Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer.

The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity-evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.

Early hyperbaric oxygen therapy improves survival in a model of severe sepsis.

Sepsis is a major clinical challenge, with therapy limited to supportive interventions. Therefore, the search for novel remedial approaches is of great importance. We addressed whether hyperbaric oxygen therapy (HBOT) could improve the outcome of sepsis using an acute experimental mouse model. Sepsis was induced in male CD-1 mice by cecal ligation and puncture (CLP) tailored to result in 80-90% mortality within 72 h of the insult. After CLP, mice were randomized into two groups receiving HBOT or not at different times after the initial insult or subjected to multiple HBOT treatments. HBOT conditions were 98% oxygen pressurized to 2.4 atmospheres for 1 h. HBOT within 1 h after CLP resulted in 52% survival in comparison with mice that did not receive the treatment (13% survival). Multiple HBOT at 1 and 6 h or 1, 6, and 21 h displayed an increase in survival of >50%, but they were not significantly different from a single treatment after 1 h of CLP. Treatments at 6 or 21 h after CLP, excluding the 1 h of treatment, did not show any protective effect. Early HBO treatment did not modify bacterial counts after CLP, but it was associated with decreased expression of TNF-α, IL-6, and IL-10 expression in the liver within 3 h after CLP. The decrease of cytokine expression was reproduced in cultured macrophages after exposure to HBOT. Early HBOT could be of benefit in the treatment of sepsis, and the protective mechanism may be related to a reduction in the systemic inflammatory response.

The Contribution of the Omentum to the Outcome From Sepsis: An Experimental Animal Study.

The omentum is a large mesenchymal fibro-fatty tissue with remarkable healing capability. It is also rich in immune cells, including macrophages and lymphocytes, within particular structures named milky spots. Clinical observations indicate a high incidence of peritonitis after the removal of the omentum suggesting that it may play a role in sepsis. To test this possibility, male CD-1 mice underwent simultaneous omentectomy and cecal ligation and puncture (CLP), omentectomy-sham operation and CLP alone, and mortality was documented within 72 h post the insults. A significant increase in mortality was observed in mice subjected to omentectomy and CLP in comparison with CLP alone. Mortality was correlated with an increase in cytokine gene expression within the lung after omentectomy and CLP as opposed to CLP alone. However, no differences in bacterial load were observed within the peritoneum or blood between groups. To test the long-term effect of omentectomy, mice were subjected to omentum removal or sham operation, allowed to recover from surgery for 14 or 28 days, and then both were subjected to CLP. In these cases, no differences in mortality were observed between the groups suggesting that the lack of omentum triggers a compensatory mechanism. Finally, omentectomy and sham operation altered the composition of peritoneal immune cells with the disappearance of F4/80 macrophages and the appearance of a new population of F4/80 macrophages within 1 or 14 days post-surgery. The F4/80 positive cells reappeared after 28 days following the procedures. All of these observations suggest that the omentum plays an early role in the outcome from sepsis.

Why Antibiotic Treatment Is Not Enough for Sepsis Resolution: an Evaluation in an Experimental Animal Model.

Sepsis remains a major health problem at the levels of mortality, morbidity, and economic burden to the health care system, a condition that is aggravated by the development of secondary conditions such as septic shock and multiple-organ failure. Our current understanding of the etiology of human sepsis has advanced, at least in part, due to the use of experimental animal models, particularly the model of cecum ligation and puncture (CLP). Antibiotic treatment has been commonly used in this model to closely mirror the treatment of human septic patients. However, whether their use may obscure the elucidation of the cellular and molecular mechanisms involved in the septic response is questionable. The objective of the present study was to determine the effect of antibiotic treatment in the outcome of a fulminant model of CLP. Various dosing strategies were used for the administration of imipenem, which has broad-spectrum coverage of enteric bacteria. No statistically significant differences in the survival of mice were observed between the different antibiotic dosing strategies and no treatment, suggesting that live bacteria may not be the only factor inducing septic shock. To further investigate this hypothesis, mice were challenged with sterilized or unsterilized cecal contents. We found that exposure of mice to sterilized cecal contents also resulted in a high mortality rate. Therefore, it is possible that bacterial debris, apart from bacterial proliferation, triggers a septic response and contributes to mortality in this model, suggesting that additional factors are involved in the development of septic shock.

Diffusion tensor imaging in lissencephaly.

Lissencephaly is a rare brain malformation characterized histologically by arrested neuronal migration such that the brain resembles that of a fetus before 23-24 weeks gestation. We studied a neonate with lissencephaly by using diffusion tensor imaging and suggest the dysplastic densely cellular layer IV is visible as a band of anisotropic diffusion. Fiber tracking showed lack of connectivity between the cortex and deep white matter and an abnormal limbic system.

Cerebral MR venography in children: comparison of 2D time-of-flight and gadolinium-enhanced 3D gradient-echo techniques.

PURPOSE: To prospectively compare two-dimensional (2D) time-of-flight cerebral magnetic resonance (MR) venography with gadolinium-enhanced three-dimensional (3D) gradient-echo cerebral MR venography in children. MATERIALS AND METHODS: This investigation had investigational review board approval and was Health Insurance Portability and Accountability Act compliant; parental informed consent was obtained. Thirty-seven patients (20 boys, 17 girls) who ranged in age from 4 days to 15 years underwent 2D and 3D MR venography. Two pediatric neuroradiologists compared the visibility of the superior sagittal, straight, transverse, and sigmoid sinuses and the internal jugular veins on images obtained with the two sequences. RESULTS: In 17 (46%) of the 37 patients, the sequences were equivalent in terms of their depiction of venous anatomy. In 19 (51%) of the 37 patients, 3D MR venography was superior to 2D MR venography. Suboptimal enhancement of veins occurred in one (3%) patient at 3D MR venography. Venous anomalies suggested at 2D MR venography but not present at 3D MR venography included flow gaps in the nondominant transverse sinuses of four patients, unilateral transverse sinus atresia in eight, and a narrowed superior sagittal sinus in two. Two-dimensional MR venography results failed to reveal a persistent falcine sinus associated with straight sinus atresia in one patient and suggested transverse sinus thrombosis in two patients in whom 3D MR venography results were normal. Additionally, the extent of dural thrombosis was overestimated at 2D MR venography in one patient. As compared with 3D MR venography, 2D MR venography failed to reveal sigmoid sinus stenosis in one patient and poorly depicted posterior fossa dural sinus anatomy in two patients with dural arteriovenous fistula. CONCLUSION: Three-dimensional MR venography is often superior to 2D MR venography in the delineation of major cerebral venous structures in children. Most of the artifactual loss of vascular signal seen with the use of 2D MR venography occurred in nondominant transverse sinuses.