Clinical characteristics and prognosis of SARS-CoV-2 infection in children with hematological malignancies: A multicenter, retrospective study in China.

BACKGROUND: Data on SARSCoV-2 infection in children with hematological malignancies (HM) are limited. Here, we describe the clinical features of children with HM after SARS-CoV-2 infection and investigate the potential risk factors for disease severity. METHODS: Children with HM and SARS-CoV-2 infection from five hospitals in five cities in Henan, China from October 2022 to January 2023 were retrospectively included. Clinical information and Coronavirus disease 2019 (COVID-19) vaccination status were collected for further analyses. RESULTS: A total of 285 children with HM and SARS-CoV-2 infections were included. COVID-19 was asymptomatic in 3.2% of the patients (n = 9), mild in 89.1% (n = 254), moderate in 5.3% (n = 15), severe in 1.8% (n = 5), and critical in 0.7% (n = 2). Fever (92.4%) and cough (56.9%) were the most common symptoms. Most (249, 88.3%) children were managed at home during their COVID-19 illness. Of the 36 children admitted to the hospital, two required intensive care unit care, 11 required supplementary oxygen, and two non-invasive ventilation. A total of 283 (99.3%) children fully recovered and two (0.7%) died due to COVID-19. Significant risk factors for increased severity of infection in multivariable analyses were the presence of comorbidity (OR, 10.4; 95%CI, 2.8-38.7; p < 0.0001), neutropenia (OR, 10.4; 95%CI, 2.6-41.8; p = 0.001), and lymphopenia (OR, 4.2; 95%CI, 1.2-15.4; p = 0.029). A total of 30.9% (88/285) of the children received at least one dose of the inactivated COVID-19 vaccine at COVID-19 diagnosis. Compared with children who received at least one dose of the COVID-19 vaccine, fever was significantly more common in unvaccinated children (79.3% vs. 93.8%, p < 0.001). CONCLUSIONS: Children with HM are not at an increased risk of severe COVID-19 compared to the general pediatric population. However, comorbidities such as lymphopenia and neutropenia may increase the risk of developing moderate or severe/critical disease. Our data may help in management decisions for this vulnerable population.

RAB3D/MDM2/ß-catenin/c-MYC axis exacerbates the malignant behaviors of acute myeloid leukemia cells in vitro and in vivo.

RAB3D, a small Ras-like GTPase involved in regulating secretory pathway, plays a cancer-promoting role in several solid tumors. However, its role in leukemogenesis remains unknown yet. Acute myeloid leukemia (AML) is a common acute leukemia with a high mortality. Here, we found the higher expression of RAB3D in bone marrow mononuclear cells derived from AML patients (n = 54) versus healthy participants (n = 20). The following loss- and gain-of-function experiments demonstrated that RAB3D promoted growth, enhanced colony formation and accelerated G1/S transition of U937, THP-1 and KG-1 AML cells. RAB3D silencing inhibited tumorigenesis of AML cells in vivo and delayed AML cells-induced death of mice. Interestingly, the expression of RAB3D is positively correlated with that of an oncogene mouse double minute 2 (MDM2) in bone marrow mononuclear cells of AML patients (r = 0.923, p < 0.001). Intracellular MDM2 was conjugated with more ubiquitins and degraded faster when RAB3D was silenced. A commonly therapeutic target of AML, ß-catenin signaling, was activated by RAB3D overexpression, but deactivated after MDM2 was silenced. The RAB3D-induced proliferation acceleration and ß-catenin activation were abolished by MDM2 knockdown, implying that RAB3D function by stabilizing MDM2. In addition, c-MYC, a ß-catenin downstream effector, was recruited directly to the RAB3D gene promoter (-360/-349 and -136/-125 sites) and induced its transcription. Collectively, this study demonstrates that RAB3D may exacerbate the malignant behaviors of AML cells through forming a positive feedback loop with MDM2/ß-catenin/c-MYC signaling. RAB3D might be a novel target of clinical AML treatment.

[Genotypic and hematological characteristics of 83 ß-thalassemia mutation carriers and patients from Henan Province].

OBJECTIVE: To investigate the genotypic and hematological characteristics of ß-thalassemia patients and carriers from Henan Province of China. METHODS: Clinical data of the patients and carriers were collected. Results of routine blood test, hemoglobin electrophoresis and genetic testing were retrospectively analyzed. RESULTS: Of the 83 ß-thalassemia patients and carriers, there were 46 females and 37 males, and their mean age was 27.37 ± 14.71, ranging from 5 months to 83 years. A total of 13 types of ß-thalassemia alleles (86 alleles in total) were detected, with the most common three including ISV-II-654(C>T) (33.72%), CD41-42(-TTCT) (26.74%) and CD17(A>T) (18.60%). Five rare alleles, including CD8-9(+G), IVS-II-1(G>A), CD42(T>G), and start codons ATG>AGG and ATG>ACG were identified. Among these, HBB: c.128T>G(CD42T>G) was previously unreported in China. Fifteen ß-thalassemia genotypes were detected, which included 12 simple heterozygote genotypes (80 cases, 96.40%), 2 double heterozygote genotypes (2 cases, 2.40%) and 1 homozygote genotype (1 case, 1.20%). The main manifestations were mild microcytic hypochromic anemia and raised HbA2. Compared with those with a ß+/ßN genotype, carriers with a ß0/ßN genotype have lower mean corpuscular volume (MCV) and mean corpusular hemoglobin (MCH) but higher HbA2 (P<0.05). CONCLUSION: ß-thalassemia is not rare in Henan Province and its characteristics are different from those in high incidence areas, which deserves close attention. The newly discovered HBB: c.128T>G (CD42T>G) has enriched the spectrum of ß-thalassemia mutations in China. Above results will also facilitate genetic counseling and prenatal diagnosis of ß-thalassemia in Henan Province.

MicroRNA-92b acts as an oncogene by targeting PTEN/AKT in NSCLC.

MicroRNAs can act as tumour suppressors or oncogenes by regulating cellular differentiation, proliferation and apoptosis, and the dysregulation of miRNA is involved in the occurrence and development of NSCLC. Here, we provided evidence that miR-92b as an oncogene in NSCLC by targeting PTEN/AKT. We found that miR-92b was up-regulated in human NSCLC tissues and cell lines. MiR-92b knockdown suppressed the NSCLC cells proliferation and migration in both in vivo and in vitro models. Conversely, miR-92b overexpression induced an aggressive phenotype. Moreover, miR-92b-mediated regulation of NSCLC cell proliferation and migration depended on binding to PTEN mRNA, which then led to the degradation of PTEN and activation of the downstream AKT signalling pathway. Overall, this study revealed the oncogenic roles of miR-92b in NSCLC by targeting PTEN/AKT, and provided novel insights for future treatments of NSCLC patients. SIGNIFICANCE OF THE STUDY: MiR-92b was up-regulated in human NSCLC tissues and cell lines. Our study demonstrated that miR-92b as an oncogene in NSCLC by targeting PTEN/AKT in both in vivo and in vitro models and provided novel insights for future treatments of NSCLC patients.

Oridonin induces Mdm2-p60 to promote p53-mediated apoptosis and cell cycle arrest in neuroblastoma.

Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis- and cell cycle arrest-related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53-induced Mdm2 (E3 ubiquitin-protein ligase Mdm2) to generate Mdm2-p60. The generation of Mdm2-p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2-p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.

[Antitumor effect of CpG oligonucleotides on human neuroblastoma xenografts in nude mice].

BACKGROUND AND OBJECTIVE: Synthetic CpG oligodeoxynucleotides(CpG ODN) containing unmethylated CpG dinucleotide motifs, which mimic the effects of bacterial DNA, can stimulate the host's immune defense to reject cancer cells as "non-self" signal. This study was to evaluate the antitumor effect of CpG ODN against human neuroblastoma xenografts in nude mice depending on the innate immunity. METHODS: The cytotoxicity of CpG ODN on neuroblastoma SK-N-MC cells was detected by WST-1 assay in vitro. Neuroblastoma xenografts were built subcutaneously in nude mice. When palpable tumor developed, the mice were randomized into normal saline (NS), non-CpG ODN, and CpG ODN groups (each group contained six mice), and were administered every other day for two weeks. When tumor grew to 5 cm3, the mice were killed to observe tumor morphology by histology and histochemistry. RESULTS: CpG ODN had no cytotoxicity on SK-N-MC cells in vitro. Tumor volume was significantly smaller in CpG ODN group than in NS and non-CpG ODN groups at the end of the observation [(0.14+/-0.03) cm3 vs. (2.97+/-0.40) cm3 and (3.80+/-1.12) cm3, P<0.01]. On HE-stained sections, the tumor tissues of CpG ODN group showed intratumoral infiltration of inflammatory cells and large areas of necrosis, whereas those of controls showed less infiltration and no necrosis. By immunohistochemistry, the tumor tissues of CpG ODN group showed more natural killer (NK) cells and macrophages as compared with those of control groups. CONCLUSION: CpG ODN may have therapeutic effect on neuroblastoma in nude mice via mediating the activity of NK cells and macrophages.