10.70-90.96). College degree and above and brushing teeth at least once a day were negatively associated with crown caries (odds ratio = 0.28, 95% confidence interval: 0.09-0.89; odds ratio = 0.39, 95% confidence interval: 0.21-0.72, respectively). Rural area, high income level and brushing teeth at least once a day were negatively and tooth with attachment loss was positively associated with root caries. CONCLUSIONS: The status of dental caries in the adults in Tibet is severe and the treatment rate is very low. The study suggests a correlation between crown caries and the variables age, level of education and frequency of tooth brushing; correlation between root caries and residence, income level, frequency of tooth brushing and exposed root surfaces. These findings could be as reference to develop community based interventions to reduce the prevalence of caries in Tibet.

[Influence of Critical Care Ultrasound Oriented Fluid Management in Different Stages of Shock to the Outcome].

OBJECTIVE: To investigate the relationship between fluid management oriented by critical care ultrasound and prognosis in patients with shock. METHODS: We analyzed the data of a randomized controlled trial called Critical Care Ultrasound Oriented Shock Treatment (CCUSOST) in the Department of Critical Care Medicine, West China Hospital retrospectively. 77 patients in the critical care ultrasound oriented treatment group (experimental group) and 70 patients in the conventionally treated group as control were included in the statistics, to evaluate the relationship between fluid intake and prognosis. Univariate and multivariate logistic regression analyses were used to analyze risk factors for ICU mortality. RESULTS: The baseline indexes of the patients in the experimental group and the control group were consistent. The ICU mortality of the experimental group was significantly lower than that of the control group (P < 0.05).The fluid intake in the stabilization and de-escalation phases was less than the the control group (P < 0.05). We divided these shock patients into survival group (92 cases) and non-survival (55 cases) according to whether they died in ICU, and the univariate analysis for ICU mortality showed that acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, SOFA score, Lac, hourly urine output, total fluid intake, fluid intake in the salvage and optimization stages, fluid intake in the stabilization and de-escalation stages were significantly different (P < 0.05) between survivers and non-survivers. Multivariete analysis showed that the fluid intake during the salvage and optimization phases, fluid intake in the stabilization and de-escalation phases were independent risk factors for ICU mortality. CONCLUSION: Critical care ultrasound oriented shock fluid management could reduce fluid intake of stabilization and de-escalation phases, and improved adverse outcome; whether the fluid intake during stabilization and de-escalation phases, or the fluid intake during the salvage and optimization phases, both were associated with patient prognosis.

[The Clinical Value of the Pathophysiology Oriented Critical Care Ultrasound Exam (POCCUE) Protocol in Acute Respiratory and Circulatory Compromise of Critically Ill Patients].

OBJECTIVE: The aim of this study is to explore the diagnostic and therapeutic accuracy of pathophysiology and clinic oriented critical care ultrasound exam (POCCUE) protocol in acute respiratory and circulatory compromise of critically ill patients. METHODS: Prospectively included patients with acute respiratory and circulatory compromise from ICU of West China Hospital of Sichuan University from March to April 2018. The POCCUE protocol designed according to the pathophysiological changes of acute respiratory and circulatory disorders includes: the first part is the acquiring an ultrasound section and measuring corresponding indicators including pulmonary and echocardiographic indicators; the second part is a comprehensive analysis according to the former examination which evaluates the pathophysiological changes of acute respiratory and circulatory disorders, and then establish the initial etiology diagnosis and start treatment. The clinical value of the POCCUE protocol, including the accuracy of diagnosis, and the differences in treatment was verified by comparing the clinical outcome with the traditional treatment group. RESULTS: A total of 82 subjects were used for statistics. Compare with the traditional group, POCCUE can notably increase the diagnostic and therapeutic accuracy of clinic and pathophysiology (diagnostic accuracy: 93.90% vs. 68.29%, P < 0.01; therapeutic accuracy: 93.90% vs. 62.20%, P < 0.01). CONCLUSION: The POCCUE has a higher accuracy of diagnosis and treatment for patients with acute respiratory and circulatory compromise.