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.     

维生素D在孤独症谱系障碍中作用的研究进展

孤独症谱系障碍(ASD)是影响儿童健康的严重公共问题之一,以社交沟通障碍、兴趣或活动范围狭窄以及重复刻板行为为特征。近年来越来越多的研究显示,ASD患儿维生素D(VitD)水平明显低于同龄健康儿童,VitD缺乏可能与ASD的发病机制相关。本文就VitD与ASD的相关研究进行综述。     

Efficacy,effectiveness and side effects of medications used to prevent fractures

There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long‐term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit–risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and ‘drug holidays’ should be considered at this time. Further studies are needed to guide clinical practice in this area.     

Importance of serum phosphate in elderly patients with diabetes mellitus

BACKGROUND Metabolic disturbances including changes in serum calcium,magnesium or phosphate(P) influence the prevalence of type 2 diabetes mellitus(DM).We assessed the importance of serum P in elderly patients with type 2 DM vs nondiabetes mellitus(non-DM) in relation to renal function.AIM To determine the association between serum P and serum glucose or insulin resistance in diabetic and non-diabetic patients.METHODS One hundred-ten subjects with a mean age of 69.02±14.3 years were enrolled.Twenty-nine of the participants had type 2 DM(26.4%).The incidence of hypertension,smoking and receiving vitamin D(vitD) derivates were recorded.The participants were classified by both estimated glomerular filtration rate(eGFR) and albuminuria categories according to the Kidney Disease Improving Global Outcomes 2012 criteria.RESULTS We divided the patients in two groups according to the P cut-off point related to DM value.A comparison between high and low P showed that body mass index30.2±6.3 vs 28.1±4.6(P=0.04),mean glucose 63.6 vs 50.2(P=0.03),uric acid 6.7±1.6 vs 6.09±1.7(P=0.05),mean intact-parathyroid hormone 68.06 vs 47.4(P=0.001),systolic blood pressure 147.4±16.7 vs 140..2±16.1(P=0.02),mean albuminuria 63.2 vs 50.6(P=0.04) and eGFR 45.6±22.1 vs 55.4±21.5(P=0.02)were significantly different.χ~2 tests showed a significant association between high P and DM,hypertension,receiving vitD,smoking and eGFR stage(χ~2=6.3,P=0.01,χ~2=3.9,P=0.03,χ~2=6.9,P=0.009,χ~2=7.04,P=0.01 and χ~2=7.36,P=0.04,respectively).The adjusted model showed that older age,female gender and increased body mass index were significant predictors of type 2 DM when entering the covariates.CONCLUSION High serum P contributes to vascular and metabolic disturbances in elderly patients with type 2 DM and renal impairment.     

中日友好医院分型股骨头坏死腓骨植入治疗的三维有限元分析

文题释义：股骨头坏死中日友好医院分型的有限元分析：根据李子荣等提出的中日友好医院分型，建立股骨头坏死三维模型，分为 M型(内侧型)、C型(中央型)和 L型(外侧型)，其中 L型包括L1型(次外侧型)、L2型(极外侧型)和 L3型(全头型)。通过对建立的模型进行有限元分析，为该分型的保髋治疗提供了一定力学依据，显示外侧柱的存留是精准预防塌陷的重要因素，为进一步实现个体化治疗提供力学基础。 腓骨支撑坏死股骨头保髋手术：是对于早中期股骨头坏死需要保留股骨头患者进行的一种手术方式。首先需对股骨头进行髓芯减压，清除一定坏死骨，空腔填塞松质骨(髂骨为主)，打压结实后植入腓骨(异体或自体)支撑，给坏死区的提供力学支撑及生物学修复，预防股骨头进一步坏死及塌陷。 背景：研究报道股骨头坏死的保髋疗效与外侧柱存留密切相关，中日友好医院分型是根据三柱结构确立的，对股骨头塌陷的预测准确性高。 目的：建立股骨头坏死中日友好医院分型各分型仿真的三维有限元模型，通过有限元分析各分型腓骨植入的力学变化，探讨外侧柱存留对保髋疗效的意义，为该分型的塌陷精准预测提供基础。 方法：建立正常股骨头、中日友好医院分型(M型、C型、L1型、L2型、L3型)股骨头坏死及其腓骨植入3组11种三维有限元模型，运用ANSYS软件进行有限元分析计算，观察各组模型的最大应力值、最大位移值及股骨头内部载荷传递模式。 结果与结论：①坏死组位移最大，应变最大，且因坏死分型不同而位移不同，位移变化如下：M型相似文献   

Customized three-dimensionally printed mandibular external fixator

The advent of customized three-dimensional (3D) printing allows the affordable manufacturing of sophisticated medical devices, thereby providing swift and simple solutions to specific needs in modern healthcare. Meanwhile, certain devices such as industrial mandibular external fixators (EFs) have become less and less available from medical device companies because of decreased indications. What is more, their handling is often complex. The authors report, step by step, the original design and uneventful clinical use of a 3D-printed, customized mandibular EF. This device was designed together with a positioning and drilling guide for the fixation of a septic mandibular pseudarthrosis. It provided an adequate and satisfactory balance between lightness and rigidity. A simple, accurate and safe placement of the EF was achieved thanks to the skin-supported positioner and drilling guide, thereby making the procedure minimally invasive and time-efficient. To our knowledge, this is the first reported clinical use of a 3D-printed, customized mandibular EF to date. Because such 3D technology is becoming increasingly available to a large number of surgeons, the authors believe that the present innovation could become an alternative to reusable standard EFs.