钛金属内植物表面抗菌肽的应用进展

抗菌肽广泛存在于多种生物体内,是生物体非特异性免疫功能的重要组成部分。其可以保护机体免受细菌、真菌、寄生虫和病毒等病原体的侵袭,还具有介导催化、凋亡、免疫调节活性、促进伤口愈合和促成骨等作用,是钛金属内植物表面抗菌涂层研究的热点,具有良好的应用前景。本文就应用于钛金属内植物表面的抗菌肽的抗菌机制、加载方式和应用现状等进行综述。     

Special issue “The advance of solid tumor research in China”: Multi-omics analysis based on 1311 clear cell renal cell carcinoma samples identifies a glycolysis signature associated with prognosis and treatment response

In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8⁺ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.     

Real-world data on the efficacy and safety of pazopanib in IMDC favorable- and intermediate-risk metastatic renal cell carcinoma: a multicenter retrospective cohort study of Chinese patients

BackgroundPazopanib was recommended as first-line treatment option for Metastatic renal cell carcinoma (mRCC), while evidence from strictly selected patients has poor external validity and clinical characteristics are complex in real-world clinical practice. This study aimed to illustrate the survival benefits and safety of pazopanib monotherapy using real-world data of mRCC patients.MethodsThis was a retrospective, multicenter, cohort study. We recruited adult patients with International Metastatic renal cell carcinoma Database Consortium (IMDC) favorable- and intermediate-risk mRCC receiving first-line pazopanib from May 2017 to February 2020. Patients were treated with pazopanib 800 mg or 600 mg orally once daily. Treatment efficacy, and drug safety were analyzed. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Drug safety was assessed according to the grade of treatment-related adverse reactions.ResultsBased on IMDC risk stratification, there were 46 (32.2%) patients in the favorable-risk group and 97 (67.8%) patients in the intermediate-risk group. The median progression-free survival (PFS) of the entire cohort, favorable- and intermediate risk groups was 21.2, 27.1 and 17.2 months, respectively. In the intermediate-risk group, PFS was much longer in patients with 1 risk factor than in patients with 2 risk factors, with a median of 25.9 months versus 11.2 months (P<0.0001). Patients with lung metastasis only had longer PFS than those with bone metastasis only, with a median PFS of 25.9 vs. 21.2 months, respectively. Furthermore, local therapy for the metastatic site appeared to benefit patients in the IMDC favorable-risk group but not those in the IMDC intermediate-risk group. The best response was 40/140 (29%) partial response (PR), 86/140 (61%) stable disease (SD), and 14/140 (10%) progressive disease (PD). The most common adverse drug reactions (ADRs) were change in hair color (47.7%), hypertension (40.0%), diarrhea (40.0%), proteinuria (38.5%), elevation of transaminase (35.4%), and hand–foot skin reaction (32.3%).ConclusionsThis real-world data analysis recommended that patients in intermediate-risk group need to be further stratified according to the number of risk factors. Pazopanib was most suitable for patients with lung metastasis only. Local treatment for metastatic lesions should only be recommended in IMDC favorable patients.     

Identification of prognostic biomarkers in papillary renal cell carcinoma and PTTG1 may serve as a biomarker for predicting immunotherapy response

ObjectiveThis study aims to identify potential prognostic and therapeutic biomarkers in papillary renal cell carcinoma (pRCC).MethodsTwo microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. The protein-protein interaction (PPI) networks and functional annotations of DEGs were established. Survival analysis was utilized to evaluate the prognostic significance of the DEGs and the association between the expression level of candidate biomarkers and various tumour-infiltrating immune cells was explored. The role of PTTG1 in tumour microenvironments (TME) was further explored using Single-cell RNA-seq and its prognostic and therapeutic significance was validated in Fudan University Shanghai Cancer Centre (FUSCC) cohort.ResultsEight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with patients’ prognosis. The expression level of PTTG1 was found to be significantly associated with lymphocytes, immunomodulators, and chemokine in the TCGA cohort. Single-cell RNA-seq information indicated that PTTG1 was strongly associated with the proliferation of T cells. In the FUSCC cohort, the expression level of PTTG1 was also statistically significant for both progression-free survival (PFS) and overall survival (OS) prediction (HR = 2.683, p < .001; HR = 2.673, p = .001). And higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in the FUSCC cohort (χ²=3.99, p < .05).ConclusionsEight genes were identified as a prognostic biomarker and the expression level of PTTG1 was also found to serve as a potential predictor for ICB response in pRCC patients.

Key messages:

• Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with pRCC patients’ prognosis.
• Expression level of PTTG1 was significantly associated with tumour microenvironment including lymphocytes, immunomodulators, and chemokines.
• Higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in FUSCC cohort

     

人工智能在泌尿系统肿瘤中的应用研究进展

近年来,机器学习和神经网络技术的进步使得人工智能(artificial intelligence,AI)在指导临床诊断、治疗和资源投入等方面产生了巨大影响。在泌尿系统肿瘤领域,AI在改善前列腺癌、肾癌和膀胱癌的诊断和治疗方面取得了诸多进步,已可利用机器学习和神经网络技术自动化进行预后预测、治疗计划优化和患者随访教育等。有证据表明,AI指导可以显著降低泌尿系统肿瘤的诊断和治疗管理的主观性。尽管AI在泌尿系统肿瘤中的应用已经成为现代科技的热点,但对比真实世界的医疗决策时,AI仍然存在明显的局限性。通过对AI目前的优势和不足进行概述,旨在为未来AI在泌尿系统肿瘤的精准化、个性化诊治和长期管理中的应用提供参考。     

Multi-omics reveals novel prognostic implication of SRC protein expression in bladder cancer and its correlation with immunotherapy response

PurposeThis study aims to identify potential prognostic biomarkers of bladder cancer (BCa) based on large-scale multi-omics data and investigate the role of SRC in improving predictive outcomes for BCa patients and those receiving immune checkpoint therapies (ICTs).MethodsLarge-scale multi-comic data were enrolled from the Cancer Proteome Atlas, the Cancer Genome Atlas and gene expression omnibus based on machining-learning methods. Immune infiltration, survival and other statistical analyses were implemented using R software in cancers (n = 12,452). The predictive value of SRC was performed in 81 BCa patients receiving ICT from aa validation cohort (n = 81).ResultsLandscape of novel candidate prognostic protein signatures of BCa patients was identified. Differential BECLIN, EGFR, PKCALPHA, ANNEXIN1, AXL and SRC expression significantly correlated with the outcomes for BCa patients from multiply cohorts (n = 906). Notably, risk score of the integrated prognosis-related proteins (IPRPs) model exhibited high diagnostic accuracy and consistent predictive ability (AUC = 0.714). Besides, we tested the clinical relevance of baseline SRC protein and mRNA expression in two independent confirmatory cohorts (n = 566) and the prognostic value in pan-cancers. Then, we found that elevated SRC expression contributed to immunosuppressive microenvironment mediated by immune checkpoint molecules of BCa and other cancers. Next, we validated SRC expression as a potential biomarker in predicting response to ICT in 81 BCa patient from FUSCC cohort, and found that expression of SRC in the baseline tumour tissues correlated with improved survival benefits, but predicts worse ICT response.ConclusionThis study first performed the large-scale multi-omics analysis, distinguished the IPRPs (BECLIN, EGFR, PKCALPHA, SRC, ANNEXIN1 and AXL) and revealed novel prediction model, outperforming the currently traditional prognostic indicators for anticipating BCa progression and better clinical strategies. Additionally, this study provided insight into the importance of biomarker SRC for better prognosis, which may inversely improve predictive outcomes for patients receiving ICT and enable patient selection for future clinical treatment.     

Simvastatin nanoliposome induces myocardial and hepatic toxicities due to its absorption enhancement in mice

Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.     

TCGA database analysis of the tumor mutation burden and its clinical significance in colon cancer

BackgroundColon cancer is one of the most common malignant tumors, with high rates of incidence and death. The tumor mutational burden (TMB), which is characterized by microsatellite instability, has been becoming a powerful predictor which can show tumor behavior and response to immunotherapy.MethodsIn this study, we analyzed 437 mutation data of colon cancer samples obtained from The Cancer Genome Atlas (TCGA) and divided patients into low- and high-TMB groups according to the TMB value. Then we identified differentially-expressed genes (DEGs), conducted immune cell infiltration and survival analyses between groups.ResultsThe higher TMB of the patients with colon cancer predicts a poorer prognosis. Functional analysis was performed to assess the prognostic value of the top 30 core genes. The CIBER-SORT algorithm was used to investigate the correlation between the immune cells and TMB subtypes. An immune prognosis model was constructed to screen out immune genes related to prognosis, and the tumor immunity assessment resource (TIMER) was then used to determine the correlation between gene expression and the abundance of tumor-infiltrating immune cell subsets in colon cancer. We observed that APC, TP53, TTN, KRAS, MUC16, SYNE1, PIK3CA have higher somatic mutations. DEGs enrichment analysis showed that they are involved in the regulation of neuroactive ligand-receptor interaction, the Cyclic adenosine monophosphate (cAMP) signaling pathway, the calcium signaling pathway, and pantothenate and Coenzyme A (CoA) biosynthesis. The difference in the abundance of various white blood cell subtypes showed that Cluster of Differentiation 8 (CD8) T cells (P=0.008), activated CD4 memory T cells (P=0.019), M1 macrophages (P=0.002), follicular helper T cells (P=0.034), activated Natural killer (NK cell) cells (P=0.017) increased remarkably, while M0 macrophages significantly reduced (P=0.025). The two immune model genes showed that secretin (SCT) was negatively correlated with survival, while Guanylate cyclase activator 2A (GUCA2A) was positively correlated.ConclusionsThis study conducted a systematically comprehensive analysis of the prediction and clinical significance of TMB in colon cancer in identification, monitoring, and prognosis of colon cancer, and providing reference information for immunotherapy.     

肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。