Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma.
血小板衍生生长因子 β 是儿童高级别胶质瘤的有效炎症驱动因子。
- 作者列表："Ross JL","Chen Z","Herting CJ","Grabovska Y","Szulzewsky F","Puigdelloses M","Monterroza L","Switchenko J","Wadhwani NR","Cimino PJ","Mackay A","Jones C","Read RD","MacDonald TJ","Schniederjan M","Becher OJ","Hambardzumyan D
:Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.
: 儿童高级别胶质瘤 (HGGs) 是儿童中与脑肿瘤相关的死亡最多的原因，中位生存期为12-15个月。一个有希望的研究途径是开发靶向肿瘤内非肿瘤细胞类型 (例如肿瘤相关巨噬细胞 (tam)) 特性的新疗法。在成人HGG中，TAMs具有免疫抑制性并促进肿瘤恶性; 然而，在儿童髓母细胞瘤中，TAMs表现出抗肿瘤特性。多少人知道TAMs在成人HGG，但鲜为人知的是，他们在儿科设置.这就提出了一个问题，即儿科igg是否因为其独特的遗传景观而拥有TAMs的独特选区。使用人儿科HGG组织样品和儿科HGG的鼠模型，我们证明弥漫性中线胶质瘤与半球儿科HGGs相比具有更大的炎症基因表达谱。我们还展示了尽管拥有稀疏T细胞浸润，人类儿科HGGs具有高渗入渗出的IBA1 + tam.CD31、pdgfr β 和PDGFB均与IBA1 + TAM浸润强烈相关。为了研究TAM群体，我们使用RCAS/tv-a系统在新生免疫活性小鼠中重现儿科HGG。通过PDGFA或PDGFB与Cdkn2a或Tp53共突变的过度表达在Nestin阳性脑细胞中诱导肿瘤。与PDGFA驱动的肿瘤相比，由PDGFB驱动的肿瘤具有显著较低的中值存活，并且具有增加的TAM浸润。纳米串和定量PCR分析表明PDGFB驱动的肿瘤具有以高趋化因子表达为特征的高度炎性微环境。体外骨髓来源的单核细胞和小胶质细胞培养物证明，骨髓来源的单核细胞最负责在肿瘤微环境中响应于PDGFB刺激而产生炎性信号。最后，使用缺乏单个趋化因子的敲除小鼠，我们证明了在PDGFA和PDGFB驱动的肿瘤中减少TAM浸润和延长存活的可行性。我们确定CCL3是人类和小鼠中这些过程中潜在的关键趋化因子。总之，这些研究为PDGFB在儿科HGGs中的有效炎症作用提供了证据。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.