To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.
Systematic review and network meta-analysis.
...Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.
Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.
36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.
Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.
PROSPERO CRD42017082553.
An improved maximum power point tracking (MPPT) algorithm based on the fusion firefly algorithm (FFA) with a novel simplified propagation process (SPP) for photovoltaic (PV) systems under partial ...shading conditions (PSCs) is proposed in this study. By integrating the neighborhood attraction firefly algorithm (NaFA) and simplified firefly algorithm (SFA), the proposed FFA is capable of tracking the global maximum power points (GMPPs) with high accuracy. In addition, the proposed SPP process reduces the sampling events by omitting redundant propagations, thereby accelerating the tracking speed and reducing the energy loss and oscillations during the sampling process. The performance of the proposed FFA and the speed improvement using the SPP process were simulated using MATLAB software and verified with a hardware evaluation system. Experimental results confirmed that the proposed FFA algorithm offers high accuracy and efficiency with rapid tracking speed. In addition, the proposed SPP process is capable of significantly reducing the sampling events not only when integrating it with the FFA, but also with other conventional FA algorithms.
This study explores the effects of immersive VR on an individual's creativity and factors related to creativity including flow, attention and meditation (i.e., mental relaxation or stress). Sixty ...undergraduate students were invited to participate in an open-ended challenge to design a wearable technology functioning as a smart phone individually, either in the immersive VR condition (N = 30) or in the paper-and-pencil condition (N = 30). Surveys and electroencephalography (EEG) measurements were used to collect data. Findings showed that the participants in the immersive VR condition had higher quality creative products than those in the paper-and-pencil condition. The sequence analysis of the participants' EEG brainwaves also showed that the participants in the immersive VR condition maintained a more stable focus or attention, while those in the paper-and-pencil condition were more relaxed. Research results led to a deeper understanding of using a VR support system for individual creativity. Recommendations for the design and application of an immersive VR creativity support system are discussed.
Electrochemical reduction of carbon dioxide (CO2RR) into value‐added chemicals is a promising tactic to mitigate global warming. However, this process resists catalyst preparation, low faradaic ...efficiency (FE%) towards multi‐carbon products, and insights into mechanistic understanding. Indeed, it is demonstrated that this Fe single‐atom catalyst (Fe SAC) exists in three oxygen coordination of Fe–(O)3 configuration in Nafion coated functionalized multi‐wall carbon nanotubes (Fe‐n‐f‐CNTs), which is obtained via a simple ionic exchange method under ambient conditions. The electrochemical performance reveals that Fe SACs achieve an FE of 45% and a yield rate of 56.42 µmol cm−2 h−1 at −0.8 VRHE for ethanol. In situ X‐ray analysis reveals that the Fe SACs have variable electronic states and keeps close +3 of the oxidation state at the potential range of CO2RR. The catalytic feature reduces the reaction energy and induces the electrons transferred to the adsorbed products intermediates of *COOH and *OCHO, thus promoting CO. The carboxylic functional group on the CNTs stabilizes the Fe active sites via electrostatic interaction, verified by density functional theory calculations. The yield rate of Fe SACs indicates that the Fe single‐atom site can instantly provide a large CO to help conversion of CO2‐to‐C2 product on the CNTs.
The Fe–(O)3 single‐atom catalyst synthesis via a simple ionic exchange method on Nafion‐coated functionalized multi‐wall carbon nanotubes (Fe‐n‐f‐CNTs). The Fe SACs and functionalized CNTs are dual active sites toward CO2RR with enhanced selectivity of C2 products. During CO2RR, the carboxylic functional group stabilizes the Fe single‐atom active catalytic site via electrostatic interactions.
We set out in this study to review a vast amount of recent literature on machine learning (ML) approaches to predicting financial distress (FD), including supervised, unsupervised and hybrid ...supervised–unsupervised learning algorithms. Four supervised ML models including the traditional support vector machine (SVM), recently developed hybrid associative memory with translation (HACT), hybrid GA-fuzzy clustering and extreme gradient boosting (XGBoost) were compared in prediction performance to the unsupervised classifier deep belief network (DBN) and the hybrid DBN-SVM model, whereby a total of sixteen financial variables were selected from the financial statements of the publicly-listed Taiwanese firms as inputs to the six approaches. Our empirical findings, covering the 2010–2016 sample period, demonstrated that among the four supervised algorithms, the XGBoost provided the most accurate FD prediction. Moreover, the hybrid DBN-SVM model was able to generate more accurate forecasts than the use of either the SVM or the classifier DBN in isolation.
•This paper reviewed the pros and cons of recent literature on various MLmodels for FDP.•This paper compared the performance of six ML-based approaches using real-life data.•Among the four supervised models, the XGBoost algorithm provided the most accurate FD prediction.•The hybrid DBN-SVM model gave betterforecasts than both the SVM and the classifier DBN models.
Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and ...PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.
•Luteolin and apigenin can downregulate the PD-L1 expression in NSCLC with KRAS mutation.•The combination of apigenin or luteolin with PD-1 mAb enhanced tumor growth control and improved survival.•Apigenin but not luteolin exhibited anti-tumor activity in KRASLA2 mice.
The triglyceride–glucose (TyG) index has been correlated with insulin resistance. We aim to investigate the role of the TyG index on cardiovascular (CV) events in type 2 diabetes mellitus and compare ...the roles of fasting glucose, hemoglobin A1c, and the TyG index in predicting CV events. This retrospective study enrolled 3524 patients with type 2 diabetes from the Kaohsiung Medical University Research Database in 2009 in this longitudinal study and followed them until 2015. The TyG index was calculated as log (fasting triglyceride level (mg/dL) × fasting glucose level (mg/dL)/2). CV events included myocardial infarction, unstable angina, stroke, hospitalization for coronary artery disease, peripheral artery disease, and CV-related death. The association between variables and CV events was assessed using a multivariable stepwise Cox proportional hazard analysis. Two hundred and fifteen CV events (6.1%) were recorded during a follow-up period of 5.93 years. The multivariable stepwise analysis showed that high fasting glucose (HR, 1.007; p < 0.001) and a high TyG index (HR, 1.521; p = 0.004) but not hemoglobin A1c or triglycerides were associated with a higher rate of CV events. Adding fasting glucose and the TyG index to the basic model improved the predictive ability of progression to a CV event (p < 0.001 and p = 0.018, respectively), over that of hemoglobin A1c (p = 0.084) and triglyceride (p = 0.221). Fasting glucose and the TyG index are useful parameters and stronger predictive factors than hemoglobin A1c and triglyceride for CV events and may offer an additional prognostic benefit in patients with type 2 diabetes.
Objective: Zebrafish has been recently considered an ideal vertebrate for studying developmental biology, genetics, particularly for modeling tumorigenesis, angiogenesis, and regeneration in vivo. ...However, when a zebrafish matures completely, its body loses transparency, thus making conventional optical imaging techniques difficult for imaging internal anatomy and vasculature. Acoustic wave penetration outperforms optical methods, high-frequency (>30 MHz) ultrasound (HFUS) was consequently an alternative imaging modality for adult zebrafish imaging, particularly for echocardiography However, visualizing peripheral vessels in a zebrafish by using conventional HFUS is still difficult. Methods: In the present study, high-frequency micro-Doppler imaging (HFμDI) based on ultrafast ultrasound imaging was proposed for zebrafish dorsal vascular mapping in vivo. HFμDI uses a 40-MHz ultrasound transducer, which is an ultrafast ultrasound imaging technology with the highest frequency available currently. Blood flow signals were extracted using an eigen-based clutter filter with different settings. Experiments were performed on an 8-month-old wild-type AB-line adult zebrafish. Results: Blood vessels, including intersegmental vessels, parachordal vessel, dorsal longitudinal anastomotic vessel, and dorsal aorta, from the dorsal side of the zebrafish were clearly observed in two-dimensional (2-D) and 3-D HFμDI. Conclusion: The maximum image depth of HFμDI and the minimal diameter of vessel can be detected were 4 mm and 36 μm, respectively; they were determined without any use of microbubbles. The maximum flow velocity range was approximately 3-4 mm/s on the dorsal vessels of the adult zebrafish. Significance: Compared with conventional ultrasound Doppler imaging, HFμDI exhibited superior small vessel imaging.
Abstract
Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory ...diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not ...completely known but include deletion of the p16 (
) locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature.
This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease.
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