Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors

BackgroundDiffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.MethodsSyngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models.ResultsExpression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity.ConclusionsVirus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.     

Nano-curcumin therapy,a promising method in modulating inflammatory cytokines in COVID-19 patients

BackgroundAs an ongoing worldwide health issue, Coronavirus disease 2019 (COVID–19) has been causing serious complications, including pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. However, there is no decisive treatment approach available for this disorder, which is primarily attributed to the large amount of inflammatory cytokine production. We aimed to identify the effects of Nano-curcumin on the modulation of inflammatory cytokines in COVID-19 patients.MethodForty COVID-19 patients and 40 healthy controls were recruited and evaluated for inflammatory cytokine expression and secretion. Subsequently, COVID-19 patients were divided into two groups: 20 patients receiving Nano-curcumin and 20 patients as the placebo group. The mRNA expression and cytokine secretion levels of IL-1β, IL-6, TNF-α and IL‐18 were assessed by Real‐time PCR and ELISA, respectively.ResultOur primary results indicated that the mRNA expression and cytokine secretion of IL-1β, IL-6, TNF-α, and IL-18 were increased significantly in COVID-19 patients compared with healthy control group. After treatment with Nano-curcumin, a significant decrease in IL-6 expression and secretion in serum and in supernatant (P = 0.0003, 0.0038, and 0.0001, respectively) and IL-1β gene expression and secretion level in serum and supernatant (P = 0.0017, 0.0082, and 0.0041, respectively) was observed. However, IL-18 mRNA expression and TNF-α concentration were not influenced by Nano-curcumin.ConclusionNano-curcumin, as an anti-inflammatory herbal based agent, may be able to modulate the increased rate of inflammatory cytokines especially IL-1β and IL-6 mRNA expression and cytokine secretion in COVID-19 patients, which may cause an improvement in clinical manifestation and overall recovery.     

早期无神经症状的HIV感染者脑代谢和脑血流灌注的MR检测及其与CD4~+T细胞计数的相关性分析

目的 通过磁共振(MR)检测患者脑代谢和血流灌注情况,并探讨人类免疫缺陷病毒(HIV)感染者脑代谢、血流灌注与患者CD4+T细胞计数之间的关系。方法选取2017年7月～2019年7月于我院进行治疗且经过临床确诊的30例获得性免疫缺陷综合征(AIDS)患者和12名志愿者作为研究对象。依据患者和志愿者的CD4+T细胞计数水平分别为A组(13例)、B组(17例)和对照组。全部受检者行常规MRI及MRS扫描,利用MRS自带的软件完成基线校准和代谢物识别并检测三组的N-乙酰天门冬氨酸(NAA)、胆碱(Cho)、肌醇(Mi)和谷氨酰胺复合物(Glx6)等脑代谢指标。脑血流灌注情况采用ASL序列分析,通过rCBF图对灌注情况进行定性分析。结果A组的NAA、Cho和Mi的峰面积均显著低于对照组,Glx6显著高于对照组(P0.05)。B组的Cho峰面积均显著低于对照组,Glx6显著高于对照组(P0.05)。A组患者的皮质、基底节和丘脑的脑血流低灌注比例显著高于对照组(P0.05)。A组和B组的NAA、Cho和Mi与CD4+T淋巴细胞计数呈正相关,而与Glx6呈负相关(P0.05)。A组的皮质和基底节低血流灌注与CD4+T淋巴细胞计数呈显著负相关,B组的皮质、基底节和丘脑与CD4+T淋巴细胞计数呈显著负相关(P0.05)。结论 MR检测技术可以对HIV感染者脑代谢和血流灌注进行有效检测,HIV感染者脑代谢、血流灌注情况与患者CD4+T细胞计数水平有关。     

火针联合卤米松乳膏治疗稳定期白癜风患者的疗效观察及对CD4+、CD8+、CD4+/CD8+水平的影响

 目的 观察火针联合卤米松乳膏治疗稳定期白癜风的临床疗效，检测对患者CD4⁺、CD8⁺及CD4⁺/CD8⁺水平的影响。方法 选择我院皮肤科及中医科门诊自2018年1月—2019年12月诊治的60例稳定期白癜风患者作为研究对象，随机分成对照组 (30例) 和试验组(30例)，对照组采用卤米松乳膏治疗，试验组予以火针联合卤米松乳膏治疗，比较两组患者治疗前后的白癜风面积评分指数(VASI),观察总有效率以及不良反应发生率。同时检测患者治疗前后CD4⁺、CD8⁺及 CD4⁺/CD8⁺的表达水平。结果两 组患者治疗前的VASI对比无显著差异(P＞0.05)。治疗后，试验组VASI明显低于对照组(9.73±0.56比10.79±1.13，t=4.60,P＜0.05），总有效率明显高于对照组(86.67%比63.33%,X²=4.36,P=0.037）。两组治疗后CD3⁺、CD4⁺、CD4⁺/CD8⁺均高于治疗前，试验组治疗后CD3+为(69.23±5.27)%，CD4⁺ 为(44.03±3.94)%,CD4⁺/CD8⁺比值为 (2.54±0.99)，对照组治疗后CD3⁺为(66.60±7.56)%，CD4⁺为(38.13±6.51)%, CD4⁺/CD8⁺比值为(1.91±0.87)，试验组各指标均高于对照组（均P＜0.05）；治疗后试验组CD8⁺为(19.30±5.55)%，低于对照组的(23.20±8.36)%，差异有统计学意义（P＜0.05）。结论 火针联合卤米松乳膏治疗不仅能有效促进稳定期白癜风患者皮肤恢复正常肤色，提高有效率，且能调节患者T淋巴细胞亚群，提高患者细胞免疫功能。因此火针是一种安全、高效的治疗方法，值得临床推广。     

蛋白质因子在调控骨改建过程中的作用机制研究进展

目的综述蛋白质因子在骨改建过程中的作用及机制，为进一步阐明骨相关疾病的发病机制及临床治疗提供理论依据。方法广泛查阅国内外近年相关研究成果，并加以分析、归纳和总结。结果骨改建是维持骨稳态的重要生理过程，蛋白作为骨改建过程中的重要刺激因子，调控着骨吸收与骨形成之间的平衡。结论目前对于蛋白在骨改建过程中的作用机制研究还不够充分，因此需要进一步深入研究相关蛋白在骨改建过程中的具体作用时间、作用过程以及蛋白质因子间相互作用网络，并确证其在骨改建中的作用机制，为骨相关疾病发病机制的揭示及治疗奠定基础。     

Delayed diapedesis of CD8 T cells contributes to long-term pathology after ischemic stroke in male mice

ObjectiveStroke is a debilitating disorder with significant annual mortality and morbidity rates worldwide. Immune cells are recruited to the injured brain within hours after stroke onset and can exhibit either protective or detrimental effects on recovery. However, immune cells, including CD8 T cells, persist in the injured brain for weeks, suggesting a longer-term role for the adaptive immune system during functional recovery. The aim of this study was to determine if the delayed secondary diapedesis of CD8 T cells into the ischemic brain negatively impacts functional recovery after transient ischemic stroke in male mice.ResultsMice exhibited an increased number of leukocytes in the ipsilesional hemispheres at 14 days (3-fold; p < 0.001) and 30 days (2.2-fold; p = 0.02) after transient middle cerebral artery occlusion (tMCAo) compared to 8 days post-tMCAo, at which time acute neuroinflammation predominantly resolves. Moreover, mice with higher ipsilesional CD8 T cells at 30 days (R² = 0.52, p < 0.01) exhibited worse functional recovery. To confirm a detrimental role of chronic CD8 T cell diapedesis on recovery, peripheral CD8 T cells were depleted beginning 10 days post-tMCAo. Delayed CD8 T cell depletion improved motor recovery on the rotarod (F_(1,28) = 4.264; p = 0.048) compared to isotype control-treated mice. CD8 T cell-depleted mice also exhibited 2-fold (p < 0.001) reduced leukocyte infiltration at 30 days post-tMCAo. Specifically, macrophage, neutrophil, and CD4 T cell numbers were reduced in the ipsilesional hemisphere of the CD8 T cell-depleted mice independent of inflammatory status of the post-stroke CNS (e.g. microglial phenotype and cytokine production). RNAseq identified a unique profile for brain infiltrating CD8 T cells at 30 days post-tMCAo, with 46 genes differentially expressed relative to CD8 T cells at 3 days post-tMCAo.ConclusionOur data reveal a role for CD8 T cells in the chronic phase post-stroke that can be therapeutically targeted. We demonstrate long-term CD8 T cell recruitment into the ipsilesional hemisphere that affects both immune cell numbers present in the injured brain and functional recovery through one month after stroke onset.