Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR).     

非小细胞肺癌新辅助靶向及免疫治疗研究进展和展望

肺癌是全球发病率和死亡率最高的恶性肿瘤。近年来,随着新型药物的出现和治疗模式的优化,肺癌患者的预后已有一定改善。新辅助治疗是指对潜在可接受手术切除的患者,先给予术前抗肿瘤治疗后再行手术治疗。新辅助治疗通过术前治疗可以缩小肿瘤体积,降低肿瘤分期;并且可以杀灭患者机体中循环肿瘤细胞及微转移病灶,令患者远期生存获益。靶向治疗及免疫治疗已被应用于晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的一线治疗。因此,有临床试验尝试将以上两种治疗手段应用于早期可切除NSCLC患者的新辅助治疗。本文针对新辅助靶向及免疫治疗对早期可切除NSCLC患者的疗效、治疗中的潜在风险予以综述,并探讨新辅助治疗的未来发展方向。     

Outcomes of Early Decompressive Craniectomy Versus Conventional Medical Management After Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis

This meta-analysis examined whether early decompressive craniectomy (DC) can improve control of intracranial pressure (ICP) and mortality in patients with traumatic brain injury (TBI).Medline, Cochrane, EMBASE, and Google Scholar databases were searched until May 14, 2015, using the following terms: traumatic brain injury, refractory intracranial hypertension, high intracranial pressure, craniectomy, standard care, and medical management. Randomized controlled trials in which patients with TBI received DC and non-DC medical treatments were included.Of the 84 articles identified, 8 studies were selected for review, with 3 randomized controlled trials s having a total of 256 patients (123 DCs, 133 non-DCs) included in the meta-analysis. Patients receiving DC had a significantly greater reduction of ICP and shorter hospital stay. They also seemed to have lower odds of death than patients receiving only medical management, but the P value did not reach significance (pooled odds ratio 0.531, 95% confidence interval 0.209–1.350, Z = 1.95, P = 0.183) with respect to the effect on overall mortality; a separate analysis of 3 retrospective studies yielded a similar result.Whereas DC might effectively reduce ICP and shorten hospital stay in patients with TBI, its effect in decreasing mortality has not reached statistical significance.     

Exploration of D022-Type Al3TM(TM = Sc,Ti, V,Zr, Nb,Hf, Ta): Elastic Anisotropy,Electronic Structures,Work Function and Experimental Design

The structural properties, elastic anisotropy, electronic structures and work function of D0₂₂-type Al₃TM (TM = Sc, Ti, V, Y, Zr, Nb, La, Hf, Ta) are studied using the first-principles calculations. The results indicate that the obtained formation enthalpy and cohesive energy of these compounds are in accordance with the other calculated values. It is found that the Al₃Zr is the most thermodynamic stable compound. The mechanical property indexes, such as elastic constants, bulk modulus, shear modulus, Young’s modulus, Poisson’s ratio, and Vickers hardness are systematically explored. Moreover, the calculated universal anisotropic index, percent anisotropy and shear anisotropic factors of D0₂₂-type Al₃TM are analyzed carefully. It demonstrates that the shear modulus anisotropy of Al₃La is the strongest, while that of Al₃Ta is the weakest. In particular, the density of states at Fermi level is not zero, suggesting that these phases have metal properties and electrical conductivity. More importantly, the mechanisms of correlation between hardness and Young’s modulus are further explained by the work function. Finally, the experimental design proves that D0₂₂-Al₃Ta has an excellent strengthening effect.     

肛肠疾病手术前后肛管直肠压力测定的应用

目的:探讨肛肠疾病手术前后肛管直肠压力测定的应用。方法:将2018年5月-2019年5月在上海市松江区方塔中医医院及上海中医药大学附属曙光医院肛肠科行手术治疗的826例肛肠疾病患者作为研究对象,其中,选择性痔上黏膜吻合术246例、单纯外剥内扎术115例、外剥内扎结合内痔套扎术(Automatic Ligation of Hemorrhoids,RPH)153例、低位肛瘘切除术177例、高位肛瘘切开挂线术135例,分别于术前及术后1个月测定肛管直肠压力。结果:选择性痔上黏膜吻合术后直肠静息压、肛管静息压明显低于术前,肛管舒张压高于术前(P<0.05),但肛管最大收缩压与术前相比无明显差异(P>0.05);单纯外剥内扎术术后直肠静息压、肛管静息压明显低于术前,肛管舒张压、肛管最大收缩压明显高于术前(P<0.05);外剥内扎结合内痔套扎术术后直肠静息压、肛管静息压明显低于术前,肛管舒张压、肛管最大收缩压明显高于术前(P<0.05);低位肛瘘切除术术后直肠静息压、肛管静息压、肛管舒张压均高于术前(P<0.05),而肛管最大收缩压与术前相比无明显差异(P>0.05);高位肛瘘切开挂线术术后直肠静息压高于术前,肛管静息压、肛管舒张压低于术前(P<0.05),而与肛管最大收缩压术前相比无明显差异(P>0.05)。结论:肛肠疾病手术前后肛管直肠压力测定的应用效果显著,能准确判断手术效果及患者恢复情况,为医师的进一步诊治奠定了良好基础。     

VEGF在膀胱移行细胞癌中的表达研究

目的研究血管内皮生长因子（VEGF）在膀胱移行细胞癌（TCC）中的表达。方法应用免疫组织化学染色方法观察62例TCC标本VEGF的表达情况。结果TCC组中VEGF的阳性表达率为56．5％（35，62），而8例正常膀胱粘膜组织VEGF表达均为阴性，两组比较差异有高度显著性p〈0．01（x^2=9．032）；VEGF表达与膀胱肿瘤病理分级、临床分期、复发密切相关。结论VEGF的异常表达在TCC的发生、发展过两组比较差异有程中起重要作用；该指标的检测有助于预后判断。