Glycosylation of DMP1 maintains cranial sutures in mice

Craniosynostosis, a severe craniofacial developmental disease, can only be treated with surgery currently. Recent studies have shown that proteoglycans are involved in the suture development. For the bone matrix protein, dentin matrix protein 1 (DMP1), glycosylation on the N-terminal of it could generate a functional proteoglycan form of DMP1 during osteogenesis. We identified that the proteoglycan form of DMP1 (DMP1-PG) is highly expressed in mineralisation front of suture. But, the potential role of DMP1-PG in suture fusion remain unclear. To investigate the role of DMP1-PG in cranial suture fusion and craniofacial bone development. By using a DMP1 glycosylation site mutation mouse model, DMP1-S89G mice, we compared the suture development in it with control mice. We compared the suture phenotypes, bone formation rate, expression levels of bone formation markers in vivo between DMP1-S89G mice and wild-type mice. Meanwhile, cell culture and organ culture were performed to detect the differences in cell differentiation and suture fusion in vitro. Finally, chondroitin sulphate (CHS), as functional component of DMP1-PG, was employed to test whether it could delay the premature suture fusion and the abnormal differentiation of bone mesenchymal stem cells (BMSCs) of DMP1-PG mice. DMP1-S89G mice had premature closure of suture and shorter skull size. Lack of DMP1-PG accelerated bone formation in cranial suture. DMP1-PG maintained the essential stemness of BMSCs in suture through blocking the premature differentiation of BMSCs to osteoblasts. Finally, chondroitin sulphate, a major component of DMP1-PG, successfully delayed the premature suture fusion by organ culture of skull in vitro. DMP1-PG could inhibit premature fusion of cranial suture and maintain the suture through regulating the osteogenic differentiation of BMSCs.     

改良肌激动器治疗安氏Ⅱ类Ⅰ分类错(牙合)畸形的X线头影测量分析

目的探讨改良肌激动器矫治早期安氏Ⅱ类Ⅰ分类下颌后缩的错[牙合]畸形的临床疗效。方法选择口腔正畸门诊就诊的安氏Ⅱ类Ⅰ分类下颌后缩的错[牙合]患者20例,年龄在10~12岁之间,平均年龄10.6岁。采用改良肌激动器进行功能矫治,用winceph8.0对矫治前后X线头颅侧位片进行定点测量,所得数据应用SPSS23.0软件进行配对t检验。结果矫治后患者面型改善明显,磨牙基本中性关系,前牙覆[牙合]、覆盖基本正常,治疗后角度测量值SNB、ANB、NA-PA和U1-SN变化,差异有显著性(P<0.01),角度测量值SNA、SNMP、L1-MP、L1-NB、FH-Y轴和Z角变化,无显著性(P>0.05),线距测量值L1-NB、UL-EP和LL-EP跟治疗前比,变化无显著性(P>0.05)。结论改良肌激动器能够矫治早期安氏Ⅱ类Ⅰ分类错[牙合]畸形,值得在临床推广使用。     

A patent update on PDK1 inhibitors (2015-present)

Introduction: 3-Phosphoinositide-dependent kinase 1 (PDK1), the ‘master kinase of the AGC protein kinase family’, plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme.

Areas covered: This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso.

Expert opinion: The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways.     

Microtubule-targeting agents in the treatment of non-small cell lung cancer: insights on new combination strategies and investigational compounds

Introduction: The management of non-small cell lung cancer (NSCLC) has been substantially improved in the last few years; it has been revolutionized by a patient-tailored approach, especially in the oncogene addicted disease, and by novel combinations containing immune checkpoint inhibitors. However, chemotherapy still represents a mainstay that persists over the decades with limited novelties. Tubulin inhibitors belong to different sub-classes of drugs that share the capability to interfere with mitosis by a direct action on the microtubule system. Among them, taxanes and vinca alkaloids still have a prominent role in clinical practice.

Areas covered: This review summarizes the mechanisms of action, current role and future directions of microtubule targeting agents; we focus on investigational agents in phase I and II clinical trials.

Expert opinion: Chemotherapy maintains a pivotal role in the treatment of NSCLC. New generation agents that have the potential to overcome the mechanisms of resistance to the available drugs may provide new therapeutic opportunities. Predictive biomarkers derived from combination strategies and phase III studies are necessary going forward.     

慢性温和不可预知应激抑郁模型大鼠脑组织1H-NMR代谢组学研究

目的 采用高分辨核磁共振¹H谱（¹H-NMR）代谢组学技术研究慢性温和不可预知应激（CUMS）抑郁大鼠脑组织中代谢物及代谢通路的变化，探讨抑郁症的发病机制。方法 12只雄性SD大鼠随机分为模型组和对照组，采用CUMS对模型组大鼠进行为期4周的造模，进行称体质量、旷场实验和糖水偏爱实验验证模型是否成功，造模结束后收集大鼠脑组织。采用两相提取法（甲醇/氯仿/水）对脑组织进行提取，得到水溶性和脂溶性代谢物。应用¹H-NMR技术结合多元统计和代谢通路分析筛选出与抑郁相关的脑内差异代谢物，并构建其代谢通路。结果 行为学数据显示，与对照组比较，模型组大鼠的体质量、糖水偏爱率、旷场的穿格数和直立次数均显著降低（P<0.05），显示了抑郁状态。在大鼠脑组织的¹H-NMR图谱中共指认出35种内源性代谢产物。脑组织中水溶性和脂溶性代谢物主成分分析（PCA）均显示模型组与对照组分开，与行为学结果一致，表明造模成功；OPLS-DA分析找到9个水溶性差异代谢物和6个脂溶性差异代谢物。就水溶性代谢物而言，与对照组比较，模型组中肌酐、谷氨酰胺、牛磺酸和γ-氨基丁酸含量显著增加（P<0.05、0.01、0.001），丙二醇、谷氨酸、亮氨酸、缬氨酸和赖氨酸含量显著降低（P<0.05、0.01、0.001）。就脂溶性代谢物而言，与对照组比较，模型组-（CH₂） n和-N （Me₃）₃含量显著升高（P<0.05、0.001），胆固醇的C18/19甲基、R-CH₃、CH₂OPO₂-、-CH=CH-含量显著降低（P<0.05、0.01、0.001）。与对照组比较，CUMS造模后5条代谢通路发生显著变化：缬氨酸、亮氨酸和异亮氨酸生物合成，牛磺酸和亚硫磺酸代谢，丙氨酸、天冬氨酸和谷氨酸代谢，糖降解和糖异生通路和丙酮酸代谢。结论 运用¹H-NMR代谢组学技术结合多元统计分析和代谢通路分析，阐明抑郁症的发病机制与能量代谢、氨基酸代谢和神经递质合成等相关。