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.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
This article presents a control scheme for robot manipulators with the consideration of output error constraints, unknown dynamics, and bounded disturbances. A modified virtual input variable in the ...second stage design of the dynamic surface control scheme is proposed, which can enhance the robustness of the controller. Bounded disturbances due to the situations that the base is not well fixed if the robot manipulator is mounted at a mobile platform are considered and suppressed. Besides, the detailed implementation process of the composite learning laws adopted for enhancing the radial basis function neural network is presented. Lyapunov stability analysis verifies that the proposed control scheme ensures the trajectory tracking errors stay within predefined boundaries and parameter estimate errors converge without a stringent condition termed persistent excitation. Experimental results show the superiority of the proposed controller regarding parameter estimation and tracking capabilities.
MXene aerogels have shown great potential for many important functional applications, in particular electromagnetic interference (EMI) shielding. However, it has been a grand challenge to create ...mechanically hyperelastic, air‐stable, and durable MXene aerogels for enabling effective EMI protection at low concentrations due to the difficulties in achieving tailorable porous structures, excellent mechanical elasticity, and desired antioxidation capabilities of MXene in air. Here, a facile strategy for fabricating MXene composite aerogels by co‐assembling MXene and cellulose nanofibers during freeze‐drying followed by surface encapsulation with fire‐retardant thermoplastic polyurethane (TPU) is reported. Because of the maximum utilization of pore structures of MXene, and conductive loss enhanced by multiple internal reflections, as‐prepared aerogel with 3.14 wt% of MXene exhibits an exceptionally high EMI shielding effectiveness of 93.5 dB, and an ultra‐high MXene utilization efficiency of 2977.71 dB g g−1, tripling the values in previous works. Owing to the presence of multiple hydrogen bonding and the TPU elastomer, the aerogel exhibits a hyperelastic feature with additional strength, excellent stability, superior durability, and high fire safety. This study provides a facile strategy for creating multifunctional aerogels with great potential for applications in EMI protection, wearable devices, thermal management, pressure sensing, and intelligent fire monitoring.
Hyperelastic, robust, fire‐safe multifunctional MXene aerogels with superior electromagnetic interference (EMI) shielding, thermal insulation, and air/moisture resistance are created by an encapsulation strategy. The MXene aerogel shows high EMI shielding effectiveness of 93.5 dB and ultra‐high EMI utilization efficiency of MXene of 2977.71 dB g g−1, resulting from efficient utilization of pore structure and multiple internal reflections.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Weyl semimetals provide the realization of Weyl fermions in solid-state physics. Among all the physical phenomena that are enabled by Weyl semimetals, the chiral anomaly is the most unusual one. ...Here, we report signatures of the chiral anomaly in the magneto-transport measurements on the first Weyl semimetal TaAs. We show negative magnetoresistance under parallel electric and magnetic fields, that is, unlike most metals whose resistivity increases under an external magnetic field, we observe that our high mobility TaAs samples become more conductive as a magnetic field is applied along the direction of the current for certain ranges of the field strength. We present systematically detailed data and careful analyses, which allow us to exclude other possible origins of the observed negative magnetoresistance. Our transport data, corroborated by photoemission measurements, first-principles calculations and theoretical analyses, collectively demonstrate signatures of the Weyl fermion chiral anomaly in the magneto-transport of TaAs.
•A bio-inspired flexible and superhydrophobic fabric is prepared for electromagnetic interference shielding.•The conductivity of the composite fabric could reach 4000 S/m.•The composite fabric ...possesses a high specific shielding effectiveness of 209.6 dB cm3 g−1.•The excellent EMI shielding performance could be maintained after multiple abrasion and cyclic bending tests.
Electromagnetic pollution often causes disturbances to nearby electronic apparatus and also severely threatens people’s health, and it is therefore urgent to develop electromagnetic interference (EMI) shielding materials. However, preparation of EMI shielding materials with lightweight, good flexibility, superior corrosion-resistance, excellent EMI shielding performance remains challenging. Here, a facile method is proposed to prepare flexible, superhydrophobic and highly conductive polymer composite fabrics for the EMI shielding. The polydopamine (PDA) is first decorated onto the fabric surface, and the functional groups in the PDA could promote the Ag precursor adsorption. The electrically conductive PP fabric becomes superhydrophobic and anti-corrosive after further treatment with a fluorine containing molecule. The average shielding effectiveness (SE) and specific SE (SSE) of the composite fabric could reach as high as 48.2 dB and 209.56 dB cm3 g−1 at the frequency of 8.2–12.4 GHz, respectively, which could even be maintained after the composite fabric undergoes cyclic abrasion and bending tests. Furthermore, the superhydrophobic surface ensures the reliability of the conductive fabric as shielding materials when they are used in harsh conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This work reports the preparation of N-doped reduced graphene oxide decorated NiSe2 nanoparticles (N-rGO/NiSe2) in the presence of different amount of graphene oxide reactant by a simple two-step ...process, which contains hydrothermal preparation of Ni(OH)2 precursor and then solvothermal synthesis of N-rGO/NiSe2 composites with different content of N-rGO. The as-prepared N-rGO/NiSe2 composites is characterized by power X-ray diffraction, Raman spectroscopy, high-resolution X-ray photoelectron spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy and N2 adsorption–desorption isotherm. The results show that N-rGO acts as supporter of NiSe2 nanoparticles to prevent them from aggregation, leading to the increase in specific surface area and electrical conductivity of material. The optimized N-rGO/NiSe2 composite can deliver high specific capacitance of 2451.4 F g−1 at a current density of 1 A g−1. Using activated carbon (AC) as negative electrode and the optimized N-rGO/NiSe2 composite as positive electrode, an asymmetric supercapacitor is constructed. This fabricated asymmetric supercapacitor can work stably under the potential window of 0–1.6 V, and presents the maximum energy density of 40.5 Wh kg−1 at a power density of 841.5 W kg−1. Moreover, the N-rGO/NiSe2//AC asymmetric supercapacitor exhibits good cyclic stability.
•N-rGO/NiSe2 composite is prepared by a simple two-step method.•N-rGO increases the specific surface area and electrical conductivity of material.•N-rGO/NiSe2 composite-based asymmetric supercapacitor is assembled.•The asymmetric supercapacitor shows high energy density.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•We evaluated PD-L1 expression on tumor cells (TCs) and immune cells (ICs).•Relationship between M2 tumor-associated macrophages (TAMs) and PD-L1 was studied.•PD-L1 expression on TCs and ICs was ...higher in patients with M2 TAM-high tumors.•PD-L1 on ICs rather than TCs was more related to aggressive malignant behaviors.•The presence of M2 TAMs might affect PD-L1 expression both on TCs and ICs in NSCLC.
PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) plays important roles in regulating the antitumor T cell response. However, the mechanistic and clinical significance of the effect of PD-L1 on TCs versus ICs remains unclear. On the other hand, tumor-associated macrophages (TAMs), M2 macrophages in particular, can promote tumor progression.
We evaluated PD-L1 expression on TCs and ICs using Ventana SP263 assay and the stromal M2 TAM distribution using CD163 staining in 160 consecutive patients with resected non-small cell lung cancer (NSCLC).
PD-L1 expression on TCs and ICs was significantly higher in stromal M2 TAM-high group than in stromal M2 TAM-low group (p < 0.001 and p < 0.001, respectively). Regarding the clinical significance of PD-L1, PD-L1 expression on TCs was significantly associated with histology (p = 0.001), tumor differentiation (p < 0.001) and nodal status (p = 0.029). Furthermore, PD-L1 expression on ICs was significantly associated with histology (p < 0.001), tumor differentiation (p < 0.001), tumor status (p = 0.024), nodal status (p = 0.016), and pathologic stage (p = 0.004). The disease-free survival rate was significantly lower in patients with PD-L1-positive TC than in those with PD-L1-negative TC (p = 0.023), as well as in patients with PD-L1-positive IC than in those with PD-L1-negative IC (p < 0.001). Furthermore, the overall survival rate was significantly lower in patients with PD-L1-positive IC than in those with PD-L1-negative IC (p = 0.023).
During tumor progression in NSCLC, the presence of M2 TAMs might affect PD-L1 expression both on TCs and ICs. In patients with NSCLC, PD-L1 expression both on TCs and ICs was associated with malignant behaviors, which was more in case of ICs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this trial was to address whether elective ipsilateral upper-neck irradiation (UNI) sparing the uninvolved lower neck provides similar regional relapse-free survival compared with standard ...whole-neck irradiation (WNI) in patients with nasopharyngeal carcinoma.
This open-label, non-inferiority, randomised, controlled, phase 3 trial was done at three Chinese medical centres. Patients aged 18–65 years with untreated, non-keratinising, non-distant metastatic (M0) nasopharyngeal carcinoma; with N0–N1 disease (according to International Union Against Cancer–American Joint Committee on Cancer TNM classification, seventh edition); and a Karnofsky performance status score of 70 or higher were randomly assigned (1:1) to receive elective UNI or WNI of the uninvolved neck. Total radiation doses of 70 Gy (for the primary tumour volume and the enlarged retropharyngeal nodes), 66–70 Gy (for the involved cervical lymph nodes), 60–62 Gy (for the high-risk target volume), and 54–56 Gy (for the low-risk target volume) were administered in 30–33 fractions, five fractions per week. Patients with stage II–IVA disease were recommended to receive combined intravenous cisplatin-based chemotherapy (either induction chemotherapy followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone). Randomisation was done centrally by the Clinical Trials Centre of Sun Yat-sen University Cancer Centre by means of a computer-generated random number code with a block size of four. Patients were stratified according to treatment centre and nodal status. Investigators and patients were not masked to treatment allocation. The primary endpoint was regional relapse-free survival in the intention-to-treat population. Non-inferiority was indicated if the upper limit of the 95% CI of the difference in 3-year regional relapse-free survival between the UNI and WNI groups was within 8%. Adverse events were analysed in the safety population (defined as all patients who commenced the randomly assigned treatment). This study is registered with ClinicalTrials.gov, NCT02642107, and is closed.
Between Jan 22, 2016, and May 23, 2018, 446 patients from 469 screened were randomly assigned to receive UNI (n=224) or WNI (n=222). Median follow-up was 53 months (IQR 46–59). 3-year regional relapse-free survival was similar in the UNI and WNI groups (97·7% 95% CI 95·7–99·7 in the UNI group vs 96·3% 93·8–98·8 in the WNI group; difference −1·4% 95% CI −4·6 to 1·8; pnon-inferiority<0·0001). Although acute radiation-related toxic effects were similar between the groups, the incidence of late toxicity was lower in the UNI group than in the WNI group, including any-grade hypothyroidism (66 30% of 222 patients vs 87 39% of 221), skin toxicity (32 14% vs 55 25%), dysphagia (38 17% vs 71 32%), and neck tissue damage (50 23% vs 88 40%). No patients died during treatment. After treatment, one patient in the WNI group died from a non-cancer-related cause (dermatomyositis).
Elective UNI of the uninvolved neck provides similar regional control and results in less radiation toxicity compared with standard WNI in patients with N0–N1 nasopharyngeal carcinoma.
Sun Yat-sen University Clinical Research 5010 Program, the Natural Science Foundation of Guangdong Province, and the Overseas Expertise Introduction Project for Discipline Innovation.
For the Chinese translation of the abstract see Supplementary Materials section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Piezoelectric-actuated stick-slip device (PASSD) is a highly promising equipment that is composed of one end-effector, one piezoelectric actuator (PEA) and one driving object adhered to the PEA. ...Since the end-effector can slip on the surface of the driving object, the PASSD is capable of realizing the macrolevel motion with the microlevel precision. Due to the following two reasons: the complicated relative motion between the end-effector and the driving object, and the inherent hysteresis nonlinearity in the PEA, the ultraprecision displacement control of the end-effector of PASSDs raises a real challenge, which is rarely reported in the literature. Toward solving this challenge, a neural-network-based controller is proposed in this paper. First, a neural-network-based model is proposed to capture the relative motion between the end-effector and the driving object. Second, a neural-network-based inversion model is developed to online calculate the desired position of the PEA under the predesigned reference of the end-effector. Third, a dynamic linearized neural-network-based model predictive control method, which can effectively handle the hysteresis nonlinearity, is employed to implement the displacement control of the PEA, which finally results in an overall high-precision controller of the end-effector. Finally, a PASSD prototype has been implemented and tested through experimental studies to demonstrate the effectiveness of the proposed approach.
Piezoelectric actuators (PEAs) are widely used in the nanopositioning applications due to their high stiffness, fast response, and ultrahigh precision. However, PEAs inherently have the hysteresis ...nonlinearity which can dramatically degrade the tracking performance. This paper proposes an adaptive Takagi-Sugeno (T-S) fuzzy model-based predictive controller with a parallel distributed control structure. Compared to the previous results, the proposed controller does not require the inverse hysteresis model of PEAs, and is easy to be calculated because the predictive subcontroller for each T-S fuzzy rule has an explicit form. Meanwhile, the parameters in the T-S fuzzy model can be online adjusted according to the real-time tracking error feedback, and the offline training accuracy of the T-S fuzzy model is no longer a serious concern. In addition, some physical constraints of the proposed controller can be well handled. To verify the proposed method, experiments are conducted on a commercial PEA product, and experiment results show that the proposed method has a satisfactory tracking performance. Furthermore, comparisons with some existing controllers are made and the proposed adaptive fuzzy model-based predictive controller outperforms these controllers.
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