p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

This study shows that ICG fluorescence imaging allows highly sensitive image-guided intraoperative SN mapping in cases of gastric cancer. Our data suggest that SN mapping guided by ICG fluorescence imaging might be useful for predicting the metastatic status in lymph nodes in cases of gastric cancer, especially those with cT1-stage cancer.

We demonstrated here that near-infrared fluorescence imaging system is a novel and reliable intraoperative technique to identify hepatic segment and subsegment for anatomical hepatic resection.

Background Preoperative imaging is widely used and extremely helpful in hepatobiliary surgery. However, transfer of preoperative data to a intraoperative situation is very difficult. Surgeons need intraoperative anatomical information using imaging data for safe and precise operation in the field of hepatobiliary surgery. We have developed a new system for mapping liver segments and cholangiograms using intraoperative indocyanine green (ICG) fluorescence under infrared light observation. Method The imaging technique for mapping liver segments and cholangiogram based on ICG fluorescence used an infrared-based navigation system. Eighty one patients with liver tumors underwent hepatectomy from 2006, January to 2009, March. In liver surgery, 1 ml of ICG was injected via the portal vein under observation by the fluorescent imaging system. Fourteen patients were underwent laparoscopic cholecystectomy for chronic cholecystitis with gallstones. In laparoscopic cholecystectomy, 5 ml of ICG was administered intravenously just before operation and the bile duct was observed using the infrared-based navigation system. Result This new technique successfully identified stained subsegments and segments of the liver in 73 of 81 patients (90.1%). Moreover, clear mapping of liver segments was obtained even against a background of liver cirrhosis. Fluorescent cholangiography clearly showed the common bile duct and cystic duct in 10 of 14 patients (71.4%). No adverse reactions to the ICG were encountered. Conclusion Application of this technique allows intraoperative identification of anatomical landmark in hepatobiliary surgery.

al cooperation between LPA4 and LPA6 is essential for embryonic development. Since Lpa4;Lpa5-DKO and Lpa5;Lpa6-DKO mice were born at the expected Mendelian ratios and had no obvious abnormalities (Supplemental Tables 4 and 5), LPA5 is unlikely to be involved in embryonic development. To examine the roles of LPA4 and LPA6 in embryonic development, yolk sac and embryo proper were observed at various stages of gestation. At E8.5, both Lpa4;Lpa6-DKO yolk sac and embryo proper appeared normal (Supplemental Figure 1, A and B). However, at E9.5-10.5, almost all of Lpa4;Lpa6-DKO embryos proper had various morphological abnormalities, such as severe pericardial effusion (Figure 1A and Supplemental Figure 1, B-D), axial turning abnormality (Supplemental Figure 1, B, E, and F), and developmental delay (Figure 1, A and B, and Supplemental Figure 1, B, G, and H). DKO yolk sacs lacked large blood vessels at E9.5-10.5, whereas WT yolk sacs had well-developed blood vessels (Figure 1B and Supplemental Figure 1, A, I, and J). We observed that all DKO embryos died by E11.5 (Supplemental Figure 1, B, K, and L, and Supplemental Table 6). Histological analysis showed that the endoderm and mesoderm of the yolk sacs were more widely separated in the DKO tissue (Figure 1C). Despite this vascular defect, erythrocytes were present in Lpa4;Lpa6-DKO yolk sacs (Figure 1C). Blood vessel-stained whole-mount embryos at E10.5 revealed that DKO embryos had enlarged dorsal aortae and poor vascular networks in the head and intersomitic regions, compared with WT embryos (Figure 1D). Furthermore, blood vessel-stained cross sections of embryos at E9.5 also revealed that DKO embryos had enlarged dorsal aortae and thinned neural tubes, compared with WT embryos (Figure 1E). These results strongly suggest that both LPA4 and LPA6 are indispensable for embryonic angiogenesis. Endothelial LPA4 and LPA6 are involved in retinal angiogenesis. Previously, we detected mRNA expression of Lpa4 and LPA6 in vascular ECs (8, 16). To investigate the functional roles of endothelial LPA4 and LPA6, we generated a tamoxifen-inducible and EC-specific Lpa4/Lpa6 deletion mouse line by crossing Lpa4;Lpa6 double-floxed mutants with transgenic mice carrying Cdh5-CreER T2 (ref. 37, Figure 2A, and Supplemental Figure 2A). The resulting Lpa4 fl/fl(Y) Lpa6 fl/fl Cdh5-CreER T2 mice (termed hereafter Lpa4; Lpa6 iΔEC) were treated with tamoxifen from P1 to P3. Allele-specific PCR confirmed recombination of both floxed alleles in the tails of Lpa4;Lpa6 iΔEC mice at P5 (Supplemental Figure 2B). At P5, we found that the radial expansion, EC area, and retinal blood vessel branching were significantly reduced in Lpa4;Lpa6 iΔEC mice compared with those in control CreER T2-negative Lpa4 fl/fl(Y) ;Lpa6 fl/fl littermates (Figure 2, C and F-H). At the angiogenic front, sprouts of retinal vessels were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, D and I). Additionally, both the number and length of sprouting filopodia were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, E, J...