Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.

Desensitization by different strategies of epidermal growth factor receptor and ErbB4.

Four transmembrane tyrosine kinases constitute the ErbB protein family: epidermal growth factor receptor (EGFR) or ErbB1, ErbB2, ErbB3, and ErbB4. In general, the structure and mechanism of the activation of these members are similar. However, significant differences in homologous desensitization are known between EGFR and ErbB4. Desensitization of ligand-occupied EGFR occurs by endocytosis, while that of ErbB4 occurs by selective cleavage at the cell surface. Because ErbB4 is abundantly expressed in neurons from fetal to adult brains, elucidation of the desensitization mechanism is important to understand neuronal development and synaptic functions. Recently, it has become clear that heterologous desensitization of EGFR and ErbB4 are induced by endocytosis and cleavage, respectively, similar to homologous desensitization. It has been reported that heterologous desensitization of EGFR is induced by serine phosphorylation of EGFR via the p38 mitogen-activated protein kinase (p38 MAP kinase) pathway in various cell lines, including alveolar epithelial cells. In contrast, the protein kinase C pathway is involved in ErbB4 cleavage. In this review, we will describe recent advances in the desensitization mechanisms of EGFR and ErbB4, mainly in alveolar epithelial cells and hypothalamic neurons, respectively.

[Cyanamide-ethanol reaction induced shock: report of a case and literature review].

Cyanamide is a known alcohol deterrent, and it may cause severe cyanamide-ethanol reaction if a patient consumes high amounts of alcohol during treatment. We report a rare case of cyanamide-ethanol reaction-induced shock in a 73-year-old man who was taking cyanamide for the treatment of alcohol dependence. The patient complained of acute onset of dyspnea after drinking. On arrival, he was in a state of shock. We immediately started hydration and administered 0.3 mg adrenaline by intramuscular injection. However, the patient's general condition did not improve. We could rescue him only after a high dose of adrenaline was administered by continuous intravascular injection. In general, in the treatment of cyanamide-ethanol reaction-induced shock, adrenaline or noradrenaline should be used instead of dopamine. Some cases of severe cyanamide-ethanol reactions have been recently reported in Japan. We performed a literature review and have discussed these cases in the text.

Vascular hyperpermeability in pulmonary decompression illness: 'the chokes'.

Decompression illness (DCI) develops during or after diving. Pulmonary decompression illness ('Chokes') is rarely seen because the affected individual usually dies in the water. We encountered a rare and interesting case. A 60-year-old man complained of leg pain after diving. Despite rapid transfer to a nearby hospital, advanced respiratory failure and shock had set in. He was then transferred to our hospital for hyperbaric oxygen therapy (HBOT). On account of his poor general condition, we initially treated him in the intensive care unit without HBOT, where he showed extreme hyperpermeability and a high level of serum procalcitonin (PCT; 20.24 ng/mL). Despite large-volume fluid therapy, severe intravascular dehydration and shock status remained. We assume that the injured endothelial cells induced vascular hyperpermeability and increased levels of inflammatory cytokines leading to the high serum PCT level. PCT might be a useful stress marker of endothelial damage and severity in DCI, including Chokes.

Impact of sorafenib on health-related quality of life in Japanese patients with metastatic renal cell carcinoma: a prospective evaluation.

OBJECTIVE: To characterize the impact of sorafenib treatment on health-related quality of life (HRQL) in Japanese patients with mRCC. PATIENTS AND METHODS: We performed a prospective observational study including 85 consecutive patients undergoing radical nephrectomy who were diagnosed as having mRCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 3 months. HRQL in these patients was assessed using the Medical Outcomes Study 36-Item Short Form (SF-36). RESULTS: Before treatment all eight scores in the 85 patients were significantly inferior to those in the age-matched control population in Japan. Three months after sorafenib treatment, one score (mental health) in the 85 patients was significantly higher than what it was before treatment. Three scores (body pain, role limitations because of emotional problems, mental health) in patients who had some degree of tumour shrinkage were significantly better than those in the remaining patients, while there were no significant differences in all but one score (social function) between patients with and without severe AEs. Furthermore, there were no significant differences in any scores 3, 6 and 12 months after sorafenib treatment in 26 patients who could be followed for at least 12 months. CONCLUSIONS: Despite non-randomized study including a comparatively small number of patients, the findings of the present study suggest that sorafenib treatment may not impair HRQL in patients with mRCC, and HRQL in patients receiving sorafenib is likely to be affected by the efficacy rather than AEs during treatment.