Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine.

Chemotherapy resistance is the dominant challenge in the treatment of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Nevertheless, the potential molecular mechanism of Nrf2 regulating the base excision repair pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and base excision repair pathway gene encoding 8-hydroxyguanine DNA glycosidase (OGG1) was associated with AML disease progression. In vitro, Nrf2 and OGG1 were highly expressed in drug-resistant leukemia cells. Upregulation of Nrf2 in leukemia cells by lentivirus transfection could decrease the sensitivity of leukemia cells to cytarabine, whereas downregulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cells. Our chromatin immunoprecipitation assay revealed that Nrf2 could bind to the promoter of OGG1. Furthermore, the use of OGG1 inhibitor TH5487 could partially reverse the inhibitory effect of upregulated Nrf2 on leukemia cell apoptosis. In vivo, downregulation of Nrf2 could increase the sensitivity of leukemia cell to cytarabine and decrease OGG1 expression. Mechanistically, Nrf2-OGG1 axis-mediated AML resistance might be achieved by activating the AKT signaling pathway to regulate downstream apoptotic proteins. Thus, this study reveals a novel mechanism of Nrf2-promoting drug resistance in leukemia, which may provide a potential therapeutic target for the treatment of drug-resistant/refractory leukemia.

Low TYROBP expression predicts poor prognosis in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is the second most common refractory hematologic cancer. Searching for new targets and prognostic markers for MM is significant. METHODS: GSE39754, GSE6477 and GSE24080 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in MM versus healthy people from GSE39754 and GSE6477 were screened using limma package, and MM-related module genes were chosen with the use of Weighted gene co-expression network analysis (WGCNA), and the two were intersected using ggVennDiagram for obtaining MM-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Then, protein-protein interactions (PPI) analysis in String database was used to obtain hub genes, while prognosis was analyzed by survival package in GSE24080. Receiver operating characteristic (ROC) curve was adopted for evaluating diagnostic value of hub genes. Besides, univariable/multivariable Cox regression were employed to screen independent prognostic biomarkers. Gene set enrichment analysis (GSEA) was used to find possible mechanism. Finally, western-blotting and reverse transcription-polymerase chain reaction (RT-PCR) verify TYROBP expression within MM and healthy people. We performed cell adhesion and transwell assays for investigating TYROBP function in MM cell adhesion and migration. RESULTS: Through differential analyses, 92 MM-related DEGs were obtained. 10 hub genes were identified by PPI and CytoHubba. Their diagnostic and prognostic significance was analyzed. Down-regulation of genes like TYROBP, ELANE, MNDA, and MPO related to dismal MM prognosis. Upon univariable/multivariable Cox regression, TYROBP independently predicted MM prognosis. GSEA pathway was enriched, indicating that TYROBP expression affected MM development via cell adhesion molecular pathway. Upon Western-blotting and RT-PCR assays, TYROBP expression among MM patients decreased relative to healthy donors. Cell adhesion and transwell migration assays revealed increased MM cell adhesion and decreased migration upon TYROBP up-regulation. CONCLUSION: In summary, TYROBP is a potential prognostic marker for MM.

Elevated Id2 expression causes defective meiosis and spermatogenesis in mice.

BACKGROUND: Inhibitors of DNA binding (ID) proteins mainly inhibit gene expression and regulate cell fate decisions by interacting with E-proteins. All four ID proteins (ID1-4) are present in the testis, and ID4 has a particularly important role in spermatogonial stem cell fate determination. Several lines of evidence indicate that ID proteins are involved in meiosis; however, functional experiments have not been conducted to validate this observation. RESULTS: In this study, we report that ID2 is enriched in spermatocytes and that forced ID2 expression in germ cells causes defects in spermatogenesis. A detailed analysis demonstrated that Id2 overexpression (Id2 OE) decreased the total number of spermatogonia and changed the dynamics of meiosis progression. Specifically, spermatocytes were enriched in the zygotene stage, and the proportion of pachytene spermatocytes was significantly decreased, indicating defects in the zygotene-pachytene transition. The number of MLH1-positive foci per cell was decreased in pachytene spermatocytes from Id2 OE testes, suggesting abnormalities in recombination. Transcriptome analysis revealed that forced Id2 expression changed the expression of a list of genes mainly associated with meiosis and spermatid development. CONCLUSIONS: ID2 protein is expressed in spermatocytes, and its genetic ablation in the germline does not affect spermatogenesis, likely due to genetic compensation of its family members. However, forced Id2 expression changes meiosis progression and causes defects in spermiogenesis. These data provide important evidence that ID proteins play pivotal roles in male meiosis and spermatid development.

BM-MSCs display altered gene expression profiles in B-cell acute lymphoblastic leukemia niches and exert pro-proliferative effects via overexpression of IFI6.

BACKGROUND: The tumor microenvironment (TME) is a supportive environment responsible for promoting the growth and proliferation of tumor cells. Current studies have revealed that the bone marrow mesenchymal stem cells (BM-MSCs), a type of crucial stromal cells in the TME, can promote the malignant progression of tumors. However, in the adult B-cell acute lymphoblastic leukemia (B-ALL) microenvironment, it is still uncertain what changes in BM-MSCs are induced by leukemia cells. METHODS: In this study, we mimicked the leukemia microenvironment by constructing a BM-MSC-leukemia cell co-culture system. In vitro cell experiments, in vivo mouse model experiments, lentiviral transfection and transcriptome sequencing analysis were used to investigate the possible change of BM-MSCs in the leukemia niche and the potential factors in BM-MSCs that promote the progression of leukemia. RESULTS: In the leukemia niche, the leukemia cells reduced the MSCs' capacity to differentiate towards adipogenic and osteogenic subtypes, which also promoted the senescence and cell cycle arrest of the MSCs. Meanwhile, compared to the mono-cultured MSCs, the gene expression profiles of MSCs in the leukemia niche changed significantly. These differential genes were enriched for cell cycle, cell differentiation, DNA replication, as well as some tumor-promoting biofunctions including protein phosphorylation, cell migration and angiogenesis. Further, interferon alpha-inducible protein 6 (IFI6), as a gene activated by interferon, was highly expressed in leukemia niche MSCs. The leukemia cell multiplication was facilitated evidently by IFI6 both in vitro and in vivo. Mechanistically, IFI6 might promote leukemia cell proliferation by stimulating SDF-1/CXCR4 axis, which leads to the initiation of downstream ERK signaling pathway. As suggested by further RNA sequencing analysis, the high IFI6 level in MSCs somewhat influenced the gene expression profile and biological functions of leukemia cells. CONCLUSIONS: BM-MSCs in the leukemia niche have varying degrees of changes in biological characteristics and gene expression profiles. Overexpression of IFI6 in BM-MSCs could be a key factor in promoting the proliferation of B-ALL cells, and this effect might be exerted through the SDF-1/CXCR4/ERK signal stimulation. Targeting IFI6 or related signaling pathways might be an important measure to reduce the leukemia cell proliferation.

Heme oxygenase-1 inhibits the cytotoxicity of natural killer cells to acute myeloid leukemia by downregulating human leukocyte antigen-C.

BACKGROUND AIMS: Recently, immune escape has been considered as a factor leading to relapse of acute myeloid leukemia (AML). In our previous study, heme oxygenase 1 (HO-1) proved to play an essential role in the proliferation and drug resistance of AML cells. In addition, recent studies by our group have shown that HO-1 is involved in immune escape in AML. Nevertheless, the specific mechanism by which HO-1 mediates immune escape in AML remains unclear. METHODS: In this study, we found that patients with AML and an overexpression of HO-1 had a high rate of recurrence. In vitro, overexpression of HO-1 attenuated the toxicity of natural killer (NK) cells to AML cells. Further study indicated that HO-1 overexpression inhibited human leukocyte antigen-C and reduced the cytotoxicity of NK cells to AML cells, leading to AML relapse. Mechanistically, HO-1 inhibited human leukocyte antigen-C expression by activating the JNK/C-Jun signaling pathway. RESULTS: In AML, HO-1 inhibits cytotoxicity of NK cells by inhibiting the expression of HLA-C, thus causing immune escape of AML cells. CONCLUSIONS: NK cell-mediated innate immunity is important for the fight against tumors, especially when acquired immunity is depleted and dysfunctional, and the HO-1/HLA-C axis can induce functional changes in NK cells in AML. Anti-HO-1 treatment can promote the antitumor effect of NK cells and may play an important role in the treatment of AML.

Stability analysis of riverbanks with a dual structure under water-root-soil coupling.

The collapse mechanism of dual-structure vegetation riverbanks at different water levels is unclear. A method for calculating the critical collapse width of a dual-structure vegetation bank under different failure modes that consider the variations in river and groundwater levels and the influence of vegetation roots is proposed. Combined with the influence of flow lateral erosion and slope toe accumulation, a calculation model of riverbank stability was established. The results show that shear failure is the main failure mode when the cohesive soil layer on a dual-structure bank is thick, and the critical collapse width of the bank with root soil is higher than that of the soil bank. The critical collapse width of the bank varied with the water level during different water level periods. Compared with a soil riverbank, a rooted soil riverbank can significantly prolong the bank collapse time. The collapse width of a soil bank without vegetation roots is smaller than that of a rooted soil bank, and the cumulative collapse width is related to calculation time. The greater the thickness of rooted soil, the slower the decay rate of bank stability under water flow erosion.

Clinical analysis of a case of neonatal exfoliative esophagitis in an 18-day-old neonate.

BACKGROUND: This study aims to provide guidance for clinical work through analysis of the clinical characteristics, endoscopic and pathological manifestations, diagnosis, and treatment of an 18-day-old neonate with exfoliative esophagitis. CASE PRESENTATION: The patient presented with vomiting but the parents did not pay too much attention. The pathological report revealed numerous fibrinous exudative necrotic, and inflammatory cells, as well as a small amount of squamous epithelium. Furthermore, milk allergy factors were considered. Conservative treatments, such as fasting, acid suppression, mucosal protection, parenteral nutrition, and the replacement of anti-allergic milk powder were given. Thereafter, endoscopic examination revealed that the patient returned to normal, and was discharged after 21 days. CONCLUSIONS: Exfoliative esophagitis has multiple causes; and has characteristic clinical and endoscopic manifestations. Endoscopic examination after 18 days presentation and conservative therapy revealed that the esophagus had returned to a normal appearance and the patient was discharged. Following discharge, the parents were advised to feed the patient ALFERE powder. Attention should be given to the timely detection of complications and corresponding treatment.

Baicalein Inhibits Proliferation of Myeloma U266 Cells by Downregulating IKZF1 and IKZF3.

BACKGROUND Baicalein can suppress the growth of multiple tumors, including multiple myeloma (MM), but the exact mechanisms remains elusive. Here, we investigated the exact mechanisms of the anti-myeloma activity of baicalein. MATERIAL AND METHODS Proliferation and rates of apoptosis of myeloma U266 cells exposed to baicalein were detected. Microarray, polymerase chain reaction (PCR) assay, and Western blot analysis were applied to evaluate the mRNA and protein levels of associated molecules. Survival analysis of IKZF1 and IKZF3 was conducted as well. RESULTS Baicalein suppressed the growth and stimulated apoptosis of myeloma U266 cells in a dose- and time-dependent way. Baicalein increased mRNA level of CRBN, and further studies suggested that baicalein downregulated IKZF1 and IKZF3 on a post-transcriptional level. Although the differences did not reach statistical significance, IKZF1 and IKZF3 were associated with poor overall survival. CONCLUSIONS Our results suggest that baicalein suppresses the growth and promotes apoptosis of myeloma U266 cells through downregulating IKZF1 and IKZF3. Baicalein increased the expression of CRBN, which might exert a reversion effect on resistance of IMiDs. MM patients in IKZF1 and IKZF3 low-expression groups had better overall survival than those in IKZF1 and IKZF3 high-expression groups. Thus, the present results indicate that baicalein might be a therapeutic choice for targeting IKZF1 and IKZF3.

[Study on High-yield Cultivation Measures for Arctii Fructus].

OBJECTIVE: To find out the high yield cultivation measures for Arctii Fructus. METHODS: Completely randomized block experiment design method was used in the field planting, to analyze the effect of different cultivation way on agronomic characters, phenological phase,quality and quantity of Arctii Fructus. RESULTS: Arctium lappa planted on August 28 had the best results of plant height, thousand seeds weight and yield. The highest yield of Arctii Fructus was got at the density of 1,482 plants/667 m2. Arctiin content was in an increase trend with the planting time delay and planting density increasing. The plant height, thousand seeds weight, yield and arctiin content by split application of fertilizer were significantly higher than that by one-time fertilization. Compared with open field Arctium lappa, plant height, yield, arctiin content and relative water content of plastic film mulching Arctium lappa was higher by 7.74%, 10.87%, 6.38% and 24.20%, respectively. In the topping Arctium lappa, the yield was increased by 11.09%, with 39. 89% less branching number. Early planting time and topping shortened the growth cycle of Arctium lappa plant. CONCLUSION: The high-yield cultivation measures of Arctii Fructus are: around August 28 to sowing, planting density of 1 482 plants/667 m2, split application of fertilizer for four times, covering film on surface of the soil and topping in bolting.

Expression of cancer-testis antigen in multiple myeloma.

Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen (CTA) has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new approach for multiple myeloma (MM) immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow (BM) cells of 25 MM patients and 18 healthy volunteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% (7/25), 80% (20/25), 40% (10/25) and 68% (17/25), respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% (20/25) MM patients, and that of at least one CTA in 88% (22/25). The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II (P<0.05). No statistically significant differences were observed in the mRNA expression levels of MAGE-C1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM (P>0.05). In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immunotherapy in the future.

Proteomic analysis reveals potential therapeutic targets for childhood asthma through Mendelian randomization.

BACKGROUND: Asthma is the most common chronic disease among children and poses a significant threat to their health. This study aims to assess the relationship between various plasma proteins and childhood asthma, thereby identifying potential therapeutic targets. METHODS: Based on publicly available genome-wide association study summary statistics, we employed a two-sample Mendelian randomization (MR) approach to elucidate the causal relationship between plasma proteins and asthma. Mediation analysis was then conducted to evaluate the indirect influence of plasma proteins on childhood asthma mediated through risk factors. Comprehensive analysis was also conducted to explore the association between plasma proteins and various phenotypes using the UK Biobank dataset. RESULTS: MR analysis uncovered a causal relationship between 10 plasma proteins and childhood asthma. Elevated levels of seven proteins (TLR4, UBP25, CBR1, Rac GTPase-activating protein 1 [RGAP1], IL-21, MICB, and PDE4D) and decreased levels of three proteins (GSTO1, LIRB4 and PIGF) were associated with an increased risk of childhood asthma. Our findings further validated the connections between reported risk factors (body mass index, mood swings, hay fever or allergic rhinitis, and eczema or dermatitis) and childhood asthma. Mediation analysis revealed the influence of proteins on childhood asthma outcomes through risk factors. Furthermore, the MR analysis identified 73 plasma proteins that exhibited causal associations with at least one risk factor for childhood asthma. Among them, RGAP1 mediates a significant proportion (25.10%) of the risk of childhood asthma through eczema or dermatitis. Finally, a phenotype-wide association study based on these 10 proteins and 1403 diseases provided novel associations between these biomarkers and multiple phenotypes. CONCLUSION: Our study comprehensively investigated the causal relationship between plasma proteins and childhood asthma, providing novel insights into potential therapeutic targets.

Transcription factor E4F1 dictates spermatogonial stem cell fate decisions by regulating mitochondrial functions and cell cycle progression.

BACKGROUND: Spermatogonial stem cells (SSCs) provide a foundation for robust and continual spermatogenesis in mammals. SSCs self-renew to maintain a functional stem cell pool and differentiate to supply committed progenitors. Metabolism acts as a crucial determinant of stem cell fates; however, factors linking metabolic programs to SSC development and maintenance are poorly understood. RESULTS: We analyzed the chromatin accessibility of undifferentiated spermatogonia at the single-cell level and identified 37 positive TF regulators that may have potential roles in dictating SSC fates. The transcription factor E4F1 is expressed in spermatogonia, and its conditional deletion in mouse germ cells results in progressive loss of the entire undifferentiated spermatogonial pool. Single-cell RNA-seq analysis of control and E4f1-deficient spermatogonia revealed that E4F1 acts as a key regulator of mitochondrial function. E4F1 binds to promotors of genes that encode components of the mitochondrial respiratory chain, including Ndufs5, Cox7a2, Cox6c, and Dnajc19. Loss of E4f1 function caused abnormal mitochondrial morphology and defects in fatty acid metabolism; as a result, undifferentiated spermatogonia were gradually lost due to cell cycle arrest and elevated apoptosis. Deletion of p53 in E4f1-deficient germ cells only temporarily prevented spermatogonial loss but did not rescue the defects in SSC maintenance. CONCLUSIONS: Emerging evidence indicates that metabolic signals dictate stem cell fate decisions. In this study, we identified a list of transcription regulators that have potential roles in the fate transitions of undifferentiated spermatogonia in mice. Functional experiments demonstrated that the E4F1-mediated transcription program is a crucial regulator of metabolism and SSC fate decisions in mammals.

[Study on the Relationship between Integrin 2A and Drug Resistance in Chronic Myeloid Leukemia].

OBJECTIVE: To explore the expression pattern and clinical significance of Integral membrane protein 2A（ITM2A） in drug resistant patients with chronic myeloid leukemia (CML). METHODS: The expression of ITM2A in CML was evaluated by qRT-PCR, Western blot and immunocytochemistry. In order to understand the possible biological effects of ITM2A, apoptosis, cell cycle and myeloid differentiation antigen expression of CML cells were detected by flow cytometry after over-expression of ITM2A. The nuderlying molecular mechanism of its biological effect was explored. RESULTS: The expression of ITM2A in bone marrow of CML resistant patients was significantly lower than that of sensitive patients and healthy donors（P<0.05）. The CML resistant strain cell K562R was successfully constructed in vitro. The expression of ITM2A in the resistant strain was significantly lower than that in the sensitive strain(P<0.05). Overexpression of ITM2A in K562R cells increased the sensitivity of K562R cells to imatinib and blocked the cell cycle in G2 phase(P<0.05), but did not affect myeloid differentiation. Mechanistically, up-regulation of ITM2A reduced phosphorylation in ERK signaling (P<0.05). CONCLUSION: The expression of ITM2A was low in patients with drug resistance of CML, and the low expression of ITM2A may be the key factor of imatinib resistance in CML.

Case report: One case of umbilical vein thrombosis in the second trimester with associated portal vein thrombosis after childbirth.

Background: Umbilical vein thrombosis is a rare pregnancy complication, that is difficult to detect prenatally but can lead to poor fetal outcomes. Case presentation: We described a 33-year-old primiparae who was identified as having umbilical vein thrombosis by ultrasound at 21 weeks gestation, and the neonate was found to have a portal vein thrombus after delivery. Following enoxaparin anticoagulant therapy, the thrombus disappeared within 4 weeks. No thrombus formation occured during the 10-month follow-up, and the baby was in excellent clinical condition. Conclusion: Owing to the poor fetal outcomes related to umbilical thrombosis, pay attention to abnormal clinical signs during prenatal ultrasound, fetal heart monitoring and counting fetal movements can help in the early identification of umbilical cord thrombosis.The findings highlight the importance of regular prenatal ultrasound evaluation, enabling early detection and monitoring of any anomalies or vascular abnormalities related to the fetal umbilical vein. Further research is warranted to explore the clinical implications and long-term outcomes associated with these findings.

[Changes of Serum Complement C1q in Patients with Multiple Myeloma].

OBJECTIVE: To analyze the change of serum C1q in the course of multiple myeloma (MM) and its correlation with clinical characteristics. METHODS: A total of 138 newly diagnosed MM patients in Zhongnan Hospital of Wuhan University from June 2016 to December 2019 were selected as research objects, during the same period 50 age-matched anemia patients, 50 lymphoma patients, 50 leukemia patients, and 50 myelodysplastic syndrome (MDS) patients were selected as control groups. All the patients met WHO disease classification, and were definitely diagnosed by pathology or bone marrow smear/biopsy. The changes of C1q between MM patients and control group, as well as in different therapeutic responses of MM patients before and after treatment were compared, also the difference of clinical characteristics among MM patients with different C1q level, so as to analyze risk factors which led to C1q decline. RESULTS: The average value of C1q in MM patients was (128.18±51.24) mg/L, which was significantly lower than control group (P<0.01). The levels of white blood cell, platelet (PLT), hemoglobin (Hb), serum calcium, albumin, lactate dehydrogenase (LDH) in newly diagnosed high C1q group were significantly higher than those in low C1q group (P<0.05). Logistic analysis showed that the levels of PLT, Hb, albumin, and LDH in newly diagnosed high C1q group were higher than those in low C1q group (r=0.248, r=0.394, r=0.405, r=0.295). After treatment, the levels of C1q in MM patients with complete remission and very good partial remission were significantly higher than before treatment (P<0.05), while those with partial remission and stable disease also increased but not significantly (P>0.05). CONCLUSION: The C1q level in MM patients is significantly lower than that in patients with other hematologic system diseases, and it increases with the remission of the disease after treatment.

Overexpressed mitogen-and stress-activated protein kinase 1 promotes the resistance of cytarabine in acute myeloid leukemia through brahma related gene 1-mediated upregulation of heme oxygenase-1.

Drug resistance remains a major challenge in the current treatment of acute myeloid leukemia (AML). Finding specific molecules responsible for mediating drug resistance in AML contributes to the effective reversal of drug resistance. Recent studies have found that mitogen- and stress-activated protein kinase 1 (MSK1) is of great significance in the occurrence and development of tumors. In the current study, MSK1 was found highly expressed in drug-resistant AML patients. Heme oxygenase-1 (HO-1) has been previously validated to be associated with drug resistance in AML. Our study revealed a positive correlation between MSK1 and HO-1 in patient samples. In vitro experiments revealed that the sensitivity of AML cell lines THP-1 and U937 to cytarabine (Ara-C) significantly decreased after overexpression of MSK1. Meanwhile, downregulation of MSK1 by siRNA transfection or treatment of pharmacological inhibitor SB-747651A in AML cell lines and primary AML cells enhanced the sensitivity to Ara-C. Flow cytometry analysis showed that downregulation of MSK1 in AML cells accelerated apoptosis and arrested cell cycle progression in G0/G1 phase. However, the increased cell sensitivity induced by MSK1 downregulation was reversed by the induction of HO-1 inducer Hemin. Through further mechanism exploration, real-time PCR, immunofluorescence and Western blot analysis demonstrated that brahma related gene 1 (BRG1) was involved in the regulatory effect of MSK1 on HO-1. High expression of MSK1 could promote the resistance of AML through BRG1-mediated upregulation of HO-1. Downregulation of MSK1 enhanced the sensitivity of AML cells to Ara-C. Our findings provide novel ideas for developing effective anti-AML targets.

A Modified Slime Mould Algorithm for Global Optimization.

Slime mould algorithm (SMA) is a population-based metaheuristic algorithm inspired by the phenomenon of slime mould oscillation. The SMA is competitive compared to other algorithms but still suffers from the disadvantages of unbalanced exploitation and exploration and is easy to fall into local optima. To address these shortcomings, an improved variant of SMA named MSMA is proposed in this paper. Firstly, a chaotic opposition-based learning strategy is used to enhance population diversity. Secondly, two adaptive parameter control strategies are proposed to balance exploitation and exploration. Finally, a spiral search strategy is used to help SMA get rid of local optimum. The superiority of MSMA is verified in 13 multidimensional test functions and 10 fixed-dimensional test functions. In addition, two engineering optimization problems are used to verify the potential of MSMA to solve real-world optimization problems. The simulation results show that the proposed MSMA outperforms other comparative algorithms in terms of convergence accuracy, convergence speed, and stability.

Soluble Triggering Receptors Expressed on Myeloid Cells-1 as a Neonatal Ventilator-Associated Pneumonia Biomarker.

BACKGROUND: Neonatal ventilator-associated pneumonia (NVAP) is one of the main infections acquired in hospitals, and soluble triggering receptors expressed on myeloid cells-1 (sTREM-1) are a TREM-1 subtype that can be released into the blood or bodily fluids during an infection. METHODS: The patients included in the present study were divided into three groups: the NVAP group, the first control group, and the second control group (n = 20, each). Children requiring respiratory treatment were assigned to the NVAP group, newborns who received mechanical ventilation and had neonatal respiratory distress syndrome were assigned to the first control group, and newborns with normal X-ray and electrocardiogram results but no non-pulmonary infection was assigned to the second control group. The blood and bronchoalveolar lavage fluid (BALF) sTREM-1 levels in all newborns were analyzed. RESULTS: The acute-phase blood and BALF sTREM-1 levels were significantly higher in the NVAP group than in the first control group, and the blood sTREM-1 expression level was lower in the second control group than in the NVAP group. CONCLUSION: The present results suggest that sTREM-1 might be a useful biomarker for NVAP prediction in the Department of Pediatrics.

Neferine Protects against Hypoxic-Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3-Mediated Inflammasome Activation.

Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1ß, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1ß and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.

Norovirus gastroenteritis in young children receiving human rotavirus vaccine.

We explored whether human rotavirus vaccine had any efficacy against norovirus (NV)-associated gastroenteritis in young children. In an efficacy trial of rotavirus vaccine, 405 infants were immunized with a human rotavirus vaccine or placebo at a ratio of 2:1, and prospectively followed for acute gastroenteritis (AGE) from approximately 2 months to 2 y of age. Multiplex real-time reverse transcription polymerase chain reaction (Mrt RT-PCR) assays were used for detection and quantitation of NVs of genogroup I (GI) and genogroup II (GII) in stool specimens. NVs were detected in 155 (32%) of 485 episodes of AGE. Of these, NV was the only gastroenteritis virus detected in the stools in 142 (29%) episodes. GI and GII NVs were found in 12% and 88% of the cases, respectively. NV as the only gastroenteritis virus was detected in 36% of the infants in the rotavirus vaccine group and 27% in the placebo group. The clinical severity of NV-associated AGE in the vaccine and placebo recipients was not different. NVs were the most common etiologic agents of AGE in children under 2 y of age. Human rotavirus vaccine did not protect against NV gastroenteritis.