脂质纳米粒-mRNA递送系统及其在嵌合抗原受体T细胞治疗中的应用

尽管嵌合抗原受体（CAR）T细胞治疗在血液系统恶性肿瘤患者中取得了显著的临床疗效，但需要进一步优化。脂质纳米粒（LNP）-信使核糖核酸（mRNA）递送系统作为一种非病毒性基因载体运用于CAR-T细胞治疗研究中，一方面通过LNP将密封蛋白-6 mRNA靶向递送至抗原提呈细胞，从而实现抗原提呈细胞辅助性增强密封蛋白-6靶向的CAR-T细胞的功能，以进一步诱导对实体瘤的清除；另一方面，通过LNP将成纤维细胞激活蛋白（FAP）CARmRNA靶向递送至T细胞，实现体内FAP靶向的CAR-T细胞的制备，以通过阻断心脏纤维化过程达到治疗急性心肌损伤的目的。在CAR-T细胞研究和治疗中，LNP-mRNA递送系统具有不与细胞基因组整合、价格便宜、毒副作用小及可修饰等优点，亦存在蛋白瞬时表达导致调控细胞功能的持久性不足及制备等方面的技术局限性。本文综述了LNP-mRNA递送系统及其在CAR-T细胞治疗中的应用研究。     

微创Chevron-Akin截骨术治疗轻中度拇外翻的早期疗效分析

目的:探讨微创Chevron-Akin(minimally invasive Chevron-Akin,MICA)截骨术治疗轻中度拇外翻的早期临床疗效。方法:自2019年6月至2021年4月,采用MICA截骨术治疗26例(29足)轻中度拇外翻患者,其中男1例,女25例;年龄19~78(38.3±19.5)岁。观察并比较手术前后拇外翻角(hallux valgus angle,HVA),第1、2跖骨间角(intermetatarsal angle,IMA),第1跖骨短缩。末次随访时采用美国骨科足踝外科协会(American Orthopedic Foot and Ankle Society,AOFAS)前足评分系统及视觉模拟评分(visual analogue scale,VAS)评价治疗效果,并记录相关并发症。结果:26例(29足)均获得随访,时间12~33(19.6±5.1)个月。HVA、IMA分别由术前的(32.3±6.6)°、(11.7±3.2)°矫正为术后的(13.0±5.3)°、(6.1±3.2)°,差异有统计学意义(P<0.01);第1跖骨短缩(2.7±1.1) mm。AOFAS评分由术前的(55.7±7.4)分提高到术后的(88.5±7.9)分(P<0.01),其中优15足,良11足,可3足。VAS由术前的(6.5±1.5)分改善为术后的(0.7±0.4)分(P<0.01)。结论:MICA截骨术创伤小,术后恢复快,并发症率低,并且能有效改善拇外翻畸形,是治疗轻中度拇外翻的安全可靠手术方法。     

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

ObjectiveTo study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).Patients and MethodsThe Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).ResultsA total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.ConclusionThe identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.     

基于网络药理学和分子对接技术研究黄芪-赤芍治疗COPD的作用机制＊

目的 基于网络药理学和分子对接技术探究黄芪-赤芍配伍对治疗慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）的作用机制。方法 利用TCMSP，Pharmmaper数据库，筛选黄芪-赤芍治疗COPD的活性成分和潜在靶点；结合Genecards数据库挖掘的COPD相关靶点，对黄芪-赤芍药对与COPD靶点进行PPI网络构建，交互处理得到黄芪-赤芍药对治疗COPD的关键靶点，并进行GO分析和KEGG通路富集分析；并采用分子对接技术将主要活性成分与TNF-α（肿瘤坏死因子），IL-6（白细胞介素6）等进行分子对接；最后利用A549炎症细胞与人脐静脉内皮细胞缺氧损伤模型进行体外细胞实验对结果加以验证。结果 黄芪-赤芍药对中44个有效成分作用于COPD，核心成分为：槲皮素、山奈酚、丁子香萜、芍药苷、（2R，3R）-4-methoxyl-distylin、二氢异黄酮；黄芪-赤芍药对通过IL6、PTGS2、TNF等113个靶蛋白，调控Ras、PI3KAkt、IL-17等多条信号通路治疗COPD，且分子对接结果显示槲皮素、山奈酚、丁子香萜、芍药苷与IL-6、PTGS2、TNF大分子蛋白有良好的结合性，体外细胞试验证实，槲皮素与山奈酚均能减少IL-8，MMP-9炎症因子的分泌，具有不同程度的抗炎效果；芍药苷有明显的扩血管、抗血栓之效。结论 黄芪-赤芍药对治疗COPD具有多成分、多靶点、多通路、整体调节的作用特点。初步揭示了黄芪-赤芍药对通过抑制炎症反应、调节上皮细胞生长增强保护屏障等预测出黄芪-赤芍药对治疗COPD的潜在作用机制，以期为其活性成分的药效物质基础提供理论研究和思路。     

Radiation-associated angiosarcoma of the breast: An international multicenter analysis

IntroductionRadiation-associated angiosarcoma (RAAS) is a rare and serious complication of breast irradiation. Due to the rarity of the condition, clinical experience is limited and publications on this topic include only retrospective studies or case reports.Materials and methodsAll patients diagnosed with RAAS between January 2000 and December 2017 in twelve centers across the Czech Republic and Slovakia were evaluated.ResultsData of 53 patients were analyzed. The median age at diagnosis was 72 (range 44–89) years. The median latency period between irradiation and diagnosis of RAAS was 78 (range 36–172) months. The median radiation dose was 57.6 (range 34–66) Gy. The whole breast radiation therapy with radiation boost to the tumor bed was the most common radiotherapy regimen. Total mastectomy due to RAAS was performed in 43 patients (81%), radical excision in 8 (15%); 2 patients were not surgically treated due to unresectable disease. Adjuvant chemotherapy followed surgical therapy of RAAS in 18 patients, 3 patients underwent adjuvant radiotherapy. The local recurrence rate of RAAS was 43% and the median time from surgery to the onset of recurrence was 7.5 months (range 3–66 months). The 3-year survival rate was 56%, the 5-year survival rate was only 33%. 46% of patients died during the follow-up period.ConclusionThe present data demonstrate that RAAS is a rare condition with high local recurrence rate (43%) and mortality (the 5-year survival rate was 33%.). Early diagnosis of RAAS based on biopsy is crucial for treatment with radical intent. Surgery with negative margins constitutes the most important part of the therapy; the role of adjuvant chemotherapy and radiotherapy is still unclear.     

Innovating medication reviews through a technology-enabled process

Medication reviews are effective in improving the quality of medication use among older people. However, they are conducted to various standards resulting in a wide range of outcomes which limit generalisability of findings arising from research studies. There also appear to be funding and time constraints, lack of data storage for quality improvement purposes, and non-standardised reporting of outcomes, especially clinically relevant outcomes. Furthermore, the coronavirus disease-19 (COVID-19) pandemic has restricted many face-to-face activities, including medication reviews. This article introduces a technology-enabled approach to medication reviews that may overcome some limitations with current medication review processes, and also make it possible to conduct medication reviews during the COVID-19 pandemic by providing an alternate platform. The possible advantages of this technology-enabled approach, legislative considerations and possible implementation in practice are discussed.     

Molecular testing for melanocytic tumors: a practical update

The work-up of melanocytic tumors has undergone significant changes in the last years following the exponential growth of molecular assays. For the practicing pathologist it is often difficult to sort through the myriad of different tests available currently for clinical use. The molecular tests used in melanocytic pathology can be broadly divided into 4 categories: (i) Tests useful in the differential diagnosis of nevus versus melanoma (primarily used as an aid in the diagnosis of histologically ambiguous melanocytic tumors), (ii) Tests that predict prognosis in melanoma, (iii) Tests useful in the classification of melanocytic tumors and (iv) Tests that predict response to systemic therapy in melanoma. This review will present an updated overview of major ancillary tests used in clinical practice.     

28例原发性卵黄囊瘤患者的CT表现分析

目的分析28例原发性卵黄囊瘤(YST)患者的CT表现。方法选择2015年2月至2019年12月收治的28例YST患者的临床资料进行回顾性分析,8例YST患者入院后均予以CT检查,然后对患者的CT影像学特征和临床资料数据进行分析比较。结果本研究中28例YST患者肿瘤位于性腺的有17例(60.71%),其中位于睾丸、卵巢处的分别有7例、10例,占比分别为60.71%、41.18%,均为单侧发病;9例(39.29%)位于性腺外,其中位于骶尾部、前纵隔、阴道的分别有6例、2例、1例,占比分别为66.67%、22.22%、11.11%。CT检测可见肿瘤"浅分叶",且呈"椭网形",18例(64.29%)肿瘤边界较为清晰,9例(32.14%)呈"深分叶状"形态不规则;8例(28.57%)边界模糊,肿瘤大小分析可见,肿瘤位于前纵隔、卵巢的相对较大,位于阴道、睾丸、骶尾部的相对较小。28例YST患者中,单纯型21例YST(75.00%),混合型7例(25.00%)。结论原发性卵黄囊瘤进行CT检测尤为重要,其CT表现具有一定特征性,可为临床治疗提供一定的依据。     

Photocrosslinkable methacrylated gelatin hydrogel as a cell-friendly injectable delivery system for chlorhexidine in regenerative endodontics

ObjectivesThis work sought to formulate photocrosslinkable chlorhexidine (CHX)-laden methacrylated gelatin (CHX/GelMA) hydrogels with broad spectrum of action against endodontic pathogens as a clinically viable cell-friendly disinfection therapy prior to regenerative endodontics procedures.MethodsCHX/GelMA hydrogel formulations were successfully synthesized using CHX concentrations between 0.12 % and 5 % w/v. Hydrogel microstructure was evaluated by scanning electron microscopy (SEM). Swelling and enzymatic degradation were assessed to determine microenvironmental effects. Compression test was performed to investigate the influence of CHX incorporation on the hydrogels’ biomechanics. The antimicrobial and anti-biofilm potential of the formulated hydrogels were assessed using agar diffusion assays and a microcosms biofilm model, respectively. The cytocompatibility was evaluated by exposing stem cells from human exfoliated deciduous teeth (SHEDs) to hydrogel extracts (i.e., leachable byproducts obtained from overtime hydrogel incubation in phosphate buffer saline). The data were analyzed using One- and Two-way ANOVA and Tukey’s test (α = 0.05).ResultsCHX/GelMA hydrogels were effectively prepared. NMR spectroscopy confirmed the incorporation of CHX into GelMA. The addition of CHX did not change the micromorphology (pore size) nor the swelling profile (p > 0.05). CHX incorporation reduced the degradation rate of the hydrogels (p < 0.001); whereas, it contributed to increased compressive modulus (p < 0.05). Regarding the antimicrobial properties, the incorporation of CHX showed a statistically significant decrease in the number of bacteria colonies at 0.12 % and 0.5 % concentration (p < 0.001) and completely inhibited the growth of biofilm at concentration levels 1 %, 2 %, and 5 %. Meanwhile, the addition of CHX, regardless of the concentration, did not lead to cell toxicity, as cell viability values were above 70 %.SignificanceThe addition of CHX into GelMA showed significant antimicrobial action against the pathogens tested, even at low concentrations, with the potential to be used as a cell-friendly injectable drug delivery system for root canal disinfection prior to regenerative endodontics.