[Clinical Analysis of Mitoxantrone Liposome in the Treatment of Children with High-Risk Acute Myeloid Leukemia].

OBJECTIVE: To investigate the safety and efficacy of mitoxantrone liposome in the treatment of children with high-risk acute myeloid leukemia (AML). METHODS: The children with high-risk AML who received the mitoxantrone liposome regimen at Wuhan Children's Hospital from January 2022 to February 2023 were collected as the observation group, and the children with high-risk AML who received idarubicin regimen were enrolled as controls, and their clinical data were analyzed. Time to bone marrow recovery, the complete remission rate of bone marrow cytology, the clearance rate of minimal residual disease, and treatment-related adverse reactions were compared between the two groups. RESULTS: The patients treated with mitoxantrone liposome showed shorter time to recovery of leukocytes(17 vs 21 day), granulocytes(18 vs 24 day), platelets(17 vs 24 day), and hemoglobin(20 vs 26 day) compared with those treated with idarubicin, there were statistical differences (P <0.05). The effective rate and MRD turning negative rate in the observation group were 90.9% and 72.7%, respectively, while those in the control group were 94.1% and 76.4%, with no statistical difference (P >0.05). The overall response rate of the two groups of patients was similar. CONCLUSION: The efficacy of mitoxantrone liposome is not inferior to that of idarubicin in children with high-risk AML, but mitoxantrone liposome allows a significantly shorter duration of bone marrow suppression and the safety is better.

Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.

Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-ß-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.

Clinical Analysis of Pediatric Acute Megakaryocytic Leukemia With CBFA2T3-GLIS2 Fusion Gene.

CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in non-Down syndrome acute megakaryocytic leukemia (AMKL), which is associated with extremely poor clinical outcome. The presence of this fusion gene is associated with resistance to high-intensity chemotherapy, including hematopoietic stem cell transplantation (HSCT), and a high cumulative incidence of relapse frequency. The clinical features and clinical effects of China Children's Leukemia Group-acute myeloid leukemia (AML) 2015/2019 regimens and haploidentical HSCT (haplo-HSCT) for treatment of 6 children harboring the CBFA2T3-GLIS2 fusion gene between January 2019 and December 2021 were retrospectively analyzed. The 6 patients included 4 boys and 2 girls with a median disease-onset age of 19.5 months (range: 6-67 mo) who were diagnosed with AMKL. Flow cytometry demonstrated CD41a, CD42b, and CD56 expression and lack of HLA-DR expression in all 6 patients. All the children were negative for common leukemia fusion genes by reverse transcription polymerase chain reaction, but positive for the CBFA2T3-GLIS2 fusion gene by next-generation sequencing and RNA sequencing. All patients received chemotherapy according to China Children's Leukemia Group-AML 2015/2019 regimens, and 4 achieved complete remission. Four children underwent haplo-HSCT with posttransplant cyclophosphamide-based conditioning; 3 had minimal residual disease negative (minimal residual disease <0.1%) confirmed by flow cytometry at the end of the follow-up, with the remaining patient experiencing relapse at 12 months after transplantation. Transcriptome RNA sequencing is required for the detection of the CBFA2T3-GLIS2 fusion gene and for proper risk-based allocation of pediatric patients with AML in future clinical strategies. Haplo-HSCT with posttransplant cyclophosphamide-based conditioning may improve survival in children with AMKL harboring the fusion gene.

Global patterns of asthma burden related to environmental risk factors during 1990-2019: an age-period-cohort analysis for global burden of disease study 2019.

BACKGROUND: Change in asthma burden attributed to specific environmental risk factor has not been evaluated. OBJECTIVE: We aimed to explore the age, period, and cohort effects on asthma burden attributable to smoking and occupational asthmagens in different socio-demographic index (SDI) regions and the region and sex disparities. METHODS: Risk factor-specific asthma deaths and disability-adjusted life years (DALYs) rates were extracted from Global Burden of Disease study 2019, estimated by standard Combined Cause of Death Model and DisMod-MR 2.1 modeling tool. Age-period-cohort analysis was conducted to decompose age, period, and cohort effects on asthma burden. RESULTS: Smoking- and occupational asthmagens-related asthma deaths and DALYs rates dropped by > 45% during 1990-2019. In 2019, Africa, South and Southeast Asia had higher asthma burden than other regions. Male had higher asthma burden than female. Among nearly all age groups, low-middle SDI region had the highest smoking-related asthma burden, and low SDI region had the highest occupational asthmagens-related asthma burden. Inverse "V" shaped trend was observed in the above regions with increasing age. For smoking-related asthma deaths and DALYs rates, the most significant improvement of period rate ratio (RR) occurred in high SDI region, decreased from 1.67 (1.61, 1.74) to 0.34 (0.33, 0.36) and 1.61 (1.57, 1.66) to 0.59 (0.57, 0.61), respectively, as well as the cohort effect on smoking-related asthma burden. For occupational asthmagens-related asthma deaths and DALYs rates, the most sharply decrease of period and cohort RR appeared in the high and high-middle SDI regions. Low SDI region showed least progress in period and cohort RR of smoking- and occupational asthmagens-linked asthma burden. CONCLUSION: Smoking- and occupational asthmagens-related asthma burden sharply decreases, but region and sex disparities exist. Policy makers from low SDI region should reinforce tobacco control and prioritize workplace protection.

Robotic natural orifice specimen extraction surgery I-type F method vs conventional robotic resection for lower rectal cancer.

BACKGROUND: Robotic resection using the natural orifice specimen extraction surgery I-type F method (R-NOSES I-F) is a novel minimally invasive surgical strategy for the treatment of lower rectal cancer. However, the current literature on this method is limited to case reports, and further investigation into its safety and feasibility is warranted. AIM: To evaluate the safety and feasibility of R-NOSES I-F for the treatment of low rectal cancer. METHODS: From September 2018 to February 2022, 206 patients diagnosed with low rectal cancer at First Affiliated Hospital of Nanchang University were included in this retrospective analysis. Of these patients, 22 underwent R-NOSES I-F surgery (R-NOSES I-F group) and 76 underwent conventional robotic-assisted low rectal cancer resection (RLRC group). Clinicopathological data of all patients were collected and analyzed. Postoperative outcomes and prognoses were compared between the two groups. Statistical analysis was performed using SPSS software. RESULTS: Patients in the R-NOSES I-F group had a significantly lower visual analog score for pain on postoperative day 1 (1.7 ± 0.7 vs 2.2 ± 0.6, P = 0.003) and shorter postoperative anal venting time (2.7 ± 0.6 vs 3.5 ± 0.7, P < 0.001) than those in the RLRC group. There were no significant differences between the two groups in terms of sex, age, body mass index, tumor size, TNM stage, operative time, intraoperative bleeding, postoperative complications, or inflammatory response (P > 0.05). Postoperative anal and urinary functions, as assessed by Wexner, low anterior resection syndrome, and International Prostate Symptom Scale scores, were similar in both groups (P > 0.05). Long-term follow-up revealed no significant differences in the rates of local recurrence and distant metastasis between the two groups (P > 0.05). CONCLUSION: R-NOSES I-F is a safe and effective minimally invasive procedure for the treatment of lower rectal cancer. It improves pain relief, promotes gastrointestinal function recovery, and helps avoid incision-related complications.

Enhanced glucose homeostasis via Clostridium symbiosum-mediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery.

BACKGROUND: The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood. AIM: To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism. METHODS: Streptozotocin (STZ) was used to induce DM in Sprague-Dawley (SD) rats at a dose of 60 mg/kg. The rats were then randomly divided into two groups: The mid-small intestine bypass (MSIB) group and the sham group (underwent switch laparotomy). Following a 6-wk recovery period post-surgery, the rats underwent various assessments, including metabolic parameter testing, analysis of liver glycogen levels, measurement of key gluconeogenic enzyme activity, characterization of the gut microbiota composition, evaluation of hormone levels, determination of bile acid concentrations, and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor. RESULTS: The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism, along with increased hepatic glycogen content. Furthermore, there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase. Importantly, the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus, Clostridium symbiosum, Ruminococcus gnavus, and Bilophila. Moreover, higher levels of secondary bile acids, such as intestinal lithocholic acid, were observed in this group. Remarkably, the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1 (GLP-1) at 6 wk postoperatively, highlighting their potential role in glucose regulation. These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota. CONCLUSION: The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats. This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1, resulting in a favorable modulation of glucose homeostasis.

Differences in metabolic improvement after metabolic surgery are linked to the gut microbiota in non-obese diabetic rats.

BACKGROUND: Different metabolic/bariatric surgery approaches vary in their effect on weight loss and glucose levels, although the underlying mechanism is unclear. Studies have demonstrated that the gut microbiota might be an important mechanism of improved metabolism after metabolic/bariatric surgery. AIM: To investigate the relationship between the improvement in metabolic disturbances and the changes in gut microbiota after gastric or intestinal bypass. METHODS: We performed sleeve gastrectomy (SG), distal small intestine bypass (DSIB) or sham surgery in nonobese rats with diabetes induced by 60 mg/kg streptozotocin (STZ-DM). RESULTS: The group comparisons revealed that both SG and DSIB induced a reduction in body weight and significant improvements in glucose and lipid metabolism in the STZ-DM rats. Furthermore, DSIB exhibited a stronger glucose-lowering and lipid-reducing effect on STZ-DM rats than SG. 16S ribosomal RNA gene sequencing revealed the gut abundance of some Lactobacillus spp. increased in both the SG and DSIB groups after surgery. However, the DSIB group exhibited a more pronounced increase in the gut abundance of Lactobacillus spp. compared to the SG group, with more Lactobacillus spp. types increased in the gut. CONCLUSION: The gut abundance of Lactobacillus was significantly correlated with the improvement in glycolipid metabolism and the change in serum fibroblast growth factor 21 levels.

Umbilical cord blood exosomes from very preterm infants with bronchopulmonary dysplasia aggravate lung injury in mice.

Bronchopulmonary dysplasia (BPD) is characterized by abnormal development of the blood vessels and alveoli in lungs, which largely occurs in premature infants. Exosomes (EXO) from very preterm infants (VPI) with BPD (BPD-EXO) impair angiogenic activities of human umbilical vein endothelial cells (HUVECs) via EXO-miRNAs cargo. This study aimed to determine whether and how BPD-EXO affect the development of BPD in a mouse model. We showed that treating BPD mice with BPD-EXO chronically and irreversibly aggravated lung injury. BPD-EXO up-regulated 139 and down-regulated 735 genes in the mouse lung tissue. These differentially expressed genes were enriched to the MAPK pathway (e.g., Fgf9 and Cacna2d3), which is critical to angiogenesis and vascular remodeling. BPD-EXO suppressed expression of Fgf9 and Cacna2d3 in HUVECs and inhibited migration, tube formation, and increased cell apoptosis in HUVECs. These data demonstrate that BPD-EXO aggravate lung injury in BPD mice and impair lung angiogenesis, plausibly leading to adverse outcomes of VPI with BPD. These data also suggest that BPD-EXO could serve as promising targets for predicting and treating BPD.

Prenatal Exposure to Air Pollution and Pre-Labor Rupture of Membranes in a Prospective Cohort Study: The Role of Maternal Hemoglobin and Iron Supplementation.

BACKGROUND: Exposure to air pollution in prenatal period is associated with prelabor rupture of membranes (PROM). However, the sensitive exposure time windows and the possible biological mechanisms underlying this association remain unclear. OBJECTIVE: We aimed to identify the sensitive time windows of exposure to air pollution for PROM risk. Further, we examined whether maternal hemoglobin levels mediate the association between exposure to air pollution and PROM, as well as investigated the potential effect of iron supplementation on this association. METHOD: From 2015 to 2021, 6,824 mother-newborn pairs were enrolled in the study from three hospitals in Hefei, China. We obtained air pollutant data [particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5), PM with aerodynamic diameter ≤10µm (PM10), sulfur dioxide (SO2), and carbon monoxide (CO)] from the Hefei City Ecology and Environment Bureau. Information on maternal hemoglobin levels, gestational anemia, iron supplementation, and PROM was obtained from medical records. Logistic regression models with distributed lags were used to identify the sensitive time window for the effect of prenatal exposure to air pollutant on PROM. Mediation analysis estimated the mediated effect of maternal hemoglobin in the third trimester, linking prenatal air pollution with PROM. Stratified analysis was used to investigate the potential effect of iron supplementation on PROM risk. RESULTS: We found significant association between prenatal exposure to air pollution and increased PROM risk after adjusting for confounders, and the critical exposure windows of PM2.5, PM10, SO2 and CO were the 21th to 24th weeks of pregnancy. Every 10-µg/m3 increase in PM2.5 and PM10, 5-µg/m3 increase in SO2, and 0.1-mg/m3 increase in CO was associated with low maternal hemoglobin levels [-0.94g/L (95% confidence interval (CI): -1.15, -0.73), -1.31g/L (95% CI: -1.55, -1.07), -2.96g/L (95% CI: -3.32, -2.61), and -1.11g/L (95% CI: -1.31, -0.92), respectively] in the third trimester. The proportion of the association between air pollution and PROM risk mediated by hemoglobin levels was 20.61% [average mediation effect (95% CI): 0.02 (0.01, 0.05); average direct effect (95%): 0.08 (0.02, 0.14)]. The PROM risk associated with exposure to low-medium air pollution could be attenuated by maternal iron supplementation in women with gestational anemia. CONCLUSIONS: Prenatal exposure to air pollution, especially in the 21st to 24th weeks of pregnancy, is associated with PROM risk, which is partly mediated by maternal hemoglobin levels. Iron supplementation in anemia pregnancies may have protective effects against PROM risk associated with exposure to low-medium air pollution. https://doi.org/10.1289/EHP11134.

Screening of organophosphate esters in different indoor environments: Distribution, diffusion, and risk assessment.

ANALYSIS: of air conditioner (AC) filter dust can reveal the level of organophosphate ester (OPE) pollution in indoor environments, but comprehensive research on this topic remains lacking. This study combined non-targeted and targeted analysis to screen and analyze 101 samples of AC filter dust, settled dust, and air obtained in 6 indoor environments. Phosphorus-containing organic compounds account for a large proportion of the organic compounds found in indoor environments, and OPEs might be the main pollutants. Using toxicity data and traditional priority polycyclic aromatic hydrocarbons for toxicity prediction of OPEs, 11 OPEs were prioritized for further quantitative analysis. The concentration of OPEs in AC filter dust was highest, followed in descending order by that in settled dust and that in air. The concentration of OPEs in AC filter dust in the residence was two to seven times greater than that in the other indoor environments. More than 56% of the OPEs in AC filter dust showed significant correlation, while those in settled dust and air were weakly correlated, suggesting that large amounts of OPEs collected over long periods could have a common source. Fugacity results showed that OPEs were transferred easily from dust to air, and that dust was the main source of OPEs. The values of both the carcinogenic risk and the hazard index were lower than the corresponding theoretical risk thresholds, indicating low risk to residents through exposure to OPEs in indoor environments. However, it is necessary to remove AC filter dust in a timely manner to prevent it becoming a pollution sink of OPEs that could be rereleased and endanger human health. This study has important implications for comprehensive understanding of the distribution, toxicity, sources, and risks of OPEs in indoor environments.

Umbilical cord blood-derived exosomes from healthy term pregnancies protect against hyperoxia-induced lung injury in mice.

Bronchopulmonary dysplasia (BPD) is a chronic, devastating disease primarily occurring in premature infants. To date, intervention strategies to prevent or treat BPD are limited. We aimed to determine the effects of umbilical cord blood-derived exosomes (UCB-EXOs) from healthy term pregnancies on hyperoxia-induced lung injury and to identify potential targets for BPD intervention. A mouse model of hyperoxia-induced lung injury was created by exposing neonatal mice to hyperoxia after birth until the 14th day post birth. Age-matched neonatal mice were exposed to normoxia as the control. Hyperoxia-induced lung injury mice were intraperitoneally injected with UCB-EXO or vehicle daily for 3 days, starting on day 4 post birth. Human umbilical vein endothelial cells (HUVECs) were insulted with hyperoxia to establish an in vitro model of BPD to investigate angiogenesis dysfunction. Our results showed that UCB-EXO alleviated lung injuries in hyperoxia-insulted mice by reducing histopathological grade and collagen contents in the lung tissues. UCB-EXO also promoted vascular growth and increased miR-185-5p levels in the lungs of hyperoxia-insulted mice. Additionally, we found that UCB-EXO elevated miR-185-5p levels in HUVECs. MiR-185-5p overexpression inhibited cell apoptosis, whereas promoted cell migration in HUVECs exposed to hyperoxia. The luciferase reporter assay results revealed that miR-185-5p directly targeted cyclin-dependent kinase 6 (CDK6), which was downregulated in the lungs of hyperoxia-insulted mice. Together, these data suggest that UCB-EXO from healthy term pregnancies protect against hyperoxia-induced lung injuries via promoting neonatal pulmonary angiogenesis partially by elevating miR-185-5p.

Clinical characteristics of pediatric allogeneic hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA): a retrospective single-center analysis.

OBJECTIVES: To investigate the clinical features of thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation in children. METHODS: A retrospective analysis of continuous clinical data from HSCT received in the Department of Hematology and Oncology of Wuhan Children's Hospital from August 1, 2016 to December 31, 2021. RESULTS: During this period, 209 patients received allo-HSCT in our department, 20 (9.6%) of whom developed TA-TMA. TA-TMA was diagnosed at a median of 94 (7-289) days post-HSCT. Eleven (55%) patients had early TA-TMA within 100 days post-HSCT, while the other 9 (45%) patients had TA-TMA thereafter. The most common symptom of TA-TMA was ecchymosis (55%), while the main signs were refractory hypertension (90%) and multi-cavity effusion (35%). Five (25%) patients had central nervous system symptoms (convulsions and lethargy). All 20 patients had progressive thrombocytopenia, with 16 patients receiving transfusion of platelets that was ineffective. Ruptured red blood cells were visible in only two patients with peripheral blood smears. Cyclosporine A or Tacrolimus (CNI) dose was reduced once TA-TMA was diagnosed. Nineteen cases were treated with low-molecular-weight heparin, 17 patients received plasma exchange, and 12 patients were treated with rituximab. TA-TMA-related mortality percentage in this study was 45% (9/20). CONCLUSION: Platelet decline and/or ineffective transfusion post-HSCT should be considered an early indicator of TA-TMA in pediatric patients. TA-TMA in pediatric patients may occur without evidence of peripheral blood schistocytes. Aggressive treatment is required once diagnosis is confirmed, but the long-term prognosis is poor.

Inhibition of hippocampal cyclin-dependent kinase 5 activity ameliorates learning and memory dysfunction in a mouse model of bronchopulmonary dysplasia.

AIMS: Oxygen therapy plays a vital role in the development of bronchopulmonary dysplasia (BPD), which is the independent risk factor for neurodevelopment deficits in premature infants. However, the effect of hippocampal cyclin-dependent kinase 5 (CDK5) on BPD-associated neurodevelopment deficits is not fully understood. METHODS: Mice were placed in a hyperoxia chamber from postnatal Day 1 to Day 7. Hematoxylin and eosin staining was used to evaluate the lung histomorphological characteristics. Learning and memory functions of mice were detected by Morris water maze. TUNEL staining was applied to measure the number of apoptotic cells. The expression of CDK5, apoptosis-related protein, and neuroplasticity-related proteins were analyzed by Western blot. Golgi staining was used to assess the structure of dendritic spines. RESULTS: Hyperoxia-induced BPD mice showed a long-term learning and memory dysfunction, more severe neuronal apoptosis, and a decline of synaptic plasticity. Inhibition of CDK5 overactivation ameliorated cognitive deficits, neuronal apoptosis, and synaptic plasticity disorders in BPD mice. CONCLUSIONS: This study first found a vital role of CDK5 in BPD-associated neurodevelopmental disorders. Inhibition of CDK5 overexpression could effectively improve cognitive dysfunctions in BPD mice, which indicated that hippocampal CDK5 may be a new target for prevention and treatment in learning and memory dysfunction of BPD.

PD-1 signalling defines and protects leukaemic stem cells from T cell receptor-induced cell death in T cell acute lymphoblastic leukaemia.

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppressed disease progression. Combination therapy using PD-1 blockade and chemotherapy substantially extended the survival of mice engrafted with mouse or human T-ALL cells. Mechanistically, PD-1+ LSCs had high NOTCH1-MYC activity for disease initiation. Furthermore, PD-1 signalling maintained quiescence and protected LSCs against T cell receptor-signal-induced apoptosis. Overall, our data highlight the hierarchy of leukaemia by identifying PD-1+ LSCs and provide a therapeutic approach for the elimination of LSCs through PD-1 blockade in T-ALL.

Selenium attenuates the association of co-exposure to arsenic, cadmium, and lead with cognitive function among Chinese community-dwelling older adults.

The effects of interactions between the toxic and essential metal mixtures on cognitive function are poorly understood. This study aims to identify the joint association of arsenic (As), cadmium (Cd), and lead (Pb) with cognitive function in older adults and the moderating role of selenium (Se), zinc (Zn), and copper (Cu) in this association. This study included 1000 community-dwelling older adults. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). Blood concentrations of As, Cd, Pb, Se, Zn, and Cu were measured using inductively coupled plasma mass spectrometry. Linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess the individual and joint associations of As, Cd, and Pb with cognitive function and to examine whether Se, Zn, and Cu (individually and as a mixture) modified these associations. In the adjusted single-metal models, both Cd (ß = - 0.37, 95% CI: - 0.73 to - 0.01) and Pb (ß = - 0.44, 95% CI: - 0.86 to - 0.02) were associated with MMSE scores, while Se (ß = 0.71, 95% CI: 0.30 to 1.13) exhibited a positive relationship with MMSE scores. Univariate exposure-response functions from BKMR models showed similar results. Moreover, the toxic metal mixture (As, Cd, and Pb) exhibited a significant negative association with MMSE scores in a dose-response pattern, with Pb being the greatest contributor within the mixture. The negative association of Pb alone or the toxic metal mixture with MMSE scores became weaker at higher concentrations of Se within its normal range, especially when Se levels were greater than the median (89.18 µg/L). Our findings support that Se can attenuate the negative associations of exposure to single Pb or the As, Cd, and Pb mixtures with cognitive function. Future prospective studies are needed to replicate our findings.

The effect of phthalates exposure during pregnancy on asthma in infants aged 0 to 36 months: a birth cohort study.

This cohort study sought to investigate the effects of phthalates exposure during pregnancy on offspring asthma and its association with placental stress and inflammatory factor mRNA expression levels. A total of 3474 pregnant women from the China Ma'anshan birth cohort participated in this study. Seven phthalate metabolites were detected in urine samples during pregnancy by solid phase extraction-high-performance liquid chromatography tandem mass spectrometry. Placenta stress and inflammation mRNA expression were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Early pregnancy may be the critical period when phthalates exposure increases the risk of asthma in infants and young children, and there is a certain gender difference in the risk of asthma in infants and young children. Moreover, through the placenta stress and inflammatory factor associated with infant asthma found anti-inflammatory factor of interleukin-10 (IL-10) mRNA expression will reduce the risk of 36-month-old male infant asthma. The expression of interleukin-4(IL-4) and macrophage (M2) biomarker cluster of differentiation 206(CD206) mRNA reduced the risk of asthma in 18-month-old female infants. Placental stress and inflammatory response were analyzed using mediating effects. Tumor necrosis factor-α (TNFα) showed a complete mediating effect between mono-benzyl phthalate (MBzP) exposure in early pregnancy and asthma in 12-month-old males, and IL-10 also showed a complete mediating effect between mono-n-butyl phthalate (MBP) exposure in early and late pregnancy and asthma in 36-month-old males. In summary, exposure to phthalates during pregnancy may contribute to the development of asthma in infants, which may be associated with placental stress and inflammation.

[Clinical Analysis of Salvage Treatment of Glucocorticoid Resistant Graft-Versus-Host Disease with Vedolizumab in Children].

OBJECTIVE: To investigate the efficacy and safety of VDZ (Vedolizumab) in the salvage treatment of glucocorticoid resistance to gastrointestinal graft-versus-host disease (GR-GI GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: The clinical data of 5 patients with refractory GI GVHD who received allo-HSCT in Wuhan Children's Hospital from December 2020 to December 2021 were retrospectively analyzed with VDZ salvage therapy. RESULTS: Among the 5 children with refractory GI GVHD, there were 1 male and 4 female, including 2 cases of extremely severe aplastic anemia, 1 case of acute myeloid leukemia (M2, high-risk), 1 case of fanconi anemia and 1 case of myelodysplastic syndrome. The median age of transplant recipients was 54.4 (12-164) months. The median treatment time from transplantation to VDZ was 1.4 (0.6-6.8) months. On average, 3.5 (2-5) doses of VDZ were received. After receiving treatment, 2 patients achieved a complete response (CR), 2 patients achieved a very good partial response (VGPR), 1 patient was non-responsive (NR) after a short-term partial response (PR). Compared with that before VDZ treatment, the amount of diarrhea, stool color, blood and traits of the children after medication were effectively improved. The median follow-up time was 9.3 (7.23-12.83) months. No disseminated or severe bacterial/fungal infections occurred during VDZ treatment and follow-up, and 2 children died of leukemia recurrence and pulmonary bronchiolitis obliterans. CONCLUSION: VDZ salvage treatment of refractory GI GVHD in children has obvious short-term efficacy and good safety.

Transrectal endoscopic ultrasound-guided fine-needle aspiration biopsy for qualitative diagnosis of pelvic space-occupying lesions: a diagnostic test.

Background: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is an effective technique for qualitative diagnosis of space occupying lesions in and around the wall of the digestive tract. At present, there are many studies on EUS-FNA via the upper gastrointestinal route, while there are few studies on EUS-FNA via the lower gastrointestinal route, especially for Chinese patients with pelvic mass. Therefore, this study sought to evaluate the value of transrectal EUS-FNA in the qualitative diagnosis of pelvic masses in Chinese patients. Methods: The clinical data of 35 patients with pelvic masses who underwent EUS-FNA at our hospital were collected from September 2014 to December 2021. Among these patients, 10 underwent surgical treatment after EUS-FNA, and a diagnosis was made based on a pathologic evaluation. The EUS-FNA biopsy results were compared to the final diagnostic results to calculate the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of EUS-FNA in the diagnosis of malignant pelvic mass. For the 10 patients who underwent surgery, the final diagnoses were based on the pathologic findings of surgical specimens, and for the 25 patients who did not undergo surgery, the final diagnoses were based on the malignant pathological results of EUS-FNA or clinical follow-up results. Results: Among the 35 patients, 12 had benign lesions, including pelvic abscesses, cysts, and inflammatory masses, and 23 had malignant lesions, including mesenchymal tumors, leiomyosarcomas, teratomas, and malignant tumors with pelvic metastases. There were no complications resulting from the biopsy punctures. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EUS-FNAs for the diagnosis of malignant pelvic masses were 91.3% (21/23), 100.0% (12/12), 100.0% (21/21), 85.7% (12/14), and 94.3% (33/35), respectively. Conclusions: EUS-FNA is a safe and effective method for the qualitative diagnosis of pelvic masses, and has good clinical application value.