Programmed death ligand 1 (PD-L1) is an immune checkpoint protein, however, emerging data suggest that tumor cell PD-L1 may regulate immune-independent and intrinsic cellular functions. We demonstrate regulation of PD-L1 by oncogenic BRAF V600E and investigated its ability to influence apoptotic susceptibility in colorectal cancer (CRC) cells. Endogenous or exogenous mutant vs wild-type BRAF were shown to increase PD-L1 mRNA and protein expression that was attenuated by MEK inhibition or c-JUN and YAP knockdown. Deletion of PD-L1 reduced tumor cell growth in vitro and in vivo. Loss of PD-L1 was also shown to attenuate DNA damage and apoptosis induced by diverse anti-cancer drugs that could be reversed by restoration of wild-type PD-L1, but not mutants with deletion of its extra-or intra-cellular domain. The effect of PD-L1 on chemosensitivity was confirmed in MC38 murine tumor xenografts generated from PD-L1 knockout vs parental cells. Deletion of PD-L1 suppressed BH3-only BIM and BIK proteins that could be restored by re-expression of PD-L1; re-introduction of BIM enhanced apoptosis. PD-L1 expression was significantly increased in BRAF V600E human colon cancers, and patients whose tumors had high vs low PD-L1 had significantly better survival. In summary, BRAF V600E can transcriptionally up-regulate PD-L1 expression that was shown to induce BIM and BIK to enhance chemotherapy-induced apoptosis. These data indicate an intrinsic, non-immune function of PD-L1, and suggest the potential for PD-L1 as a predictive biomarker. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

BackgroundWe wished to evaluate the impact of S-1 combined with oxaliplatin (SOX regimen) as neoadjuvant chemotherapy on surgical outcomes after gastrectomy with D2 lymphadenectomy.MethodsFrom February 2012 to September 2013, 170 patients with American Joint Committee on Cancer (AJCC) stage II–III gastric cancer were assessed retrospectively. Eighty patients underwent neoadjuvant chemotherapy before radical gastrectomy, and 90 patients received surgical treatment with adjuvant chemotherapy. Patients received S-1 (80 mg/m2/day; days 1–14) and oxaliplatin (130 mg/m2; day 1) as neoadjuvant or adjuvant chemotherapy, and this schedule was repeated every 3 weeks. Gastrectomy with D2 lymphadenectomy was standard therapy for each patient. Surgical outcomes between the two groups were analyzed statistically.ResultsThere was no significant difference in the total prevalence of complications between neoadjuvant and adjuvant groups (18.8% vs. 22.2%, P = 0.704). The most common postoperative complications were surgical site infection (6.5%) and gastrointestinal motility disorders (3.5%). The clinical response rate was 68.8%, and ten patients (12.5%) had a pathological complete response after neoadjuvant chemotherapy. The SOX regimen as neoadjuvant chemotherapy for AJCC stage II/III gastric cancer can be effective without increasing the risk of postoperative complications.ConclusionsThe SOX regimen could be a neoadjuvant chemotherapy for advanced gastric cancer worldwide in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s12957-015-0444-6) contains supplementary material, which is available to authorized users.

Zebrafish (Danio rerio) possess a great promise in evaluating the toxicity of nanoparticles (NPs). The commonly used method on zebrafish was to calculate mortality and 5 or 6 days postfertilization (dpf) toxicity scores. However, this method could only reveal a general toxic level. To further distinguish the toxicity of NPs in the same general level, a more systematic and sensitive approach needs to be put forward. In this work, we describe a progressive approach toward the evaluation of the toxicity of MSRMs NPs we synthesized. This approach contained traditional and newly created methods. The results from traditional methods such as calculating mortality, recording 6 dpf toxicity scores and malformation types of zebrafish revealed a general low toxic level of MSRMs. Then the newly created method was conducted. By using scoring spectra of early developmental stages such as 2 or 3 dpf, we compared the malformation speeds of zebrafish exposed to different concentrations of MSRMs during the time 1 to 6 dpf. The results allowed more sensitive assessments of the toxicity of MSRMs.