BackgroundNanometer silicon dioxide (nano-SiO2) has a wide variety of applications in material sciences, engineering and medicine; however, the potential cell biological and proteomic effects of nano-SiO2 exposure and the toxic mechanisms remain far from clear.ResultsHere, we evaluated the effects of amorphous nano-SiO2 (15-nm, 30-nm SiO2). on cellular viability, cell cycle, apoptosis and protein expression in HaCaT cells by using biochemical and morphological analysis, two-dimensional differential gel electrophoresis (2D-DIGE) as well as mass spectrometry (MS). We found that the cellular viability of HaCaT cells was significantly decreased in a dose-dependent manner after the treatment of nano-SiO2 and micro-sized SiO2 particles. The IC50 value (50% concentration of inhibition) was associated with the size of SiO2 particles. Exposure to nano-SiO2 and micro-sized SiO2 particles also induced apoptosis in HaCaT cells in a dose-dependent manner. Furthermore, the smaller SiO2 particle size was, the higher apoptotic rate the cells underwent. The proteomic analysis revealed that 16 differentially expressed proteins were induced by SiO2 exposure, and that the expression levels of the differentially expressed proteins were associated with the particle size. The 16 proteins were identified by MALDI-TOF-TOF-MS analysis and could be classified into 5 categories according to their functions. They include oxidative stress-associated proteins; cytoskeleton-associated proteins; molecular chaperones; energy metabolism-associated proteins; apoptosis and tumor-associated proteins.ConclusionsThese results showed that nano-SiO2 exposure exerted toxic effects and altered protein expression in HaCaT cells. The data indicated the alterations of the proteins, such as the proteins associated with oxidative stress and apoptosis, could be involved in the toxic mechanisms of nano-SiO2 exposure.

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This study examined the reliability and validity of the instruments as used in the psychological autopsy method in China. With data from 130 informants on 66 completed suicides and 130 informants on 66 normal community controls and 66 controls themselves, the validity was examined by comparing the responses of informants and the responses (gold standards) of the target participants in the control group. All the tested instruments were shown to be reliable, and proxy respondents were generally good judges of targets' suicidal intention, social support, depression, life events, personality traits, and mental disorders. Additionally, interrater reliabilities of the five interviewers were very good on selected scales. This study has laid a partial foundation for future psychological autopsy projects to be held in Chinese culture.

PURPOSE Metastatic mucosal melanoma responds poorly to anti–programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone. PATIENTS AND METHODS We conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G4 monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers. RESULTS Thirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CONCLUSION The combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-naïve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care.

BackgroundJS001, a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor, blocks the interaction of PD-1 with its ligands and promotes T cell activation in preclinical studies. This phase I study is designed to evaluate the safety, tolerability, and clinical activity of JS001 in advanced melanoma or urologic cancer patients who are refractory to standard systemic therapy.Patients and methodsIn the dose escalation cohorts, subjects initially received a single-dose, intravenous infusion of JS001, and were followed for 28 days followed by multi-dose infusions every 2 weeks. In the dose expansion cohorts, subjects received multi-dose infusions every 2 weeks. Clinical response was evaluated after each 8-week treatment cycle according to RECIST v1.1 criteria.ResultsThirty-six subjects diagnosed with advanced melanoma (n = 22), urothelial cancer (UC) (n = 8), or renal cell cancer (RCC) (n = 6) were enrolled. Melanoma subjects included 14 acral and 4 mucosal subtypes. JS001 was well tolerated, and no dose-limiting toxicity was observed. By the safety data cutoff date, 100% of subjects had treatment-related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 36%. Among all 36 subjects, 1 confirmed complete response (acral melanoma), 7 confirmed partial responses (2 acral melanoma, 1 mucosal melanoma, 2 UC, and 2 RCC), and 10 stable disease were observed, for an objective response rate of 22.2% (95% CI, 10.1 to 39.2), and a disease control rate of 50.0% (95% CI, 32.9 to 67.1). Clinical responses were correlated with PD-L1 expression on tumor cells, the presence of tumor infiltrating lymphocytes (TIL), baseline tumor volume, ECOG performance status, serum LDH levels, high percentage of activated CD8+ T cells and CD3− CD16+ CD54+ NK cells in the peripheral blood as well as tumor mutational burden (TMB).ConclusionJS001 was well tolerated and demonstrated promising anti-tumor activity in UC and RCC as well as in previously underexplored acral and mucosal melanoma subtypes. Subjects with an immune-active profile in the tumor microenvironment or in peripheral blood responded favorably to JS001 treatment. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on acral and mucosal melanoma subtypes, representative of the regional disease epidemiology.Trial registrationClinical Trial ID: NCT02836795, registered July 19, 2016, retrospectively registered.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0693-2) contains supplementary material, which is available to authorized users.

The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.

Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population. A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival. The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors ( = 0.007, other < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all < 0.001), whereas in mucosal melanoma, only C-KIT was ( = 0.006). Although correlated with BRAF mutations ( = 0.001 and < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival ( = 0.406 and 0.256, respectively). The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. .

Background and Purpose— High rates of ischemic stroke and poor adherence to secondary prevention measures are observed in the Chinese population. Methods— We used a national, multicenter, cluster-randomized controlled trial in which 47 hospitals were randomized to either a structured care program group (n=23) or a usual care group (n=24). The structured care program consisted of a specialist-administered, guideline-recommended pharmaceutical treatment and a lifestyle modification algorithm associated with written and Internet-accessed educational material for patients for the secondary prevention of ischemic stroke. The primary efficacy outcome was the proportion of patients who adhered to the recommended measures at 12-month postdischarge. This trial is registered with ClinicalTrial.gov (NCT00664846). Results— At 12 months, 1287 (72.1%) patients in the Standard Medical Management in Secondary Prevention of Ischemic Stroke in China (SMART) group and 1430 (72%) patients in the usual care group had completed the 12-month follow-up ( P =0.342). Compared with the usual care group, those in the SMART group showed higher adherence to statins (56% versus 33%; P =0.006) but no difference in adherence to antiplatelet (81% versus 75%; P =0.088), antihypertensive (67% versus 69%; P =0.661), or diabetes mellitus drugs (73% versus 67%; P =0.297). No significant difference in the composite end point (new-onset ischemic stroke, hemorrhagic stroke, acute coronary syndrome, and all-cause death) was observed (3.56% versus 3.59%; P =0.921). Conclusions— The implementation of a program to improve adherence to secondary ischemic stroke prevention efforts in China is feasible, but these programs had only a limited impact on adherence and no impact on 1-year outcomes. Further development of a structured program to reduce vascular events after stroke is needed. Clinical Trial Registration—URL: http://www.clinicaltrials.gov . Unique identifier: NCT00664846.