Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells.

Sorafenib is the first line treatment for advanced hepatocellular carcinoma (HCC). We explored its impact on the proteostasis of cancer cells, i.e. the processes that regulate the synthesis, maturation and turn-over of cellular proteins. We observed that sorafenib inhibits the production of the tumour marker alpha-foetoprotein (AFP) in two different HCC cell lines, an effect that correlated with a radical inhibition of protein biosynthesis. This effect was observed at clinically relevant concentrations of sorafenib and was not related to the effect of sorafenib on the transport of amino acids across the plasma membrane or the induction of the unfolded protein response (UPR). Instead, we observed that sorafenib inhibits translation initiation and the mechanistic target of rapamycin (mTOR) signaling cascade, as shown by the analysis of phosphorylation levels of the protein 4EBP1 (eukaryotic translation initiation factor 4E binding protein 1). We explored the consequences of this inhibition in HCC cells. We observed that overall sorafenib is a weak inducer of the UPR that can paradoxically prevent the UPR induced by tunicamycin. We also found no direct synergistic anticancer effect between sorafenib and various strategies that inhibit the UPR. In agreement with the possibility that translation inhibition might be an adaptive stress response in HCC cells, we noted that it protects cancer cell from ferroptosis, a form of oxidative necrosis. Our findings point to the modulation of protein biosynthesis and mTOR signaling as being important, yet complex determinants of the response of HCC cells to sorafenib.

International Adoption of Children Surviving the Haitian Earthquake.

OBJECTIVE: To evaluate resilience and frequency of behavioral symptoms in Haitian children internationally adopted before and after the earthquake of January 12, 2010. METHODS: We conducted a retrospective quantitative study in 40 Haitian children. Families were also asked to participate in a qualitative study (individual interview at 18-24 months after the earthquake) and to complete State-Trait Anxiety Inventory (STAI) and STAI for children (STAI-C) questionnaires. RESULTS: Demographic and clinical characteristics were similar in the group who experienced the earthquake (n=22) and in the group who did not (n=18). The families of 30 adoptees were interviewed. There was no statistical difference between the two groups for the STAI (P=0.53) and STAI-C (P=0.75) or for the frequency of behavioral problems. Plenary adoption was pronounced for 84.6% and 33.3% of the children adopted in the pre- and post-earthquake group, respectively (P=0.02). Children rarely talked about the experience of the earthquake, which, by contrast, was a stressful experience for the adoptive families. CONCLUSIONS: Haitian children adopted after the earthquake did not express more stress or behavioral problems than those adopted before it. However, the possibility of a resurgence of mental disorders after age 10 should be borne in mind. (Disaster Med Public Health Preparedness. 2018;12:450-454).

Skin diseases in internationally adopted children.

Internationally adopted children often present diseases contracted in the country of origin. Skin diseases are common in new arrivals, and diagnosis may prove challenging for GPs or even dermatologists if they are inexperienced in the extensive geographic and ethnic diversity of international adoptees. To analyse the frequency and characteristics of skin diseases in international adoptees. In total, 142 adoptees were evaluated for a cross-sectional cohort study. The most frequent diseases observed at arrival were dermatological conditions. Of the adoptees, 70% presented at least one skin disease, of which 57.5% were infectious; Tinea capitis being the most frequent (n = 42). The recovery rate of Tinea capitis was 89% (n = 32/36). Ten cases of scabies were diagnosed. Other diseases included viral skin infection (n = 22), with 16 cases of Molluscum contagiosum and bacterial infection. Skin diseases are very common in internationally adopted children. There is a need for close collaboration between dermatologists and paediatricians to diagnose such infections, as well as clear guidelines to treat them.