Follow-up outcome analysis of 324 cases of early-onset and late-onset mild fetal ventriculomegaly: a retrospective cohort study.

BACKGROUND: Mild fetal ventriculomegaly (VM) is a nonspecific finding common to several pathologies with varying prognosis and is, therefore, a challenge in fetal consultation. We aimed to perform a constant, detailed analysis of prenatal findings and postnatal outcomes in fetuses with early-onset and late-onset mild ventriculomegaly, and provide a new evidence basis and new perspective for prenatal counseling. METHODS: This is a retrospective cohort study of women with a diagnosis of mild fetal VM between January 2018 and October 2020. The population was divided into two groups according to the gestational ages (GAs) at initial diagnosis: the early-onset group (diagnosed at/before 24+6 weeks) and the late-onset group (diagnosed after 24+6 weeks). Clinical data and pregnancy outcomes were obtained from hospital records. The children's neurodevelopment status was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3) and telephone interviews. RESULTS: Our study cohort comprised 324 fetuses, out of which 94 (29%) were classified as early-onset group and 230 (71%) late-onset group. Early-onset group was more likely to have concurrent additional abnormalities, whereas in the late-onset group, isolated enlargement was more common (P = 0.01). Unilateral enlargement was more common in the late-onset group (P = 0.05), and symmetrical enlargement in the early-onset group (P < 0.01). In addition, early-onset mild VM cases were more likely to have intrauterine progression (P = 0.03), and many had a higher proportion of complex multisystem abnormalities. Compared with the late-onset group, the early-onset group was more often associated with congenital brain structure malformations. Approximately 11% of fetuses with mild VM had postnatal neurodevelopmental delay/disorders, and the risk was higher in the early-onset group (19.4% vs. 7.4%). Regression analysis showed that the GA at first diagnosis, non-isolated, and intrauterine progression significantly correlated with neurodevelopmental abnormalities. CONCLUSIONS: Early-onset and late-onset mild VM had significantly different ultrasound features and outcomes. Early-onset mild VM may have more complex potential abnormalities and are more likely to predict poor prognosis than the late-onset.

Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase.

Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl2 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl2 downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl2 enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS-STING signaling pathway. When inhibiting the cGAS-STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl2-induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl2. Mechanistically, these results revealed that Manganese treatment-activated cGAS-STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.

Salmonella infection leads to severe intestinal inflammation and increased CD4+FoxP3+ Treg cells in streptozotocin­induced hyperglycemic mice.

Hyperglycemia promotes the growth and reproduction of bacteria, thereby increasing the probability of infection, which also causes rebound hyperglycemia. Therefore, the interactions of infection and hyperglycemia lead to the progression and deterioration of these diseases. Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Studies have shown that regulatory T cells (Tregs) play a key role in maintaining islet­specific tolerance. Treg deficiency may lead to the development of early pancreatitis and T1DM, and sufficient amounts of Tregs can restore this tolerance, thereby inhibiting the occurrence of T1DM. Moreover, different subpopulations of dendritic cells (DCs) play an important role in activating autoreactive T cells and inducing autoimmune tolerance to autoantigens, which are closely related to the functional diversity caused by different phenotypes, maturation status, and the immune microenvironment of DC subpopulations. In the present study, we used streptozotocin­induced hyperglycemic mice to model T1DM and induced a Salmonella infection in the mouse model, leading to aggravated inflammation, which resulted in an elevated proportion of CD103+CD11b+ DCs and a significantly elevated proportion of CD4+FoxP3+ Tregs in the intestinal lamina propria. After co­culturing CD4+ T cells and DCs, we found that CD103+CD11b+ DCs could significantly promote the proliferation of CD4+ T cells. The elevated proportions of CD4+FoxP3+ Tregs were considered to be correlated with the increased number of CD103+CD11b+ DCs.