健脾消癌方通过PI3K/Akt信号通路抑制结肠癌血管生成的研究＊

目的 观察结肠癌HCT116细胞健脾消癌方的条件培养液对HUVEC细胞管腔形成的影响，从PI3K/Akt生物轴调控角度探讨其作用机制。方法 培养HCT116细胞，细胞设3组：对照组，健脾消癌方组（加入15%健脾消癌方含药血清）及人参皂苷Rg3组；制备HCT116细胞健脾消癌方条件培养液（分组及制备方法见实验方法），用条件培养液干预HUVEC（脐静脉内皮细胞，Human Umbilical Vein Endothelial Cells），Matrigel基质胶法检测HCT116细胞健脾消癌方条件培养液对HUVEC小管形成的影响。随后采用蛋白免疫印迹法（Western blot）检测各组HCT116细胞磷脂酰肌醇3-激酶（PI3K）、蛋白激酶B（Akt）、p-Akt、VEGF（血管内皮生长因子，Vascular endothelial growth factor）蛋白表达。最后在结肠癌HCT116荷瘤小鼠中验证健脾消癌方对肿瘤生长速度的影响，并经瘤组织VEGF蛋白表达、CD31免疫组化染色检测肿瘤内血管生成情况。结果 模型组HUVEC细胞管腔形成较空白血清组显著增加（P<0.05）；健脾消癌方组及人参皂苷Rg3组较模型组HUVEC细胞管腔形成显著减少（P<0.01）。p-Akt和VEGF蛋白表达水平模型组高于空白血清组（P<0.05），健脾消癌方组及人参皂苷Rg3组显著低于模型组（P<0.01）；PI3K、Akt蛋白表达量组间差异无统计学意义。与对照组比较，模型组荷瘤小鼠肿瘤体积显著性增大，瘤组织内VEGF表达、CD31阳性面积显著性增加，差异有统计学意义（P<0.05）；与模型组比较，健脾消癌方组及人参皂苷Rg3组荷瘤小鼠肿瘤体积显著减小，瘤组织内VEGF表达、CD31阳性面积降低，差异有统计学意义（P<0.05）。结论 健脾消癌方可抑制肿瘤的血管生成和生长，其作用机制可能与PI3K/Akt生物轴调控VEGF表达有关。     

Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

Introduction: Collaborative interactions between several diverse biological processes govern the onset and progression of breast cancer. These processes include alterations in cellular metabolism, anti-tumor immune responses, DNA damage repair, proliferation, anti-apoptotic signals, autophagy, epithelial-mesenchymal transition, components of the non-coding genome or onco-mIRs, cancer stem cells and cellular invasiveness. The last two decades have revealed that each of these processes are also directly regulated by a component of the cell cycle apparatus, cyclin D1.

Area covered: The current review is provided to update recent developments in the clinical application of cyclin/CDK inhibitors to breast cancer with a focus on the anti-tumor immune response.

Expert opinion: The cyclin D1 gene encodes the regulatory subunit of a proline-directed serine-threonine kinase that phosphorylates several substrates. CDKs possess phosphorylation site selectivity, with the phosphate-acceptor residue preceding a proline. Several important proteins are substrates including all three retinoblastoma proteins, NRF1, GCN5, and FOXM1. Over 280 cyclin D3/CDK6 substrates have b\een identified. Given the diversity of substrates for cyclin/CDKs, and the altered thresholds for substrate phosphorylation that occurs during the cell cycle, it is exciting that small molecular inhibitors targeting cyclin D/CDK activity have encouraging results in specific tumors.     

A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma

Introduction: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.

Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.

Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.     

肿瘤免疫检查点抑制剂相关的肝毒性

肿瘤免疫检查点抑制剂治疗为肿瘤患者带来生存获益的同时,也面临了许多挑战,例如免疫介导的肝毒性的发生。深入了解免疫检查点抑制剂治疗肿瘤过程中导致肝损伤的发生情况、可能机制、危险因素等,有助于更好地临床管理。     

Dry eye signs and symptoms in aromatase inhibitor treatment and the relationship with pain

PurposeAromatase inhibitors (AIs) limit the synthesis of oestrogen in peripheral tissues thus lowering levels of oestrogen. The primary aim was to evaluate whether women treated with AIs have altered dry eye symptoms and signs. A sub-aim was to investigate whether symptoms of dry eye in postmenopausal women were associated with symptoms of non-eye pain, ocular pain and self-rated pain perception.MethodsThis cross-sectional, observational, single visit study recruited 56 postmenopausal women (mean age 64.1 + 7.9 years) and 52 undergoing AI treatment (mean age 66.6 + 9.0). Ocular symptoms (OSDI, MGD14) and pain questionnaires (PSQ, OPAS) were administered and signs of dry eye and meibomian gland dysfunction were evaluated.ResultsAlmost half of each group reported dry eye symptoms, defined as OSDI>12 (48% control, 46% AI). The PSQ score was significantly higher in the AI group (p = 0.04). Neither frequency or severity of dry eye (or MGD) symptoms scores were significantly different between groups. In the AI group, meibomian gland expressibility score was worse (p = 0.003); there were no differences in any other signs. Higher OSDI scores were associated with higher OPAS eye-pain scores (r = 0.49, p < 0.001), but not OPAS non-eye pain (r = 0.09, p = 0.35). Pain perception (PSQ) showed a moderate positive association with OPAS eye-pain (r = 0.30, p = 0.003).ConclusionsIn this study elevated ocular symptoms were observed in both the AI treated and the untreated groups, with no difference between the groups. Women undergoing AI treatment for early stage breast cancer had worse meibum expressibility score and increased pain perception compared to an untreated group of women.     

Caffeic Acid–coated Nanolayer on Mineral Trioxide Aggregate Potentiates the Host Immune Responses,Angiogenesis, and Odontogenesis

IntroductionThe aim of this study was to investigate whether mineral trioxide aggregate (MTA) can be modified with caffeic acid (CA) to form caffeic acid/mineral trioxide aggregate (CAMTA) cement and to evaluate its physicochemical and biological properties as well as its capability in immune suppression and angiogenesis.MethodsMTA was immersed in trishydroxymethyl aminomethane buffer with CA to allow coating onto MTA powders. X-ray diffractometry and tensile stress-strain tests were conducted to assess for physical characteristics of CAMTA and to evaluate for successful modification of MTA. Then, the CAMTA cement was immersed in simulated body fluid to evaluate its hydroxyapatite formation capabilities and Si release profiles. In addition, RAW 264.7 cells and human dental pulp stem cells were used to evaluate CAMTA’s immunosuppressive capabilities and cell responses, respectively. hDPSCs were also used to assess CAMTA’s angiogenic capabilities.ResultsThe X-ray diffractometry results showed that CA can be successfully coated onto MTA without disrupting or losing MTA’s original structural properties, thus allowing us to retain the initial advantages of MTA. CAMTA was shown to have higher mechanical properties compared with MTA and had rougher pitted surfaces, which were hypothesized to lead to enhanced adhesion, proliferation, and secretion of angiogenic- and odontogenic-related proteins. In addition, it was found that CAMTA was able to enhance hydroxyapatite formation and immunosuppressive capabilities compared with MTA.ConclusionsCAMTA cements were found to have improved physicochemical and biological characteristics compared with their counterpart. In addition, CAMTA cements had enhanced odontogenic, angiogenic, and immunosuppressive properties compared with MTA. All of the results of this study proved that CAMTA cements could be a biomaterial for future clinical applications and tissue engineering use.     

Interleukin-11 Overexpression and M2 Macrophage Density are Associated with Angiogenic Activity in Proliferative Diabetic Retinopathy

ABSTRACT

Purpose

To investigate the expression of IL-11 and its receptor IL-11Rα and to quantify density of CD163⁺ M2 macrophages in proliferative diabetic retinopathy (PDR).