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Background Genetic aberrations in the cyclin-dependent kinase (CDK)4 pathway occur in 82% of patients with acral melanoma (AM), which is the predominant subtype of melanoma in China. We aimed to evaluate the anti-tumour activity of palbociclib, a selective CDK4/6 inhibitor, in patients with advanced AM with CDK4 pathway gene aberrations. Methods In this phase II trial, patients with advanced AM with CDK4 or/and CCND1 gain or/and CDKN2A loss were treated with oral palbociclib (125 mg) on days 1–21 of a 28-day cycle. The primary end-point was overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Whole-exome sequencing and multiplex immunohistochemistry of the available formalin-fixed, paraffin-embedded samples of nine patients were analysed to explore the predictive biomarkers of palbociclib response. Results Fifteen patients were enrolled. Three (20.0%) patients achieved tumour shrinkage at 8 weeks, including one with confirmed partial response. At data cut-off date, treatment was ongoing for one patient. The median PFS was 2.2 mo (range: 1.5–13.3 mo; 95% confidence interval [CI]: 1.9–2.5), and the median OS was 9.5 mo (range: 2.6–14.1 mo, 95% CI: 5.7–13.4). Eight patients died due to disease progression. The most common TRAEs were leukopenia (87%; Grade III/IV, 27%), neutropenia (80%; grade III/IV, 27%), and fatigue (53%; grade III/IV, 7%). Significant JAK2 deletions and SH2B3 amplifications were observed in patients who did not achieve any clinical benefit (CB) with palbociclib treatment. MCM7 amplification or protein expression level was found to be associated with CB. Conclusions Palbociclib monotherapy demonstrated preliminary efficacy and an acceptable safety profile in advanced AM patients with CDK4 pathway aberrations. Patients with amplification or high protein levels of MCM7 were more prone to benefit from palbociclib. The JAK-STAT pathway might play a role in the mechanism of action of palbociclib in AM. Trial registration number NCT03454919 . The date of registration March 6, 2018.

PURPOSE Mucosal melanoma (MM) is a highly vascularized tumor with an extremely poor prognosis. In this randomized, open-label, phase II study, we characterized the efficacy and safety of bevacizumab in combination with carboplatin plus paclitaxel (CPB) in patients with previously untreated advanced MM. PATIENTS AND METHODS Patients were randomly assigned in a 2:1 ratio to receive carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2) once every 4 weeks in combination with (CPB arm, 5 mg/kg) or without (CP arm) bevacizumab once every 2 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS), objective response rate, and adverse events. RESULTS We recruited 114 patients to our study. The median PFS was significantly longer in the CPB arm (4.8 months; 95% CI, 3.6 to 6.0 months) than in the CP arm (3.0 months; 95% CI, 1.7 to 4.3 months) (hazard ratio, 0.461; 95% CI, 0.306 to 0.695; P < .001). Objective response rates were 19.7% and 13.2%, respectively ( P = .384). The median OS was also significantly longer in the CPB arm than in the CP arm (13.6 v 9.0 months; hazard ratio, 0.611; 95% CI, 0.407 to 0.917; P = .017). No new safety signals were observed. CONCLUSION PFS and OS were significantly better in patients with metastatic MM who received bevacizumab in addition to CPB than in those who received CPB alone. A phase III study should be performed to confirm these benefits (ClinicalTrials.gov identifier: NCT02023710 ).

Background The clinicopathological and survival profiles across primary sites in acral melanoma (AM) are still controversial and unclear. Methods This is a multi-center retrospective study. Clinicopathological data of AM patients diagnosed between 1 January 2000 and 31 December 2017 from 6 large tertiary hospitals in China were extracted. Chi square tests were used to compare basic characteristics between primary sites of sole, palm and nail bed. Melanoma-specific survival (MSS) differences based on primary sites were compared by log-rank tests and multivariate Cox regressions were used to identify prognostic factors for MSS. Results In total, 1157 AM patients were included. The sole group had a more advanced initial stage, deeper Breslow thickness, higher recurrence rate and distant metastases risk (all P P = 0.0102). The median MSS of sole, nail bed and palm patients were 65.0 months, 112.0 months, and not reached, respectively (log-rank P = 0.0053). In multivariate analyses, primary site, initial stage, ulceration and recurrence were the prognostic factors for MSS in overall population, but the statistical significance varied over primary sites. Conclusions Substantial clinicopathological and survival heterogeneities exist across different primary sites in the AM population. Sole melanoma has worse prognosis compared with palm and nail bed subtypes.

Purpose: China has much lower 5-year survival rates among melanoma patients than Western countries. This retrospective study describes real-world clinical outcomes and prognostic factors in locally advanced/metastatic melanoma in China. Materials and methods: Adults patients with unresectable stage III or IV melanoma treated between January 1, 2014 and December 31, 2015, at the Beijing Cancer Hospital were eligible (data cutoff: December 31, 2017). The Kaplan-Meier method and Log-Rank test were used to estimate the median value of time-to-event outcomes. A Cox proportional hazards model was simulated to evaluate associations of patients’ characteristics with survival. Results: Overall, there were 221 and 116 Chinese locally advanced and/or metastatic melanoma patients were enrolled in the first line (1L) and the second line (2L) treatments, respectively. The real-world objective response rate was Conclusion: The current clinical outcomes in advanced melanoma patients in China are poor. High ECOG performance score independently increase risk of death both from 1L and 2L treatments, suggesting a high unmet medical need for immunotherapy in advanced melanoma.

Objective: To describe the frequency and spectrum of treatment-related adverse events (TRAEs) of immunotherapy combined with antiangiogenic therapy in patients with melanoma.Methods: This retrospective cohort study included three clinical trials on patients with stage III/IV melanoma treated with anti–PD 1 and antiangiogenic therapy.Results: We analyzed data from 72 patients with a median follow-up time of 25.9 months (95% CI, 9.1–42.7 m). The median treatment duration was 7.5 months (range, 0.7–42.8 m), and the median of treatment cycles was 11.0 (range, 1–90). Most patients (70 of 72 or 97.2%) experienced TRAEs (mostly grades 1 or 2). No drug-related deaths were reported. Most TRAEs were hepatic (75%), endocrine (72.2%), skin (65.3%), and gastrointestinal tract (59.7%) manifestations, followed by myelosuppression (55.6%), renal dysfunction (55.6%), and dyslipidaemia (54.2%). The adverse event (AE) spectra were similar between regimens. Using multivariate Cox proportional risk models showed that hypertension was associated with a long PFS. According to our multivariable logistic regression models, TRAEs were not associated with ORR.Conclusion: We found that the prevalence of AEs was higher than that of anti–PD-1 monotherapy. Most of the AEs were mild. The AE spectra were similar to those seen after anti–PD-1 or antiangiogenic therapy monotherapy, without unexpected AEs. Immunotherapy combined with antiangiogenic therapy was well tolerated.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03955354.

Background: Exosomes in cardiovascular diseases (CVDs) have become an active research field with substantial value and potential. Nevertheless, there are few bibliometric studies in this field. We aimed to visualize the research hotspots and trends of exosomes in CVDs using a bibliometric analysis to help understand the future development of basic and clinical research.Methods: The articles and reviews regarding exosomes in the CVDs were culled from the Web of Science Core Collection, and knowledge maps were generated using CiteSpace and VOSviewer software.Results: A total of 1,039 articles were included. The number of exosome articles in the CVDs increased yearly. These publications came from 60 countries/regions, led by the US and China. The primary research institutions were Shanghai Jiao Tong University and Nanjing Medical University. Circulation Research was the journal and co-cited journal with the most studies. We identified 473 authors among which Lucio Barile had the most significant number of articles and Thery C was co-cited most often. After analysis, the most common keywords are myocardium infarction, microRNA and mesenchymal stem cells. Ischemic heart disease, pathogenesis, regeneration, stem cells, targeted therapy, biomarkers, cardiac protection, and others are current and developing areas of study.Conclusion: We identified the research hotspots and trends of exosomes in CVDs using bibliometric and visual methods. Research on exosomes is flourishing in the cardiovascular medicine. Regenerative medicine, exosome engineering, delivery vehicles, and biomarkers will likely become the focus of future research.

ObjectivesTo examine the long-term survival outcome of dabrafenib in combination with trametinib in Chinese patients with unresectable or metastatic acral/cutaneous melanoma with BRAF-V600 mutation and to explore potential predictors of effectiveness.MethodsThis was a long-term follow-up of Chinese patients with unresectable or metastatic BRAF V600-mutant acral/cutaneous melanoma administered dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) in an open-label, multicenter, single-arm, phase IIa study (NCT02083354). Efficacy endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The impacts of baseline characteristics on PFS and OS were analyzed.ResultsA total of sixty patients were included. The median age was 48 years, and 24 patients (40.0%) were male. Totally 12 individuals (20.0%) had acral melanoma, and 45 (75.0%) had failed previous systemic therapy. Up to July 2020, the median duration of follow-up was 37.0 (95% confidence interval [CI] 29.1-44.9) months. The updated ORR was 71.7% (95%CI 60.3%-83.1%). The 3-year OS rate was 28.8% (95%CI 19.1-43.6%) in the overall population, and 35.7% (95%CI 15.5–82.4%) in acral melanoma patients. The median DOR was 7.5 months (95%CI 4.5 to 10.5). Baseline normal lactic dehydrogenase (LDH), metastatic organ sitesConclusionDabrafenib combined with trametinib confer long-term survival in Chinese patients with BRAF V600-mutant, unresectable or metastatic acral/cutaneous melanoma.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02083354, identifier NCT02083354.

BackgroundAnti-PD-1 monotherapy is the standard therapy for advanced melanoma patients, including those with NRAS mutations. The influence of NRAS mutation on immunotherapy, especially in noncutaneous melanoma, is largely uncharacterized.Materials and MethodsWe analyzed clinical data of four clinical trials for advanced melanoma patients treated with anti-PD-1 monotherapy between 2016 and 2019. The impact of NRAS mutation on efficacy and outcome of immunotherapy were analyzed in cutaneous and noncutaneous groups separately.ResultsA total of 206 patients were assessed, including 92 cutaneous melanoma patients with 12 NRAS mutations and 114 noncutaneous melanoma patients with 21 NRAS mutations. In cutaneous melanoma, the response rates of NRAS mutant patients were lower than patients without NRAS mutations (9.5% vs. 23.9%), the median progression-free survival (PFS) and median overall survival (OS) were shorter for patients with NRAS mutations, although without significant difference for OS (P=0.081). In noncutaneous melanoma, the response rates were 0 and 13.7% for NRAS mutant and wild-type patients, the median PFS were 3.6 months (95% CI: 0.9-6.3) and 4.3 months (95%CI: 2.9-5.7) (P=0.015), and the median OS were 10.8 months (95% CI: 1.5-20.1) and 15.3 months (95% CI: 13.2-17.4) (P=0.025), respectively. In multivariate analysis, NRAS mutation, along with ECOG performance score and LDH level, was negatively associated with both PFS (HR 1.912, P=0.044) and OS (HR 2.210, P=0.025) in noncutaneous melanoma.ConclusionIn advanced Asian melanoma treated with anti-PD-1 monotherapy, NRAS mutant patients had lower response rates and poorer prognoses compared to wild-type patients, especially in noncutaneous subtypes.

In this contribution, we investigate why different dopant species and back-contact architectures lead to different sub-bandgap behaviors in CdSeTe solar cells. Through extraction of the absorptance from photoluminescence spectra, we parse the contributions from material properties and from cell optics. We show that, as expected, arsenic doping leads to an increase in sub-bandgap features over traditional copper doping, and that this is a material property of arsenic-doped CdSeTe. Conversely, the increase in sub-bandgap absorption and emission using alternative back contact architectures can be attributed to the cell optics, and more specifically to the increased reflectance of the back interface, leading to at least a doubling of the pathlength for sub-bandgap photons.

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.

Purpose: PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti–PD-1 therapy remains unclear. Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n = 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti–PD-1 antibody. Copy-number variations (CNVs) for the genes CDK4, CCND1, and CDKN2A were assayed using a TaqMan copy-number assay in a validation cohort (n = 85). The effect of CDK4/6 inhibitors combined with anti–PD-1 antibody monotherapy was evaluated in PD-1–humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models. Results: WES revealed several significant gene copy-number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti–PD-1 therapy was validated in 85 patients with melanoma (P < 0.05). RNA-Seq analysis of CDK4-normal cell lines and CDK4-normal tumors showed altered transcriptional output in TNFα signaling via NF-κB, inflammatory response, and IFNγ response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy (P < 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model. Conclusions: In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti–PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti–PD-1 antibody for the treatment of advanced melanomas.

Melanoma is an aggressive malignancy with a poor prognosis. Current studies show that imatinib treatment is a promising approach in treating advanced melanoma patients harboring c-Kit mutations or amplifications. We retrospectively analyzed the clinical medical records of 78 patients with metastatic melanoma harboring c-Kit mutations or amplifications. These patients were treated with imatinib at a dose of 400 mg/day continuously unless intolerable toxicities or disease progression occurred. Endpoints for exploration included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease of control rate (DCR). The median OS and PFS of all patients were 13.1 and 4.2 months, respectively. ORR and DCR were 21.8% and 60.3%, respectively. The survival time of patients who achieved partial response or stable disease was significantly superior to those with disease progression. Cox regression analysis showed that patients with M1c stage, subtype of cutaneous melanoma, or elevated LDH level (>upper limit of normal) had higher hazard ratios for overall survival. Our study, combined with those studies targeting patients with a c-Kit alteration, validates the role of imatinib as an important and promising therapeutic agent in the treatment of patients with advanced melanoma.

Introduction: Treatment options for advanced melanoma in China are lacking, particularly second-line therapies. The aim of this retrospective observational study was to describe the real-world effectiveness of available anticancer therapies in patients with locally advanced/metastatic melanoma in China. Methods: Adult patients with unresectable stage III or IV melanoma treated between January 1, 2014, and December 31, 2015, at the Beijing Cancer Hospital (BCH) were eligible (data cutoff: December 31, 2017). Data were obtained from patient electronic medical records. Responders were adjudicated per Response Evaluation Criteria in Solid Tumors, version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 248 eligible patients, 221 and 116 were treated with anticancer therapies in first-line and second-line settings, respectively (89 received both at BCH). Approximately 95% of patients had stage IV melanoma; 40.7% had acral melanoma, and 30.6% had mucosal histology. By data cutoff, 195 of 248 (78.6%) patients had died. Median OS for all patients was 10.5 months; 12-month OS rate was 43.9%. In the first-line setting, the objective response rate was 6.3% (95% confidence interval, 3.5%–10.4%) and the median duration of response was 9.1 months. Median PFS was 3.5 months and 12-month PFS rate was 10.6%; median OS was 10.5 months and 12-month OS rate was 43.5%. In the second-line setting, objective response rate was 3.4% (95% confidence interval, 0.9%–8.6%) and median duration of response was 7.5 months. Median PFS was 2.3 months and 12-month PFS rate was 5.2%; median OS was 7.5 months and 12-month OS rate was 30.5%. Conclusion: In China, first-line and second-line anticancer therapy seems to be associated with suboptimal clinical outcomes in advanced melanoma, indicating a need for effective therapies.

Lead halide perovskites (LHP) are an emerging class of photovoltaic (PV) materials that have drawn intense interest due to their power conversion efficiencies above 23% and their potential for low-cost fabrication. However, the toxicity of lead causes concern about its use in LHP-PV at large scales. Here, we quantified lead intensity and toxicity potential of LHP-PV in potential commercial production. Lead intensity in LHP-PV life cycles can be 4 times lower and potential toxic emissions can be 20 times lower than those in representative U.S. electricity mixes, assuming that PV operational lifetimes reach 20 years. We introduce the metric “toxicity potential payback time”, accounting for toxic emissions in the life cycle of energy cycles, and showed that it is

Background: The best response and survival outcomes between advanced melanoma patients treated with the anti-PD-1 monotherapy vary greatly, rendering a risk model in need to optimally stratify patients based on their likelihood to benefit from the said treatment.Methods: We performed an ad hoc analysis of 89 advanced melanoma patients treated with the anti-PD-1 monotherapy from two prospective clinical trials at the Peking University Cancer Hospital from April 2016 to May 2018. Clinicodemographical characteristics, baseline and early-on-treatment (median 0.6 months after anti-PD-1 monotherapy initiation) routine laboratory variables, including complete blood count and general chemistry, and best response/survival data were extracted and analyzed in both univariate and multivariate logistic and Cox proportional hazard models.Results: After three rounds of screening, risk factors associated with a poorer PFS included a high pre-treatment neutrophil, derived neutrophil-lymphocyte ratio (dNLR), low pre-treatment hemoglobin, and low early-on-/pre-treatment fold change of eosinophil; those with a poorer OS included a high pre-treatment neutrophil, eosinophil, PLT, early-on/pre-treatment fold change of LDH and neutrophil; and those with a poorer best response included a high pre-treatment NLR and early-on-/pre-treatment LDH fold change. Risk models (scale: low, median-low, median high, and high risk) were established based on these risk factors as dichotomous variables and M stage (with vs. without distant metastasis) for PFS (HR 1.976, 95% CI, 1.507–2.592, P < 0.001), OS (HR 2.348, 95% CI, 1.688–3.266), and non-responder (OR 3.586, 95% CI, 1.668–7.713, P = 0.001), respectively. For patients with low, median-low, median-high, and high risks of developing disease progression (PD), six-month PFS rates were 64.3% (95% CI, 43.5–95.0%), 37.5% (95% CI, 22.4–62.9%), 9.1% (95% CI, 3.1–26.7%), and 0%, respectively. For patients with OS risks of low, median-low, median-high, and high, OS rates at 12 months were 82.5% (95% CI, 63.1–100%), 76.6% (95% CI, 58.4–100%), 42.1% (95% CI, 26.3–67.3%), and 23.9% (95% CI, 11.1–51.3%), respectively. For patients with risks of low, median-low, median-high, and high of being a non-responder, objective response rates were 50.0% (95% CI, 15.7–84.3%), 27.8% (95% CI, 9.7–53.5%), 10.3% (95% CI, 2.9–24.2%), and 0%, respectively.Conclusion: A risk scoring model based on the clinicodemographical characteristics and easily obtainable routinely tested laboratory biomarkers may facilitate the best response and survival outcome prediction and personalized therapeutic decision making for the anti-PD-1 monotherapy treated advanced melanoma patients in Asia.

Purpose The combination of vascular endothelial growth factor receptor (VEGFR) inhibitor and programmed cell death-1 (PD-1) blockade provides promising therapeutic opportunities for advanced mucosal melanoma in early phase trials. The aim of this retrospective study was to evaluate the efficacy and safety of the combination regimen for advanced mucosal melanoma in the real world. Methods Patients with advanced mucosal melanoma received an anti-PD-1 antibody plus the VEGFR inhibitor axitinib until confirmed disease progression or unacceptable toxicity. In addition, those with liver metastasis were allowed to take hepatic transcatheter arterial chemoembolisation (TACE). The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), time to treatment failure (TTF), duration of response (DOR), overall survival (OS) and treatment-related adverse events (TRAEs). Results Eighty-one and sixty-six patients received axitinib plus immunotherapy as first-line and salvage therapy, respectively. Overall, ORR was 24.5% (95% CI, 17.3–31.6), DCR was 72.7% (95% CI, 65.3–80.1). Median TTF, DOR and OS were 5.2 months (95% CI, 3.7–6.6), 9.2 months (95% CI, 7.2–11.2) and 11.1 months (95% CI, 7.2–15.0). ORR was 30.0% (95% CI, 19.7–40.3) and 17.5% (95% CI, 7.8–27.1) as first-line and salvage therapy, respectively. No statistical difference among the primary sites was noted for ORR. The ORR of patients with liver metastasis with or without hepatic TACE was 26.1% (95% CI, 6.7–45.5) and 15.0% (95% CI, 2.1–32.1), respectively (P = 0.467). Elevated LDH and poor ECOG status are negative predictive factors. Conclusion This is the largest analysis of anti-PD-1 plus VEGFR inhibitor therapy for mucosal melanoma to date. Immunotherapy plus anti-angiogenesis is applicable for advanced mucosal melanoma, especially as front-line. Hepatic TACE might act synergistically with systemic immunotherapy and anti-angiogenesis.

Background Through a comprehensive analysis of the joint synovial fluid produced in the process of rabbit articular cartilage regeneration, the role and characteristics of knee synovial fluid in the process of decalcified bone transplantation-induced articular cartilage regeneration were explored. Methods Twenty New Zealand white rabbits (approximately 2.5 kg in weight) were selected, and bilateral distal femoral bones from two randomly selected rabbits were extracted. After decalcification, the bones were cut into 2 mm × 4 cm long decalcified bone strips. Meanwhile, the other 18 rabbits were randomly divided into three groups: the test group (8 rabbits), the positive control group (6 rabbits), and the blank group (4 rabbits). In the test group, the decalcified bone joint was transplanted into the rabbits at the articular cartilage defect; in the positive control group, the articular cartilage defect of the rabbits were treated and put aside; in the blank group, no rabbits were treated. On the day of transplantation, and on the 4th, 8th, 12th, and 16th weeks after transplantation, the joint synovial fluid of each group was taken for two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) analysis, and related database verification and identification, and compared with the positive control group and the blank group. Results Using 2D-PAGE to separate various proteins in the synovial fluid of the rabbit knee joints, it was found that there were differential protein spots in the test group compared with the blank group and the positive control group. After conducting a comparative search and query in the UniProt database, through comprehensive analysis, it was finally found that three proteins with molecular weights of 23,429.4, 57,431.4, and 26,071.1 that may be related to the regeneration of articular cartilage appeared in the test group. Conclusions In the process of inducing the regeneration of articular cartilage using decalcified bone transplantation, knee joint synovial fluid produced specific proteins, which may play an important role in the regeneration of articular cartilage. These findings may offer novel ideas in laying a foundation for the in-depth study of articular cartilage regeneration.

Siming Li,1,* Wentao Xu,1,* Minjun Liao,1,2,* Yuanping Zhou,2 Jun Weng,1 Liying Ren,1 Junxiong Yu,1,3 Weijia Liao,1 Zhaoquan Huang1,4 1Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 2Department of Infectious Diseases, Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People’s Republic of China; 3Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 4Department of Pathology, Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijia LiaoLaboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of ChinaEmail liaoweijia288@163.comZhaoquan HuangDepartment of Pathology, Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of ChinaEmail 191990449@qq.comBackground: Currently, there is still a lack of effective biomarkers for the recurrence monitoring and survival prognosis assessment of hepatocellular carcinoma (HCC) patients with alpha-fetoprotein (AFP)-negative (≤ 20 ng/mL) after radical resection.Methods: The clinicopathological data of 606 patients (303 in the AFP-negative group and 303 in the AFP-positive group) who underwent radical resection of HCC were analyzed retrospectively.Results: The gamma-glutamyl transpeptidase to lymphocyte count ratio (GLR) of patients in the AFP-negative group was lower than that in the AFP-positive group (p < 0.001). The GLR level of the early-recurrence group was higher than that of the non-early-recurrence group (p =0.003). GLR had fair accuracy in predicting the early-recurrence of HCC patients [c-index=0.654 (95% CI=0.606– 0.702); AUC=0.681 (95% CI=0.625– 0.733)]. Univariate analysis showed that patients with tumor size < 5 cm, no microvascular invasion, single tumor, no metastasis, BCLC stage 0–A, no recurrence, and GLR ≤ 45.0 had longer disease-free survival (DFS) and overall survival (OS) among AFP-negative HCC patients. In addition, multivariate Cox proportional hazards regression analysis showed that tumor size < 5 cm (p =0.003), no recurrence (p < 0.001), and GLR < 45.0 (p < 0.001) were independent predictors of longer OS.Conclusion: GLR may be a potential indicator for early recurrence monitoring and prognosis evaluation in HCC patients with AFP-negative after radical resection.Keywords: hepatocellular carcinoma, AFP-negative, GLR, prognosis, early-recurrence

The charging reliability of electric vehicles directly affects the owner's daily travel and charging satisfaction, while the current charging and discharging strategies for electric vehicles do not take into account the charging reliability indicators. Aiming at this quo, control method for electric vehicles based on charging reliability indicators is proposed in this paper. The method puts forward an indicator of electric vehicle charging reliability, and based on this indicator, combined with peak and valley time-of-use electricity prices, an orderly charging and discharging control process of electric vehicles is given. Taking IEEE RBTS-Bus6 system as an example, the method presented in this paper are simulated. The simulation verifies the effectiveness of the control strategy proposed in this paper. The results show that it performs effective in improving the reliability of EV charging and user satisfaction.

We aimed to establish the clinicopathological characteristics and prognostic factors of patients with melanoma brain metastases (MBM) in the East Asian population. Overall survival (OS) and intracranial progression-free survival (PFS) were evaluated by Kaplan–Meier analysis. Cox regression analyses were used to determine prognostic factors associated with intracranial PFS and OS. Between July 2007 and December 2019, 431 patients diagnosed with MBM were enrolled. Mucosal subtype (p = 0.013), LDH level (p = 0.014), the number of MBM ≥ 4 (p = 0.02), local treatment (p

Background. There was limited evidence of treatments aiming at aged coronary artery disease (CAD) patients. Yanyu decoction (YD) has been used as adjuvant therapy in aged patients with stable CAD and might be a new treatment worthy of recommendation for CAD patients. This study was to evaluate the combined effects of YD plus conventional pharmaceutical treatment (CPT) on senile patients with stable CAD. Methods. This review was designed according to the PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analysis) recommendations. A literature search was conducted in seven electronic databases from their inception until August 2020. Primary outcomes of interest were adverse cardiovascular events, including cardiac mortality, acute myocardial infarction (AMI), and unstable angina (UA). The secondary outcomes were blood lipids and hemorheology. Studies were pooled to calculate the risk ratio or weighted mean difference and corresponding 95% confidence interval. Results. Five studies recruiting 848 aged patients with stable CAD were included. Patients receiving YD as an adjuvant have fewer adverse cardiovascular events, including cardiac mortality, AMI, and UA. Besides, YD plus CPT has a better effect on reducing triglycerides, low-density lipoprotein cholesterol, and improving high-density lipoprotein cholesterol. Moreover, significant effects of YD plus CPT for reducing blood viscosity, plasma viscosity, and platelet aggregation rate were found compared with CPT alone. Conclusion. YD plus CPT showed better efficacy than CPT on reducing adverse cardiovascular events and improving hemorheology and blood lipids for aged patients with stable CAD. Our findings may suggest YD as an adjuvant natural-based treatment for CAD. However, more rigorous and larger trials are essential to validate our results, and further consideration of CAD studies specific to aged patients is needed.

Anti-programmed cell death protein 1 (PD-1) monoclonal antibody therapy is becoming a standard treatment for advanced melanoma that produces durable responses and prolonged survival, but the prognosis of patients with liver metastases is still unsatisfactory. Here, we analyzed five clinical studies (second-line or later, JS001-I-PK, CT4, KN151, BGB-A317-102, and SHR-1210-102; performed between 2015 and 2018) of anti-PD-1 monotherapy for advanced melanoma to explore prognostic variables for patients with liver metastases. A total of 168 patients with stage IV melanoma were included, among which 47 had liver metastasis and 121 did not. The objective response rate (ORR) of the no liver metastasis group was significantly higher than that of the liver metastasis group (20.7 vs. 4.3%, P < 0.05). The median progression-free survival (PFS) time was 3.6 months for the patients with liver metastasis and 7.4 months for those without liver metastasis (P < 0.05). The no liver metastasis group also had a longer median overall survival (OS) time than the liver metastasis group (22.8 vs. 15.7 months, P < 0.05). Multivariate analysis showed that liver metastasis was negatively associated with PFS. In the liver metastasis group, compared to metastases in other sites (lymph node, subcutaneous, and lung), liver metastases responded worse to anti-PD-1 monotherapy and were most likely to progress. Intrahepatic progression (defined as an increase in liver metastasis by more than 20% from baseline or having new liver metastases, P < 0.05) was negatively associated with OS, which indicates the need to find a more effective therapy that can target liver metastases. Interestingly, with a median PFS and OS time of 6.0 and 30.9 months, respectively, previous oncolytic virotherapy might bring more benefits to patients with liver metastasis, but confirmation is needed because of the limited number of samples. These findings emphasize that liver metastasis is a poor prognostic factor for advanced melanoma treated with anti-PD-1 monotherapy. Further exploration is still needed to find a new treatment approach for these patients.

We report significant advances in understanding and reducing nonradiative Shockley-Read-Hall recombination in polycrystalline CdSe x Te 1-x , leading to microsecond charge carrier lifetimes. In undoped Al 2 O 3 -passivated heterostructures we find external radiative efficiency 0.2%, quasi-Fermi level splitting 950 mV, mobility 100 cm2/(Vs), and diffusion length 14 µm. In solar cells measured lifetimes can exceed 1 µs. We interpret this data to indicate MgZnO/CdSeTe interface recombination velocity

We report seminal advances in fabrication and understanding of group V (As) doped thin-film polycrystalline CdTe-based solar cells. The devices are fabricated using a novel approach, by sublimating layers of CdSeTe and CdSeTe:As. This new method allowed us to achieve minority carrier lifetime of over 1 µs, carrier concentration of more than 5×l015cc−1 and external radiative efficiency of over 2 % in a device configuration. We find an increase in open-circuit voltage when comparing As-doped, Cu-doped and undoped devices. The choice of CdSeTe instead of a CdTe-only absorber has been explained using first-principle density functional theory model. A SCAPS device model is used to analyze the potential causes for lower open-circuit voltage.

Since excellent carrier lifetimes and front interface electronic quality are now achieved, rear interface recombination can limit V OC in $\text{CdSe}_{\mathrm{x}}\text{Te}_{1-\mathrm{x}}/\text{CdTe}$ solar cells. Several back-contact structures for devices were fabricated using combinations of tellurium, aluminum oxide, amorphous silicon, and indium tin oxide (ITO). Time-resolved photoluminescence was used to characterize such structures. We show increasingly improved interface passivation through the subsequent use of aluminum oxide, amorphous silicon, and ITO. Additionally, we show that arsenic-doped absorbers form a more passive interface with numerous back contact structures.

Green-lipped mussels, commercially known as Greenshell™ mussels (Perna canaliculus Gmelin 1791), contribute > $300 million to New Zealand’s aquaculture exports. However, mortalities during summer months and potential pathogenic outbreaks threaten the industry. Thermal stress mechanisms and immunological responses to pathogen infections need to be understood to develop health assessment strategies and early warning systems. P. canaliculus were collected during a mortality event at a commercial aquaculture farm in Firth of Thames, New Zealand. Gill tissues from six healthy and six unhealthy mussels were excised and processed for metabolomic (GC–MS) and label-free proteomic (LC–MS) profiling. Univariate analyses were conducted separately on each data layer, with data being integrated via sparse multiple discriminative canonical correlation analysis. Pathway enrichment analysis was used to probe coordinated changes in functionally related metabolite sets. Findings revealed disruptions of the tricarboxylic acid (TCA) cycle and fatty acid metabolism in unhealthy mussels. Metabolomics analyses also indicated oxidative stress in unhealthy mussels. Proteomics analyses identified under-expression of proteins associated with cytoskeleton structure and regulation of cilia/flagellum in gill tissues of unhealthy mussels. Integrated omics revealed a positive correlation between Annexin A4 and CCDC 150 and saturated fatty acids, as well as a negative correlation between 2-aminoadipic acid and multiple cytoskeletal proteins. Our study demonstrates the ability of using integrative omics to reveal metabolic perturbations and protein structural changes in the gill tissues of stressed P. canaliculus and provides new insight into metabolite and protein interactions associated with incidences of summer mortality in this species.

Purpose To investigate the clinical characteristics, chemosensitivity, and outcome of metastatic upper tract urothelial carcinoma (UTUC). Patients and Methods Records of patients with metastatic UTUC since January 2005 were retrieved from a database that included clinical and survival data. Statistical analyses including survival and multivariate analyses of factors were respectively performed by the Kaplan-Meier method and Cox proportional hazard model. Results A total of 250 consecutive UTUC cases were evaluated. There were 56 patients (22.4%) with initially diagnosed stage IV disease. The most common metastatic sites were lung (39.6%), distant lymph nodes (39.2%), bone (19.6%), liver (18.0%), and adrenal gland (7.2%), respectively, and the local recurrence rate was 10.4%. Two hundred thirteen patients received first-line chemotherapy. The overall response rate was only 28.7% and the median progression-free survival time was only 5.0 months. The overall survival time of the cohort was 18.0 months. Multivariate analyses showed that initially diagnosed stage IV disease, number of metastatic organs ≥3, no response to chemotherapy and cycles of chemotherapy ≤2 were adverse prognosticators for overall survival. Conclusion UTUC presented to be more prone to metastasize than locally recur and thought to have low chemosensitivity. Stage IV disease at initial diagnosis, number of metastatic organs, response and cycles of chemotherapy were independent prognosticators for metastatic UTUC.

Background Collecting duct carcinoma (CDC) is a rare type of renal cancer with a poor prognosis. As there are no standard guidelines for the management of metastatic CDC (mCDC), we evaluated the efficacy and safety of combined therapies of sorafenib, gemcitabine, plus cisplatin in patients with mCDC. Materials and methods A prospective, multicentre, single-arm, open-label, phase 2 trial ( ClinicalTrials.gov identifier NCT01762150 ) that enrolled 26 mCDC patients with no prior systemic chemotherapy. Patients were treated with sorafenib (400 mg orally, twice daily) combined with chemotherapy (gemcitabine 1000 mg/m2, intravenously for 30–60 min on days 1 and 8, plus cisplatin 25 mg/m2, intravenously on days 1–3, repeated every 28 days for 4 cycles), until disease progression, unacceptable toxicity, or study discontinuation for any other reason. The primary end-points were progression-free survival (PFS) and 6-month PFS rate. Results The 6-month PFS rate was 65%, and the median PFS was 8.8 months (95% confidence interval [CI]: 6.7–10.9) with a median overall survival of about 12.5 months (95% CI: 9.6–15.4). The objective response rate was 30.8%, and the disease control rate was 84.6%. The treatment was generally well tolerated. Major grade 3/4 toxicities included leucopenia (26.9%), thrombocytopenia (23.1%), anaemia (11.5%) and palmar-plantar erythrodysesthesia (7.7%). Conclusions Though the combination of sorafenib and chemotherapy demonstrated a similar outcome as that of the previously reported regimens in patients with mCDC, this combination may be a suitable option for patients who have low Eastern Cooperative Oncology Group performance status or less metastatic sites.

Background Preliminary evidence based on clinical observations suggests that meditative exercise may offer potential benefits for patients with chronic heart failure (CHF). Cardiac rehabilitation (CR), as a class-IA indication in clinical practice guidelines, has been established as an effective strategy to improve quality of life and prognosis of CHF patients. Baduanjin exercise is an important component of traditional Chinese Qigong exercises. However, its benefits for CHF have not been rigorously tested. We sought to investigate whether Baduanjin, as an adjunct to standard care, improves cardiopulmonary function, exercise tolerance, and quality of life in patients with CHF caused by coronary artery disease (CAD). Methods/design In this randomized controlled trial, 120 patients will be randomly allocated in a 1:1 ratio to Baduanjin exercise combined with conventional exercise of CR (Baduanjin exercise group) or conventional exercise of CR alone (conventional exercise group). In addition to conventional physical activity, participants in the Baduanjin exercise group will participate in a 45-min Baduanjin exercise training session twice a week, for 12 weeks. The primary outcome is walking distance in the 6-min Walk Test (6MWT), and the secondary outcomes are peak oxygen uptake (VO2 peak), ventilatory anerobic threshold (VAT), The minute ventilation to carbon dioxide production relationship (VE/VCO2 slope), left ventricular end-diastolic volume index (LVEDVi), left ventricular ejection fraction (LVEF), quality of life assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), amino-terminal pro-brain natriuretic peptide (NT-proBNP), hs-CRP, heart rate variability (HRV), New York Heart Association (NYHA) classification, and major adverse cardiovascular events. Discussion This is the first trial to evaluate the effects of a Baduanjin exercise-based CR program on cardiopulmonary function and exercise tolerance in ischemic CHF patients. If successful, it will prove the value of Baduanjin exercise in improving cardiopulmonary function and exercise tolerance in patients with ischemic heart failure on phase-II CR, and may further develop a Chinese Qigong exercise-based CR framework. Trial registration ClinicalTrials.gov, ID: NCT03229681. Registered retrospectively on 23 July 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-2759-4) contains supplementary material, which is available to authorized users.

Background and Objectives With a prevalence of approximately 71 million infected individuals globally, chronic hepatitis C virus (HCV) infection is one of the major causes of chronic hepatitis leading to hepatocellular carcinoma (HCC). This review aimed to summarize the general history of HCV and provide a perspective on future journey of HCV. Materials and Methods We searched for articles published in periodicals, monographs and edited books with the key words including ‘non-A, non-B hepatitis’, ‘HCV’, ‘interferon’ and ‘direct-antiviral agents (DAAs)’. And the data emphasized HCV emergence, identification, treatment, epidemiology as well as the cellular and animal models leading to the eradication of HCV infections, were summarized. Results and Conclusion The battle against hepatitis C is destined to be recorded in history as one of science's remarkable success. Although the revolutionary direct-antiviral agents (DAAs) are able to cure more than 95% of HCV patients, access to diagnosis and therapy remains improved. More efforts should be made to promote HCV screening, treatment delivery and vaccine development.

CuSbS2 is a semiconductor with a band gap of 1.5 eV and earth-abundant constituent elements, indicating potential promise as a photovoltaic absorber material. However, strategies to fabricate CuSbS2 films, especially using solution processing, have not been thoroughly developed. We report on two solution-based approaches to deposit CuSbS2 films: chemical bath deposition (CBD) and deposition of colloidal nanoplates. Conditions to directly deposit ternary CuSbS2 (chalcostibite) films were not found, but CuSbS2 films could be formed by annealing CBD-grown bilayers of CuS and Sb2S3. Simultaneous control over phase purity and film morphology proved elusive. To address this challenge, we synthesized colloidal nanoplates of phase-pure chalcostibite CuSbS2 capped with oleylamine ligands following a literature procedure. When colloids are condensed into thin films, these synthesis ligands are insulating and inhibit the inter-crystal charge transfer that is necessary for long-range charge transport. To solve this problem, two approaches were pursued: convective assembly followed by solid-state ligand exchange and a novel process involving solution-phase ligand exchange followed by electrophoretic deposition (EPD). Replacement of oleylamine with S2− increased the film conductivity by two orders of magnitude. S2− capping groups also increased the electrophoretic mobility and enabled EPD at bias voltages as low as 5 V. Time-resolved terahertz spectroscopy indicated transient photoconductivity persisting beyond 1 ns and carrier mobilities of ~ 1 cm2 V−1 s−1. While many challenges remain, this work indicates the potential promise of solution-processed CuSbS2 nanoplates as building blocks for photovoltaic devices.

High-sensitivity C-reactive protein (hs-CRP) is independently associated with cardiovascular events in coronary artery disease (CAD) patients and reducing the hs-CRP level may further benefit this population. We conduct this parallel design, randomized-controlled trial to assess the effectiveness of adjunct sodium tanshinone IIA sulfate (STS) therapy on circulating inflammation markers in CAD patients. Unstable angina or non-ST-elevation myocardial infarction patients with increased hs-CRP level were randomly assigned to atorvastatin-based standard medical therapy or standard therapy plus STS injection (80 mg, once daily for 14 consecutive days). The primary outcome was hs-CRP level. After the 14-day treatment, the experimental group (n = 35) exhibited significantly lower levels of hs-CRP than the control group (n = 35) (1.72 vs 3.20 mg/L, p = 0.0191). Lower levels of interleukin-6, monocyte chemotactic protein-1 (MCP-1), and soluble CD40 ligand were also observed in the experimental group. Angina symptoms were also better controlled in the experimental group. At 30 days after treatment completion, MCP-1 levels remained lower in the experimental group than in the control group (313.88 vs 337.91 pg/mL, p = 0.0078). No serious adverse events occurred. Our study demonstrates that on the basis of standard medical therapy, STS further reduce elevated hs-CRP and other circulating inflammation markers in CAD patients. (Chictr.org number: ChiCTR-TRC-12002361).

Understanding the nature of recombination and its dependence on defects and interfaces is essential for engineering materials and contacts for a higher open-circuit voltage (Voc) and power conversion efficiency in photovoltaic (PV) devices. Time-resolved photoluminescence (TRPL) has conventionally been used to evaluate recombination, but carrier redistribution often dominates the response at short times. Here, we report on the quantification of carrier dynamics and recombination mechanisms by complementary use of both time-resolved terahertz spectroscopy and TRPL combined with numerical modeling of the continuity equations and Poisson's equation. We have demonstrated this approach using CdTe thin films. A thin-film stack with CdTe fabricated by vapor transport deposition and treated with CdCl2 exhibited a bulk lifetime of 1.7 ± 0.1 ns, a negligible CdTe/CdS interface recombination velocity, and a back surface recombination velocity of 6.3 ± 1.3 × 104 cm/s. In contrast, a film stack without CdCl2 treatment had a bulk lifetime of only 68 ± 12 ps and a higher interface recombination velocity of 4 ± 2 × 108 cm/s. By determining the locus and mechanisms of performance-limiting recombination, we can accelerate the development of thin-film PVs with higher Voc and efficiency. While the method has been demonstrated here using CdTe, it is also applicable to perovskites, Cu(InGa)Se2, Cu2ZnSn(S,Se)4, and emerging technologies.

Hybrid organic/inorganic lead iodide perovskites of the formula APbI3, where A is a molecular cation such as methylammonium, exhibit remarkably slow photoinduced charge carrier recombination rates, for reasons that remain uncertain. Prevalent hypotheses credit this behavior to the unique dipolar nature of the molecular cation. Herein, transient terahertz spectroscopy is applied to solution-processed, all-inorganic, perovskite-phase cesium lead iodide (CsPbI3) thin films, which lack such a dipole. The recombination kinetics are studied as a function of the initial photoinduced carrier concentration and the wavelength of excitation. A kinetic model combining diffusion and recombination is fit to the data, from which the rate constants are determined, revealing a bimolecular recombination rate of 10–10 cm3 s–1, comparable to high-quality, single-crystal, direct-gap semiconductors. This rate, as well as a charge carrier mobility > 30 cm2 V–1 s–1 measured herein for CsPbI3, are similar to values reported for t...

Background We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites. Patients and methods Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites. Results The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%,P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%,P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively. Conclusions 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.

Two species of monodisperse nanocrystals (NCs) can self-assemble into a variety of complex 2D and 3D periodic structures, or binary NC superlattice (BNSL) films, based on the relative number and size of the NCs. BNSL films offer great promise for both fundamental scientific studies and optoelectronic applications; however, the utility of as-assembled structures has been limited by the insulating ligands that originate from the synthesis of NCs. Here we report the application of an in situ ligand exchange strategy at a liquid–air interface to replace the long synthesis ligands with short ligands while preserving the long-range order of BNSL films. This approach is demonstrated for BNSL structures consisting of PbSe NCs of different size combinations and ligands of interest for photovoltaic devices, infrared detectors, and light-emitting diodes. To confirm enhanced coupling introduced by ligand exchange, we show ultrafast (∼1 ps) directional carrier transfer across the type-I heterojunction formed by NCs of...

A general closed expression of posterior Cramer-Rao lower bound (PCRLB) for wireless sensor networks is derived and presented, based on Bayesian estimation and well suited to dynamic systems. The aim is to guide the localisation algorithm design and anchor layout fulfilling certain accuracy requirement. There is a growing need for wireless sensor systems to determine the position information indoors and in somewhere satellite positioning cannot provide service. PCRLB sets a fundamental lower limit to all kinds of localisation algorithms within consideration of dynamic state transition. This result shows that the theoretically best position solution can be obtained.

Background: Cross-linked polyethylene (HXLPE) liners have been used for total hip arthroplasty (THA) to address the problem of osteolysis and revision surgery associated with conventional polyethyl...

Enargite Cu 3 AsS 4 is a promising absorber for thin-film solar cells but little is known about its optoelectronic properties. Here, we present photoluminescence (PL) spectroscopy, time-resolved terahertz spectroscopy (TRTS), timeresolved photoluminescence (TRPL) spectroscopy, and cyclic voltammetry (CV) measurements of enargite thin films. The results indicate promising defect characteristics with minority carrier lifetimes on the order of ns, and band alignments suggest that buffer layers besides CdS must be developed to achieve high efficiency Cu 3 AsS 4 solar cells.

Understanding the relationship of photoexcited carrier lifetimes, mobilities, and recombination to structure and processing of photovoltaic absorber materials is critical to designing efficient solar cells. Using three complementary techniques, the authors elucidate photoexcited carrier dynamics in a high-quality kesterite crystal. These dynamics help to explain limitations in charge-carrier collection observed in a device's $J\ensuremath{-}V$ relation and external quantum efficiency. Combining ultrafast spectroscopy and device measurements in this way can lead to a more detailed understanding of the performance-limiting photophysical processes, accelerating the improvement of solar cells.

Background JS001, 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 methods In 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. Results Thirty-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). Conclusion JS001 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 registration Clinical Trial ID: NCT02836795, registered July 19, 2016, retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s13045-018-0693-2) contains supplementary material, which is available to authorized users.

Corn silk, a traditional Chinese medicine, has been found to exert an antihypertensive effect in clinical practice and trials. However, systematic review of current evidence on this topic was not available. Thus, this study aims to assess safety and efficacy of corn silk tea (CST) in improving clinical outcomes in patients with hypertension. A systematic literature search was conducted through popular electronic databases up to October 2018. Randomized controlled trials (RCTs) comparing CST plus conventional antihypertensive drugs with conventional antihypertensive drugs alone were included. The main outcome was total blood pressure lowering efficacy. The risk of bias assessment according to the Cochrane Handbook was used to evaluate the methodological quality of the included trials. Review Manager 5.3 software was used for data analyses. Five RCTs involving 567 participants were included. Due to the poor quality of methodologies of most trials, limited evidence showed that CST plus antihypertensive drugs might be more effective in lowering blood pressure compared with antihypertensive drugs alone (RR = 1.27; 95% CI: 1.17 to 1.38, P P = 0.51, I2 = 0%, fixed‐effect model). However, there is no evidence that CST plus conventional antihypertensive drugs has less adverse events than conventional antihypertensive drugs.

Background: Metastatic mucosal melanoma responds poorly to anti-PD-1 monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. Combination therapy of VEGF inhibition with PD-1 blockade provides therapeutic opportunities for patients otherwise refractory to either monotherapy. Methods: We conducted a single center phase Ib trial evaluating the safety and preliminary clinical efficacy of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in combination with VEGFR inhibitor axitinib in chemotherapy naive advanced mucosal melanoma patients. Patients received toripalimab at 1 mg/kg or 3 mg/kg via IV infusion once every two weeks, in combination with 5 mg axitinib orally BID 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. Findings: Thirty-three patients were enrolled in the study. No dose-limiting toxicities (DLTs) were observed. 97% of patients experienced treatment-related adverse events (TRAE). The most common TRAE were mild (grade 1/2), including diarrhea, proteinuria, hand and foot syndrome, fatigue, AST/ALT elevation, hypertension, hypo- or hyper-thyroidism, bilirubin elevation, and rash. Grade 3 and above TRAE occurred in 39.4% subjects. By the data cutoff date, 20 (60.6%; 95% CI 42.1-77.1) patients achieved an objective response (complete or partial response) and median progression-free survival was 9.1 months (95% CI 3.9 to NE). Interpretation: The treatment combination of toripalimab plus axitinib was tolerable and showed promising anti-tumor activity in patients with treatment-naive metastatic mucosal melanoma. A randomized phase III trial of toripalimab with axitinib versus standard of care is needed to validate the combination as a first-line treatment option for advanced mucosal melanoma. Trial Registration Number: Clinical trial (NCT03086174) Funding Statement: Study is sponsored by Shanghai Junshi Biosciences Co., LTD, Shanghai, China. This work was supported by grants from National Natural Science Foundation of China (81672696; 81772912), Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding support (ZYLX201603), and Beijing Municipal Science & Technology Commission (Z161100000516062). Declaration of Interests: Kai Wang is employed by OrigiMed. Xiongwen Tang, Huaning Zhou, Hai Wu, Hui Feng and Sheng Yao are employed by Shanghai Junshi Bioscience. The rest of authors have no disclosures of potential conflicts of interests. Ethics Approval Statement: The study was approved by Peking University Cancer Hospital institutional review board and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Each subject provided written informed consent.

e16559 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 translocation RCC was found in 41 cases. The median PFS and Median OS was 6.3 months (4.4 - 8.8) and 17.3 months (12.4 - 21.8) for the whole cohort, respectively. First-line treatment mainly included sunitinib (n = 12), sorafenib (n = 13), axitinib (n = 6), and pazopanib (n = 4), and the median PFS of these regimens was 5.4 months, 5.1 months, 9.4 months, 8.3 months, respectively. Twenty-three patients received subsequent therapies, the median PFS and the median OS was 4.3 months and 12 months for the second-line therapy(n = 21), 4.3 months and 14.1 months for the third-line therapy(n = 11), 2.4 months and 9.6 months for the fourth-line therapy(n = 6). Conclusions: Metastatic Xp11.2 translocation RCC is an aggressive disease. Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) agents appeared to demonstrate some efficacy, the combination of VEGFR-TKI and immune checkpoint inhibitor (ICI) might be a useful tool for the treatment of metastatic Xp11.2 translocation RCC.

e21588 Background: Primary mucosal melanoma arising in the urinary tract is rare and poorly characterized. Methods: The records of patients with urological mucosal melanoma who presented to the department of Renal Cancer and Melanoma of Peking University Cancer Hospital between September, 2004 and April, 2019 were reviewed. Available clinicopathological and molecular characteristics were summarized, including pathological parameters, gene mutation, primary surgical intervention, systemic treatment and clinical course. The rates of local recurrence rate, loco-regional lymph node metastasis and distant metastasis were assessed. American Joint Committee on Cancer (AJCC) TNM Staging System for bladder cancer/renal pelvis and ureter cancer/urethral carcinoma (8th ed., 2017) were adopted for staging. Results: Fifty-eight patients were involved in the study with a median age of 62.5 years (range: 32-82). The anatomic sites of the primary urological mucosal melanomas were from the urethra (89.7%), bladder (6.9%), ureter (0%) and kidney (0%), and the left (4.4%) were from multiple loci. At initial diagnosis, 75.9% (n=44) were stage I/II disease, 1.7% (n=1) stage III, and 22.4% (n=13) stage IV. There was 3.4% incidence of CKIT mutation and 1.7% of BRAF mutation. After median follow-up of 22.6 mo, 31.4% (16/51) relapsed locally after organ-preserved surgery. 21.6% (11/51) and 39.2% (20/51) developed metastases to reginal lymph nodes and distance, respectively. The median relapse free survival and median overall survival were 12.2 (95%CI: 7.9-16.4) mo and 33.9 (95%CI: 19.2-48.6) mo, respectively. Univariate Cox analysis showed that TNM stage and systemic adjuvant therapy were the prognostic factors of OS, while no association was found with Breslow thickness, miotic rate, ulceration and gender. Conclusions: Urological mucosal melanoma predominantly arises from lower urinary tract with rare BRAF and CKIT mutation. AJCC TNM Staging System for urothelial carcinoma is proved practical for urothelial melanoma, which should be validated in larger population. Future research is required to identify adjuvant treatment approaches to improve disease outcomes.

9559 Background: Liver metastasis was associated with reduced responses and PFS in melanoma patients (pts) treated with anti-PD-1 monotherapy, which is probably due to reduced marginal CD8+ T cell infiltration. Oncolytic virotherapy was found to increase CD8+ T cell infiltration in the injected lesions and improve the efficacy of anti-PD-1 ab in a phase 1b trial. We hypothesized that intratumoral oncolytic virus injection for liver metastasis in melanoma combined with systemic anti-PD-1 therapy might improve the efficacy, thus conducting this phase 1b trial with intratumoral OrienX010 - a HSV-1-derived oncolytic virotherapy with expression of GM-CSF combined toripalimab in liver metastatic melanoma pts. Methods: Eligible pts included those over 18 with injectable liver metastasis confirmed by biopsy with or without extra-hepatic metastasis; ocular melanoma and brain metastasis were excluded. Pts received intravenous toripalimab Q2W combined with ultrasound guided intratumoral injection of OrienX010 Q2W (8×107 pfu/ml, 10ml per injection) until intolerance or disease progression per iRECIST criteria. Liver biopsy would be performed at baseline and first tumor evaluation (8-12weeks). The primary endpoint was toxicity; secondary endpoints included ORR, DCR and PFS. Clinical trial information: NCT04206358. Results: From Jul 2019 to Dec 2020, 15 pts were eligible and enrolled. Baseline characteristics: median age 62 yrs; primary: mucosal 60%, cutaneous 20%, unknown primary 13.3%, acral 6.7%; gene mutation status: Braf 20%, Nras 6.7%; 73.3% got extra-hepatic metastasis: regional or distant lymph node 46.7%, lung 20.0%; LDH＞ULN 20%; median size of injected lesions: 32mm(10-83mm); median number of liver metastasis: 4(1-10); median number of injection: 10 (3-36). AEs were all grade 1/2: pyrexia 86.7%, rigor 66.7%, elevated transaminase 53.3%, nausea/vomiting 40.0%, fatigue 26.7%. No grade 3-4 AEs. The ORR by investigator was 13.3% (2/15), DCR 46.7% (7/15); the response rate was 40%(6/15) for injected lesions, 28.5%(4/14) for non-injected lesions in liver, and 23% (3/13) for extra-hepatic metastasis. For biopsies of injected lesions at 8 to 12weeks, 30%( 2 PR and 3 SD) showed no melanoma cells residual by immunohistochemistry, 46.7% got impressive TIL infiltration (Brisk n = 4 and Nonbrisk n = 3 according to the definition of AJCC 8th edition) compared with baseline in which all showed absence of TIL infiltration, also a large number of plasma cells, histiocyte and pigment were found with hyaline fibrosis. The PFS has reached 72 weeks for one PR pt. The median PFS was not reached. Conclusions: Systemic toripalimab combined with intrahepatic OrienX010 injection has shown remarkable pathological responses with good tolerance in melanoma liver metastases. Survival is still in follow-up. Clinical trial information: NCT04206358.

9573 Background: Immunotherapies including anti PD-1 ab and high-dose IFN-a2b (HDI) have been approved for adjuvant therapies in resected cutaneous melanoma, but their roles in mucosal melanoma are still unknown. To determine the efficacies of toripalimab versus HDI as adjuvant therapy in patients (pts) with resected mucosal melanoma, this open-label, phase randomized trial was conducted. Methods: Mucosal melanoma pts who have undergone complete resections of localized with or without regional lymphatic disease were randomly (1:1) assigned to receive HDI (15x106 IU/m2/d1-5/w/ 4weeks IH, followed by 9x106 IU tiw IH) or toripalimab (3mg/kg intravenously q2w) for 52 weeks unless disease recurrence, unacceptable toxicity or consent withdrawal. Head and neck primary would receive adjuvant radiotherapy within 6-8weeks after enrollment. The primary end point was RFS in the intention-to-treat population. Data cutoff was December 10, 2020. Clinical trial information: NCT03178123. Results: From Jul 2017 to May 2019, 187 pts were screened, and 145 were randomized into HDI group (n = 72) and toripalimab group (n = 73). The median age was 58years; M:F 37.2%: 62.8%; localized disease 80.7%, regional lymphatic disease 19.3%; local excision ± CLND 37.2%, wide excision ± CLND 62.8%; head and neck primary 39.3%( 87.5% received adjuvant radiotherapy); PDL-1positive 51.0%(CPS≥1%, 22C3), PDL-1 negative 49.0%. There was no difference in baseline characteristics between two groups. At a median follow-up of 31.5 months, there were 93 RFS events (43 in HDI group vs. 50 in toripalimab group), 76 DMFS events (35 vs. 41respectively) and 65 OS events (30 vs. 35 respectively). The median RFS, DMFS and OS were shown in the table. In the HDI group, 32.6% of pts received anti PD-1 ab in the following treatment. Grade 3/4 AEs were reported in 83.3% of pts in HDI group (most decrease of leukocytes or neutrophils) and 15.1% of pts in toripalimab group (mainly increase of amylase or liver enzymes). Discontinuations of treatment due to any AE occurred in 20.8% of HDI group and 15.1% of toripalimab group. Conclusions: Both adjuvant toripalimab and HDI therapy improve RFS of mucosal melanoma. Toripalimab shows longer RFS in PDL1 (+) subgroup and better tolerance than HDI. Clinical trial information: NCT03178123. [Table: see text]