Glutaredoxin-1 modulates the NF-κB signaling pathway to activate inducible nitric oxide synthase in experimental necrotizing enterocolitis.

Inducible nitric oxide synthase (iNOS), regulated by nuclear factor kappa B (NF-κB), is crucial for intestinal inflammation and barrier injury in the progression of necrotizing enterocolitis (NEC). The NF-κB pathway is inhibited by S-glutathionylation of inhibitory κB kinase ß (IKKß), which can be restored by glutaredoxin-1 (Grx1). Thus, we aim to explore the role of Grx1 in experimental NEC. Wild-type (WT) and Grx1-knockout (Grx1-/-) mice were treated with an NEC-inducing regimen. Primary intestinal epithelial cells (IECs) were subjected to LPS treatment. The production of iNOS, NO, and inflammation injuries were assessed. NF-κB and involved signaling pathways were also explored. The severity of NEC was attenuated in Grx1-/- mice. Grx1 ablation promoted IKKß glutathionylation, NF-κB inactivation, and decreased iNOS, NO, and O2·- production in NEC mice. Furthermore, Grx1 ablation restrained proinflammatory cytokines and cell apoptosis, ameliorated intestinal barrier damage, and promoted proliferation in NEC mice. Grx1 ablation protected NEC through iNOS and NO inhibition, which related to S-glutathionylation of IKKß to inhibit NF-κB signaling. Grx1-related signaling pathways provide a new therapeutic target for NEC.

[Correlation between 25-hydroxyvitamin D and nephroblastoma in children and its value in assessing disease prognosis]. / 25-ç¾Ÿç»´ç”Ÿç´ Dä¸Žå„¿ç«¥è‚¾æ¯ç»†èƒžç˜¤çš„ç›¸å ³æ€§åŠå¯¹ç–¾ç— é¢„åŽçš„è¯„ä¼°ä»·å€¼åˆ†æž.

OBJECTIVES: To study the correlation between 25-hydroxyvitamin D [25-(OH)D] and nephroblastoma in children and its value in assessing the prognosis of the disease. METHODS: A total of 50 children with nephroblastoma who were admitted from January 2018 to December 2022 were included as the nephroblastoma group, and according to the postoperative pathological type, they were divided into a good prognosis group with 38 children and a poor prognosis group with 12 children. A total of 50 healthy children who underwent physical examination during the same period of time served as the healthy control group. The above groups were compared in terms of serum creatinine and 25-(OH)D level. A Spearman correlation analysis was used to investigate the correlation between serum 25-(OH)D level and therapeutic effect reaction. A multivariate logistic regression analysis was used to identify the risk factors affecting the prognosis of nephroblastoma in children. RESULTS: The nephroblastoma group had significantly lower levels of serum creatinine and 25-(OH)D than the healthy control group (P<0.05). Compared with the good prognosis group, the poor prognosis group had a significantly larger tumor diameter, a significantly higher proportion of children with stage III-IV tumors, a significantly higher rate of tumor metastasis, and significantly lower serum levels of creatinine and 25-(OH)D (P<0.05). The Spearman correlation analysis showed that serum 25-(OH)D level was negatively correlated with therapeutic effect reaction (rs=-0.685, P<0.001). The multivariate logistic regression analysis showed that tumor diameter ≥10 cm, stage III-IV tumors, presence of tumor metastasis, and 25-(OH)D <19 ng/mL were closely associated with the poor prognosis of nephroblastoma in children (P<0.05). Serum 25-(OH)D level had an area under the curve of 0.805 (95%CI: 0.706-0.903, P<0.001) in evaluating the prognosis of nephroblastoma in children, with a Youden index of 0.512, a sensitivity of 0.938, and a specificity of 0.575 at the optimal cut-off value of 1.764 ng/mL. CONCLUSIONS: There is a significant correlation between 25-(OH)D level and the prognosis of nephroblastoma in children, and 25-(OH)D can be used for prognosis prediction.

Genomic and Clinical Analysis of Children with Acute Lymphoblastic Leukemia.

Objective: This study investigated the types and significance of mutant genes in children with acute lymphoblastic leukemia (ALL). Methods: The gene sequencing data of 89 ALL children were retrospectively analyzed. Log-rank test was used to analyze the effect of different numbers of mutant genes on the clinical characteristics of the patients and disease. Results: Known gene mutations were detected in 64% (57/89) of the children, including one gene mutation in 31% and two or more gene mutations in 33% of the patients. Gene sequencing showed that most mutations occurred in KRAS (17%), NRAS (15%), FLT3 (7%), TP53 (7%), and PTPN11 (7%), and functional clustering analysis showed that most were signaling pathway genes (50%). In the overall cohort, no association was found between clinical characteristics and gene mutation. The children were then classified into three groups: group A (no gene mutation), group B (one gene mutation), and group C (two or more gene mutations). Correlation analysis showed that group A had significantly more children with medium risk ALL (P = 0.037), and group C had markedly more children with high risk ALL (P = 0.001). Further analysis showed that children with mutant genes took significantly more time to enter the maintenance phase than children without mutations. Conclusion: Children with ALL had a high gene mutation rate, especially in KRAS and NRAS genes, and the mutant genes were mainly signal pathway-related. The gene mutations were significantly correlated with clinical phenotype and the time taken to enter the maintenance phase.

An isolated childhood myeloid sarcoma with germline MSH6 mutation-a case report.

Myeloid sarcoma (MS) is a type of malignant tumor that originates in the bone marrow. This study reports on the treatment of an 11-year-old Uygur girl with a 15-day history of fever and paroxysmal cough, accompanied by right hip pain. During treatment, fatigue and anemia developed, physical strength decreased, and a few petechiae were seen in the lower extremities. Multiple enlarged lymph nodes were palpable in the neck, with slight congestion in the pharynx. Routine blood screening showed three major myeloid lineage abnormalities. Pathological examination revealed the presence of CD10 (-), CD99 (+), CD20 (+), CD3 (-), CD117 (weak+), CD34 (unclear location), TdT (-), Pax5 (-), Ki-67 (50%+), MPO (-), and CD43 (+). The patient was eventually diagnosed with isolated MS. After chemotherapy, no small particles were observed in bone marrow morphology. Complete remission was confirmed by flow cytometric detection of minimal residual disease. Genomic DNA was subjected to targeted sequencing of 236 gene panels to detect somatic mutations and the MSH6 c.3953_3954insAA p.R1318fs germline mutation. Unfortunately, the patient was subsequently lost to follow-up. To our knowledge, an MSH6 germline mutation had not previously been reported in children with MS, and we speculated that an MSH6 germline mutation led to genomic instability, triggering a somatic mutation in multiple genes and ultimately led to the development of MS in this patient. It is suggested that rare base abnormalities may be involved in the development of isolated myeloid sarcomas (IMS).