肝脏中自然杀伤细胞的表型及功能

自然杀伤(NK)细胞是先天性免疫系统的重要组成部分,也是机体抗感染和防止细胞恶性转化的重要免疫调节细胞。与T淋巴细胞不同,NK细胞无需肿瘤特异性抗原识别便可以直接杀伤肿瘤细胞,是肿瘤免疫治疗的重要效应细胞。在肝脏中,NK细胞占很大比例,最近研究表明,NK细胞通过直接作用或生物信号间的协同作用活化树突状细胞或直接影响T细胞来调节T细胞的反应。肝脏NK细胞功能主要是通过激活抑制性受体的表达和炎性细胞因子的分泌调节,特别是与脾脏NK细胞相比,肝内NK细胞对白细胞介素(IL)-12、IL-18反应较低。同时,肝脏中含有较多的抑制性受体NK细胞受体2A抗体,缺乏组织相容性复合体Ⅰ类/Ly49受体。     

Hedgehog signaling in the murine melanoma microenvironment

The Hedgehog intercellular signaling pathway regulates cell proliferation and differentiation. This pathway has been implicated to play a role in the pathogenesis of cancer and in embryonic blood vessel development. In the current study, Hedgehog signaling in tumor related vasculature and microenvironment was examined using human umbilical vein endothelial cells and B16F0 (murine melanoma) tumors models. Use of exogenous Sonic hedgehog (Shh) peptide significantly increased BrdU incorporation in endothelial cells in vitro by a factor of 2 (P < 0.001). The Hedgehog pathway antagonist cyclopamine effectively reduced Shh-induced proliferation to control levels. To study Hedgehog signaling in vivo a hind limb tumor model with the B16F0 cell line was used. Treatment with 25 mg/kg cyclopamine significantly attenuated BrdU incorporation in tumor cells threefold (P < 0.001), in tumor related endothelial cells threefold (P = 0.004), and delayed tumor growth by 4 days. Immunohistochemistry revealed that the Hedgehog receptor Patched was localized to the tumor stroma and that B16F0 cells expressed Shh peptide. Furthermore, mouse embryonic fibroblasts required the presence of B16F0 cells to express Patched in a co-culture assay system. These studies indicate that Shh peptide produced by melanoma cells induces Patched expression in fibroblasts. To study tumor related angiogenesis a vascular window model was used to monitor tumor vascularity. Treatment with cyclopamine significantly attenuated vascular formation by a factor of 2.5 (P < 0.001) and altered vascular morphology. Furthermore, cyclopamine reduced tumor blood vessel permeability to FITC labeled dextran while having no effect on normal blood vessels. These studies suggest that Hedgehog signaling regulates melanoma related vascular formation and function. L. Geng and K.C. Cuneo contributed equally to this work.     

Serum from Acute-on-chronic Liver Failure Patients May Affect Mesenchymal Stem Cells Transplantation by Impairing the Immunosuppressive Function of Cells

Background and AimsThe safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of acute-on-chronic liver failure (ACLF) have been validated. However, the impact of the pathological ACLF microenvironment on MSCs is less well understood. This study was designed to explore the changes in the functional properties of MSCs exposed to ACLF serum.MethodsMSCs were cultured in the presence of 10%, 30% and 50% serum concentrations from ACLF patients and healthy volunteers. Then, the cell morphology, phenotype, apoptosis and proliferation of MSCs were evaluated, including the immunosuppressive effects. Subsequently, mRNA sequencing analysis was used to identify the molecules and pathways involved in MSC functional changes in the context of ACLF.ResultsIn the presence of ACLF serum, MSC morphology significantly changed but phenotype did not. Besides, MSC proliferation activity was weakened, while the apoptosis rate was lightly increased. Most importantly, the immunosuppressive function of MSCs was enhanced in a low-concentration serum environment but transformed into a proinflammatory response in a high-concentration serum environment. RNA sequencing indicated that 10% serum concentration from ACLF patients mediated the PI3K-Akt pathway to enhance the anti-inflammatory effect of MSCs, while the 50% serum concentration from ACLF patients promoted the conversion of MSCs into a proinflammatory function by affecting the cell cycle.ConclusionsThe 50% ACLF serum concentration is more similar to the environment in the human body, which means that direct peripheral blood intravenous infusion of MSCs may reduce the effect of transplantation. Combining treatments of plasma exchange to reduce harmful substances in serum may promote MSCs to exert a stronger anti-inflammatory effect.     

New developments in the pathology and molecular biology of retroperitoneal sarcomas

Retroperitoneal sarcomas (RPS) refer to a heterogeneous group of malignancies of mesenchymal origin developing from retroperitoneal tissues and vessels. The most frequent RPS are well differentiated/dedifferentiated liposarcomas and leiomyosarcomas, but other rare histological subtypes can be observed. Over the last decade, significant advances have been made in the pathological and molecular characterization of sarcomas. These advances have led to major changes in their diagnostic management as well as in the development of new therapeutic strategies based on tumor biology and microenvironment. This review describes the current knowledge and recent findings in the pathology and molecular biology of the most frequent RPS subtypes.     

Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony-stimulating factor (G-CSF), follistatin, angiopoietin-1 (Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF), and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic malignancy.     

胰腺癌免疫治疗研究热点的文献计量学可视化分析

背景与目的 胰腺癌是恶性程度较高的消化系统肿瘤之一，因其起病隐匿，早期常无典型症状，且肿瘤的侵袭性较强，故预后较差。随着对胰腺癌分子发病机制的深入研究，免疫治疗已成为胰腺癌治疗的新焦点。文献计量学是一种分析某一领域文献、直观地总结文献的趋势并预测研究热点的常用方法。本文旨在通过文献计量和知识图谱可视化分析胰腺癌免疫治疗的研究现状、热点和趋势，为后续的研究提供方向。方法 从Web of Science核心合集中提取相关出版物从开始到2022年5月发表的有关胰腺癌免疫治疗的文献，使用CtieSpace和VOSviewer等软件对该领域文献的国家、机构、作者、参考文献和关键词进行文献计量可视化分析。结果 共纳入2009—2022年发表与胰腺癌免疫治疗相关的英文文献2 230篇，自2016年文献数量每年都在稳定增长。这些文献的7 365位作者来自75个国家/地区的884个机构，共有7 943篇共被引参考文献。发文量最多的国家为美国（n=964），其次是中国（n=552）；发文量最多的机构为美国约翰霍普金斯大学（n=67）和德克萨斯大学MD安德森癌症中心（n=65）；发文量最多的作者为美国约翰霍普金斯大学的Elizabeth M Jaffee（n=41）和Lei Zheng（n=31）。共被引次数最多的文献为“Genomic analyses identify molecular subtypes of pancreatic cancer”（n=161），共被引参考文献时间线图显示，聚类“肿瘤微环境”是从2016年开始一直持续到现在的热点。关键词的突发检测揭示了胰腺癌免疫治疗领域的发展，最初的热点主要是“疫苗”，而近年来重点转移到“伊匹单抗”“检查点阻断”“上皮间质转化”“星状细胞”“巨噬细胞”“错配修复缺陷”和“肿瘤微环境”等。结论 与胰腺癌免疫治疗的相关研究呈持续上升趋势，是胰腺癌治疗的重要研究方向，目前美国在这一研究领域尚处于绝对领先地位。相关研究表明独特的肿瘤微环境可能是胰腺癌恶性程度较高且对放化疗不敏感的主要原因，深入研究胰腺癌肿瘤微环境（TME）的致病机理是目前研究的重点。除此之外，聚焦于“上皮间质转化”和“免疫检查点抑制”等的研究较为普遍，现有的研究表明单一的治疗手段对胰腺癌的治疗效果有限，免疫联合疗法或化疗联合免疫疗法可以进一步提高胰腺癌的临床疗效，是未来临床研究的趋势。     

多发性骨髓瘤生物标志物研究进展

多发性骨髓瘤(Multiple myeloma,MM)是一种克隆性浆细胞异常增殖的恶性疾病,在大多数国家是第二位常见的血液系统恶性肿瘤,其发病率约占全部恶性肿瘤的1%,约占血液系统恶性肿瘤的10%,在癌症相关死亡中占0.9%。目前临床上的分期和预后评估系统主要包括国际分期系统(ISS)、修订的国际分期系统(R-ISS)、mSMART分期以及国际骨髓瘤工作组(IMWG)分层标准,主要基于肿瘤生物学、肿瘤负荷和患者特征,而没有考虑免疫及微环境相关的因素,原因之一是缺乏易于获取的生物标志物。近几年,随着液体活检、分子生物学和细胞遗传学等新技术的发展,发现了许多MM相关的新型生物标志物,为MM早期诊断和预后评估提供了新方法。在这篇综述中,将从免疫因素、骨髓微环境、细胞遗传学及液体活检等几个方面论述MM生物标志物的研究进展。     

Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression

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