Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids.

Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.

Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation.

Perinatal hepatic inflammation can have devastating consequences. Monocytes play an important role in the initiation and resolution of inflammation, and their diverse functions can be attributed to specific cellular subsets: pro-inflammatory or classical monocytes (Ly6cHi) and pro-reparative or non-classical monocytes (Ly6cLo). We hypothesized that inherent differences in Ly6cHi classical monocytes and Ly6cLo non-classical monocytes determine susceptibility to perinatal hepatic inflammation in late gestation fetuses and neonates. We found an anti-inflammatory transcriptional profile expressed by Ly6cLo non-classical monocytes, and a physiologic abundance of these cells in the late gestation fetal liver. Unlike neonatal pups, late gestation fetuses proved to be resistant to rhesus rotavirus (RRV) mediated liver inflammation. Furthermore, neonatal pups were rendered resistant to RRV-mediated liver injury when Ly6cLo non-classical monocytes were expanded. Pharmacologic inhibition of Ly6cLo non-classical monocytes in this setting restored susceptibility to RRV-mediated disease. These data demonstrate that Ly6cLo monocytes promote resolution of perinatal liver inflammation in the late gestation fetus, where there is a physiologic expansion of non-classical monocytes, and in the neonatal liver upon experimental expansion of these cells. Therapeutic strategies directed towards enhancing Ly6cLo non-classical monocyte function may mitigate the detrimental effects of perinatal liver inflammation.

Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt/ß-Catenin Signaling.

In the liver, Wnt/ß-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4 ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of ß-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/ß-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.

The effectiveness of electroacupuncture versus electrical heat acupuncture in the management of chronic low-back pain.

DESIGN: Forty-two (42) subjects suffering from chronic low-back pain were matched with the nature of their occupations and then randomly allocated into: (1) an electroacupuncture group (EA); (2) an electrical heat acupuncture (EH) group or; (3) a control group. INTERVENTIONS: Subjects in the EA group and the EH group received treatment for 20 minutes on a total of 6 acupuncture points. Treatment was delivered twice per week for 4 weeks (a total of 8 sessions). Back exercise was taught to all subjects including the control group as a home program. OUTCOMES MEASURES: A numerical rating scale of pain (NPRS), straight leg raise (SLR), and Roland Morris Disability Questionnaire (RMDQ) were recorded. RESULTS: There were significant reduction of NPRS within the EA (p = 0.000), EH (p = 0.000), and control (p = 0.013) groups across sessions. Significant between-group differences were shown in session 4 (p = 0.006), session 8 (p = 0.001), and 1-month follow-up sessions (p = 0.001). Posthoc tests showed that the NPRS of the EH group was significantly lower than that of the EA group and the control group by session 4 (p = 0.004). After session 8, the NPRS of both the EA group (p = 0.003) and the EH group (p = 0.001) were significantly lower than that of the control group. Such a difference was maintained at least up to the 1-month follow-up. Only the EA group had significant improvement in the measurement of SLR across sessions (p = 0.000). The between-group difference reached significance level in session 8 (p = 0.001) and at 1-month follow-up (p = 0.002). Posthoc tests showed that EA group had significantly greater gain than the EH group and the control group. For the RMDQ score, the improvement was statistically significant within each of the three groups over time (p = 0.000). However, the between-group difference did not reach statistical significance. CONCLUSIONS: Our findings suggest that 4 sessions of EH treatment over 2 weeks produced significantly greater reduction in the NPRS than that of the EA or the control. However, EA produced greater improvement in SLR and reduction in RMDQ score than that of the EH and the control.