Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns

Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(HCC) neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully addressed.Methods: Here we integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explored its interactions with tumor clonal evolution, driver mutations and immune microenvironments.Results: We observed that higher somatic mutation/neoantigen load was associated with better clinical outcomes and HCC patients could be further divided into two subgroups with distinct prognosis based on their neoantigen expression patterns. HCC subgroup with neoantigen expression probability high(NEP-H) showed more aggressive pathologic features including increased incidence of tumor thrombus(P=0.038), higher recurrence rate(P=0.029),more inclined to lack tumor capsule(P=0.026) and with more microsatellite instability sites(P=0.006). In addition,NEP-H subgroup was also characterized by higher chance to be involved in tumor clonal evolution [odds ratio(OR)=46.7, P<0.001]. Gene set enrichment analysis revealed that upregulation of MYC and its targets could suppress immune responses, leading to elevated neoantigen expression proportion in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. Based on identified neoantigen profiles, we also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets in future.Conclusions: Our results revealed the landscape of HCC neoantigens and discovered two clinically relevant subgroups with distinct neoantigen expression patterns, suggesting the neoantigen expression should be fully considered in future immunotherapeutic interventions.

Red Blood Cell-Mimic Nanocatalyst Triggering Radical Storm to Augment Cancer Immunotherapy

Red blood cells(RBCs)have recently emerged as promosing candidates for cancer treatment in terms of relieving tumor hypoxia and inducing oxidative damage against cancer cells,but they are still far from satisfactory due to their limited oxygen transport and reactive oxygen species generation rate in tumor tissue.Herein,artificial RBCs(designated FTP@RBCM)with radical storm production ability were developed for oncotherapy through multidimensional reactivity pathways of Fe-protoporphyrin-based hybrid metal-organic frameworks(FTPs,as the core),including photodynamic/chemodynamic-like,catalase-like and glutathione peroxidase-like activities.Meanwhile,owing to the advantages of long circulation abilities of RBCs provided by their cell membranes(RBCMs),FTP with a surface coated with RBCMs(FTP@RBCM)could enormously accumulate at tumor site to achieve remarkably enhanced therapeutic efficiency.Intriguingly,this ROS-mediated dynamic therapy was demonstrated to induce acute local inflammation and high immunogenic cancer death,which evoked a systemic antitumor immune response when combined with the newly identified T cell immunoglobulin and mucin-containing molecule 3(Tim-3)checkpoint blockade,leading to not only effective elimination of primary tumors but also an abscopal effect of growth suppression of distant tumors.Therefore,such RBC-mimic nanocatalysts with multidimensional catalytic capacities might provide a promising new insight into synergistic cancer treatment.

Au/Ag_(2)S dimeric nanostructures for highly specific plasmonic sensing of mercury(Ⅱ)

Although many plasmonic nanosenosrs have been established for the detection of mercury(Ⅱ)(Hg^(2+)),few of them is feasible for analyzing natural samples with very complex matrices because of insufficient method selectivity.To address this challenge,we propose an epitaxial and lattice-mismatch approach to the synthesis of a unique Au/Ag_(2)S dimeric nanostructure,which consists of an Au segment with excellent plasmonic characteristics,and a highly stable Ag_(2)S portion with minimum solubility product (K_(sp)(Ag_(2)S)=6.3×10^(-50)).The detection relies on the chemical conversion of Ag_(2)S to HgS when reacting with Hg^(2+),resulting in a red shift in the absorption band of the connecting Au NPs.The concurrent color changes of the solution from gray purple to dark green and finally to navy correlate well with Hg^(2+)concentration,thus enables UV-vis quantitation and a naked-eye readout of the Hg^(2+)concentration.This method exhibits superior selectivity towards Hg^(2+) over other interfering ions tested because Hg^(2+) is the only ion that can react with Ag_(2)S to form HgS with even smaller solubility product (K_(sp)(HgS)=4×10^(-53)).The detection limit of this method is 1.21μmol/L,calculated by the signal-to-noise of 3.The practicability of the method was verified by analyzing the Hg^(2+)in sewage water samples without sample pretreatment with satisfactory recoveries (93.1%-102.8%) and relative standard deviations (1.38%-2.89%).We believe this method holds great potential for on-the-spot detection of Hg^(2+) in environmental water samples with complex matrices.

Embedding lead halide perovskite quantum dots in carboxybenzene microcrystals improves stability

The stability of lead halide perovskite quantum dots （PQDs） was improved by embedding them in carboxybenzene microcrystals. The resulting needle-shaped mixed microcrystals preserved the strong photoluminescence of the PQDs. Compared with previously reported polystyrene-encapsulated PQDs, the carboxybenzene crystals were robust and protected the dots from moisture and photodegradation. The enhanced stability was attributed to the tight matrix of carboxybenzene microcrystals, which protected the PQDs from moisture. This versatile strategy protected various QDs, including all-inorganic PQDs and chalcogenide QDs （e.g., CdSe/ZnS QDs and CuInS/ZnS QDs）. It provides a facile and versatile method of protecting PQDs and may enable applications in solid-state systems with high color quality requirements such as displays, lasers, and light emitting diodes.

Colloidal CsPbBr3 perovskite nanocrystal films as electrochemiluminescence emitters in aqueous solutions

Perovskite nanocrystals （NCs）, which have emerged as a new class of phosphors with superb luminescence properties and bandgaps that can be easily tuned using chemical methods, have generated tremendous interest for a wide variety of applications where colloidal quantum dots have been very successful as carrier sources. In this study, self-assembled films of CsPbBr3 NCs were produced via drop casting of colloidal NCs onto glassy carbon electrodes （GCEs） to form an NC film-modified electrode. The possible fabrication process of the CsPbBr3 NCs films was discussed. We further studied the anodic electrochemiluminescence （ECL） behavior of the perovskite CsPbBr3 NCs film using cyclic voltammetry with tripropylamine （TPA） as a coreactant, and a possible ECL mechanism was proposed. Briefly, TPA was oxidized to produce strongly reducing radical spedes, which can react with electrochemically oxidized CsPbBr3 NCs to generate excited CsPbBr3 NCs＊ capable of light emission. The relative stability of the ECL emission of the CsPbBr3 NC films under aqueous conditions was also investigated, and it was found that they showed operational stability over the first three hours, indicating suitable reliability for application as sensing materials. The results suggested that semiconducting perovskite NCs have great potential for application in the ECL field.

循环肿瘤DNA对中国肝癌诊断价值的Meta分析

目的系统评价循环肿瘤DNA(ctDNA)在中国人群原发性肝癌(肝癌)中的诊断价值。方法检索PubMed、Web of Science、Embase、中国知网、万方、维普数据库中从建库至2021年11月关于应用ctDNA诊断肝癌的文献。中英文检索词为循环肿瘤DNA、ctDNA、游离DNA、循环DNA、cfDNA、血浆DNA、血清DNA,以及肝癌、肝细胞癌、肝肿瘤、肝脏肿瘤、原发性肝癌等。对纳入文献进行数据提取和质量评估后,采用Review Manager 5.3和Stata 15.1统计软件计算合并敏感度、特异度,绘制森林图和综合受试者操作特征(sROC)曲线并计算曲线下面积(AUC)。通过Meta回归分析和亚组分析分析异质性来源。绘制Deek's漏斗图检验发表偏倚。结果共纳入符合标准的文献25篇,包括4063例肝癌患者和3509例对照。其中5项研究为检测ctDNA浓度的定量分析,14篇为检测ctDNA中的肿瘤特异性单基因甲基化的定性分析,6篇通过ctDNA的特征构建模型进行诊断。定量研究组的合并敏感度、特异度及AUC分别为0.68(0.58~0.77)、0.82(0.71~0.89)和0.81(0.77~0.84);定性研究组相应为0.55(0.47~0.62)、0.99(0.93~1.00)和0.80(0.77~0.83);模型构建组相应为0.81(0.72~0.87)、0.91(0.85~0.94)和0.93(0.90~0.95)。Deek's漏斗图检验显示,定量研究组(t=1.080,P>0.05)、定性研究组(t=0.690,P>0.05)和模型构建组(t=0.230,P>0.05)均不存在明显的发表偏倚。结论ctDNA在我国肝癌诊断中具有良好的应用价值,利用ctDNA构建模型的诊断性能优于定量分析和定性分析。