Immune evasion mechanisms and therapeutic strategies in gastric cancer

Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.     

微创超声乳化手术前后角膜前后表面及不同区域范围角膜参数的变化

目的：比较白内障微创超声乳化手术前后角膜前表面屈光力(ASF)、角膜真实净屈光力(TNP)和总角膜屈光力(TCRP)分布特点及角膜前后表面曲率半径比(B/F ratio)差异。

方法：前瞻性研究。收集2020-12/2021-05就诊于潍坊眼科医院行2.2mm微切口超声乳化白内障吸除联合人工晶状体植入术的年龄相关性白内障患者156例156眼。术前及术后3mo行Pentacam眼前节生物测量仪检查，收集以角膜顶点和以瞳孔为中心2、4、6mm环上和区域内ASF、TNP和TCRP，以及手术前后B/F ratio。

结果：术后3mo，以角膜顶点为中心2mm直径环上和区域内ASF值较术前均无差异(均P>0.05)，而4、6mm直径环上和区域内ASF值较术前均有差异(均P<0.05)； 以瞳孔为中心2mm直径环上及区域内ASF值较术前均无差异(均P>0.05)。以角膜顶点为中心和以瞳孔为中心2、4、6mm直径环上和区域内TNP、TCRP值较术前均有差异(均P<0.05)。术前以角膜顶点为中心和瞳孔为中心在2mm与6mm之间环上和4mm与6mm之间环上TCRP值均有差异(均P<0.0167)； 在2mm与6mm区域内TCRP值均有差异(均P<0.0167)； 术后3mo，以角膜顶点为中心和瞳孔为中心环上TCRP值在2mm与6mm之间、4mm与6mm之间均有差异(均P<0.0167)，而以角膜顶点为中心和瞳孔为中心区域内TCRP值仅在2mm与6mm直径范围内有差异(P<0.0167)。B/F ratio术前为81.79%±1.87%，术后3mo为80.68%±2.23%(P<0.001)。

结论：白内障手术前后以角膜顶点和以瞳孔为中心的不同直径环上及区域内各项角膜屈光力参数会有一定的变化和差异，人工晶状体度数计算的K值选择及基于角膜特性的人工晶状体个体化选择时应予以考虑。     

Time-varying association of second primary malignancy and long-term survival outcomes in patients with head and neck cancer

A high risk of developing second primary malignancy (SPM) has been reported among head and neck cancer patients. Here, we aimed to statistically quantify the impact of SPM development on the survival of head and neck cancer patients. Our study was conducted using the Surveillance, Epidemiology and End Results database to collect the data of 48 316 patients who received curative surgical resection for initial primary head and neck squamous cell carcinoma (IP-HNSCC) in 1975 to 2019. SPM diagnosis was treated as a time-varying covariate and multivariable Cox regression analysis was conducted to estimate the association between SPM development and survival, overall or by the subsite of IP-HNSCC. Of the included patients, 11 238 patients (23.3%) developed SPM during the follow-up period. A significant reduction in survival was observed among patients with SPM (hazard ratio [HR] for overall survival, 3.30; 95% confidence interval [CI]: 3.20-3.41). The impact of SPM development on reduced survival was more significant in patients with localized IP-HNSCC vs regional IP-HNSCC (HR_OS, 3.41; 95% CI: 3.24-3.6 vs HR_OS, 3.18; 95% CI: 3.05-3.31; P for interaction <.001). The survival impact of SPM development was more evident in younger patients than in older patients. SPM in lung and bronchus was associated with the most pronounced reduction in survival, overall and across all subsites of HNSCC. Our results indicated that SPM development led to a significant reduction in survival. A greater survival benefit may be achieved through intensive surveillance for SPM in lung and bronchus targeting younger patients and those with localized HNSCC.     

Tumor Mutation Burden,Immune Cell Infiltration,and Construction of Immune-Related Genes Prognostic Model in Head and Neck Cancer

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and the prognosis of HNSCC remains bleak. Numerous studies revealed that the tumor mutation burden (TMB) could predict the survival outcomes of a variety of tumors.Objectives: This study aimed to investigate the TMB and immune cell infiltration in these patients and construct an immune-related genes (IRGs) prognostic model.Methods: The expression data of 546 HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) database. All patients were divided into high- and low- TMB groups, and the relationship between TMB and clinical relevance was further analyzed. The differentially expressed genes (DEGs) were identified using the R software package, limma. Functional enrichment analyses were conducted to identify the significantly enriched pathways between two groups. CIBERSORT algorithm was adopted to calculate the abundance of 22 leukocyte subtypes. The IRGs prognostic model was constructed via the multivariate Cox regression analysis.Results: Missense mutation and single nucleotide variants (SNV) were the most predominant mutation types in HNSCC. TP53, TTN, and FAT1 were the most frequently mutated genes. Patients with high TMB were observed with worse survival outcomes. The functional analysis of TMB associated DEGs showed that the identified DEGs mainly involved in spliceosome, RNA degradation, proteasome, and RNA polymerase pathways. We observed that macrophages, T cells CD8, and T cells CD4 memory were the most commonly infiltrated subtypes of immune cells in HNSCC. Finally, an IRGs prognostic model was constructed, and the AUC of the ROC curve was 0.635.Conclusions: Our results suggest that high TMB is associated with poor prognosis in HNSCC patients. The constructed model has potential prognostic value for the prognosis of these individuals, and it needs to be further validated in large-scale and prospective studies.     

Clinical Implications of HSC70 Expression in Clear Cell Renal Cell Carcinoma

Purpose: The role of heat shock protein 70 (HSC70) in the progression of clear cell renal cell carcinoma (ccRCC) is unclear. This study explored the effect of the HSC70 on the survival of ccRCC patients.Methods: Immunohistochemical analysis was performed to determine HSC70 expression in samples obtained from 121 ccRCC patients with at least 5 years of follow-up. We also analyzed the association between HSC70 expression and clinicopathological characteristics. Furthermore, the association of overall survival (OS) with HSC70 expression was analyzed using Kaplan-Meier curves. Finally, we used the Oncomine and CCLE databases to determine the effects of HSC70 mRNA expression on ccRCC.Results: HSC70 expression was associated with distant metastasis and death of ccRCC patients. HSC70 was expressed in the nucleus and/or cytoplasm of ccRCC cells. The incidence of distant organ metastasis and death was higher in patients with HSC70 expression than in those without it. Survival analysis revealed that patients with HSC70 expression had significantly shorter OS. Oncomine analyses also showed that the HSC70 mRNA was significantly upregulated in ccRCC tissues.Conclusions: HSC70 expression was related to adverse prognosis, and patients with HSC70 expression had a worse prognosis than those without HSC70 expression. HSC70 may thus serve as a potential therapeutic target for ccRCC.     

Long-term durable repaired cartilage induced by SOX9 in situ with bone marrow-derived mesenchymal stem cells

Background: Microfracture is a common procedure for cartilage repair, but it often produces inferior fibrocartilage. We previously reported that a super positively charged SOX9 (scSOX9) promoted hyaline-like cartilage regeneration by inducing bone marrow derived mesenchymal stem cell differentiation into chondrocytes in vivo. Here we examined the long-term efficacy of cartilage repair induced by microfracture with scSOX9 by assessing the biomechanical property of the repaired cartilage.Methods: A cartilage defect was created at the right femoral trochlear groove in New Zealand female rabbits and microfracture was performed. The scSOX9 protein was administered at the site of microfracture incorporated in a collagen membrane.Results: At 12 and 24 weeks, scSOX9 treatment induced hyaline-like cartilage while collagen-membrane alone induced fibrocartilage and mutant scSOX9-A76E poorly induced cartilage repair. The cartilage matrix in scSOX9-treated group showed highly enriched proteoglycan content. Consistent with the histological feature and the thickness of the repaired cartilage, the mechanical property of scSOX9-induced cartilage was also similar to that of normal cartilage.Conclusion: This long-term in vivo study demonstrated that in combination with microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage which was durable in long-term. This technology has the potential to translate into clinical use for cartilage repair to prevent progression to osteoarthritis.     

基于扎根理论的中成药上市后再评价专家访谈资料分析＊

目的 开展更全面的中成药临床应用资料收集，并对非定量化资料进行定性处理。方法 运用专家深度访谈的方法，以某中成药的临床应用为例，对临床上使用过该中成药的专家进行半结构式访谈，记录并整理访谈资料，引入扎根理论方法进行访谈资料分析。结果 本研究共访谈了10位专家，经扎根理论分析编码，将该中成药的临床应用编码为该药的背景、有效性、安全性、经济便宜性、依从性、临床定位6个主范畴，最终提炼出一个核心类属，并围绕这几个方面的具体信息进行详细分析。结论 通过收集、整理和分析专家经验性信息，丰富了中成药上市后再评价的临床证据集，明确了已上市中成药的临床应用范围，可为后续的临床和科研研究提供证据支持，同时，专家深度访谈和扎根理论分析是对专家经验的挖掘和利用，还可应用于中医经验传承、医者诊疗思维研究等领域。本研究进行了方法探讨和实例验证，以期为后续更高阶的研究奠定基础。