预测急性脑卒中缺血半暗带的最优Tmax阈值

背景:挽救缺血半暗带对减少梗死范围有重要意义,一般以PWI与DWI的不匹配区域来评估半暗带.但PWI评估的低灌注范围可能会包括良性缺血区,从而使评估所得的半暗带体积大于实际值.为减少这种弊端,近来引入一新的参数:PWI的达峰时间(Tmax)阈值.Tmax为PWI成像信号强度-时间曲线中从对比剂开始出现到对比剂浓度达到峰值的时间.以对侧相应部位正常脑组织的Tmax为参考,脑组织中Tmax延迟超过阈值的区域即为PWI病灶区.     

Hygienic causal aspects of chronic biogeochemical stress

Chronic biogeochemical stress results in enteric dysbiosis and is one of the active triggers, that cause deviations of integrative homeostatic parameters, and responsible for the high prevalence of atherosclerotic changes, including myocardial infarction, among the population of the silicon biogeochemical province of the Chuvash Republic, which is associated with the body's nonspecific adaptive reactions.     

Switchable targeting of solid tumors by BsCAR T cells

The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable in vitro effectiveness, the problem of safety and efficacy of CAR T cell therapy against solid tumors is challenged by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating the cytotoxic function of CAR T cells from tumor antigen recognition provided by protein mediators allows for the precise control of CAR T cell cytotoxicity. Here, the high affinity and capability of the bacterial toxin-antitoxin barnase-barstar system were adopted to guide CAR T cells to solid tumors. The complementary modules based on (1) ankyrin repeat (DARPin)-barnase proteins and (2) barstar-based CAR (BsCAR) were designed to provide switchable targeting to tumor cells. The alteration of the DARPin-barnase switches enabled the targeting of different tumor antigens with a single BsCAR. A gradual increase in cytokine release and tunable BsCAR T cell cytotoxicity was achieved by varying DARPin-barnase loads. Switchable BsCAR T cell therapy was able to eradicate the HER2⁺ ductal carcinoma in vivo. Guiding BsCAR T cells by DARPin-barnase switches provides a universal approach for a controlled multitargeted adoptive immunotherapy.

The transfusion of genetically engineered autologous T cells has created a revolution in adoptive cell cancer therapy of disseminated hematologic cancers during the last decade (1–3). chimeric antigen receptor (CAR) T cell therapy has proven its efficacy in therapy-resistant chronic lymphocytic leukemia (4, 5). Despite the unequivocal success of the approach, substantial side effects are also well documented (6–10). The administered CAR T cells, constantly stimulated by the target antigen, can rapidly proliferate to large numbers in the recipient and release proinflammatory cytokines, which, in some cases, lead to severe and sometimes fatal side effects such as cytokine release syndrome (CRS) (11), neurotoxicity, and cerebral edema (12, 13). Another concern in CAR-based therapy is the choice of target. CD19 is a suitable target for CAR T cells because it is expressed only by B cell populations. However, in solid tumors, targeted antigens are also expressed at low levels but broadly across various normal tissues. The on-target off-tissue activity of CAR T cells has resulted in severe toxicities in the translation of CAR T therapy to solid tumors in the clinic (14, 15). Therefore, developing approaches to control CAR T cell activity after infusion is a high priority. A promising solution to this problem is the design of switchable CARs. In this case, artificial molecular switchers “bridge” the tumor cell with CAR T cells. By varying the switcher concentration, it became possible to control cytotoxicity and the sensitivity of the CAR T cells to antigen density. The predictable pharmacokinetics and pharmacodynamics of the switcher allow for the control of CAR T cell effector functionality and persistency. Several reports have demonstrated that bifunctional moieties could be used to control CAR T activity in vivo (16–21).Small molecules such as fluorescein isothiocyanate (FITC) (22), folate (23), rimiducid (24), rapamycin (25), proteolysis-targeting chimera compounds (26), and dasatinib (27) are being investigated to design such safety switches. US Food and Drug Administration (FDA)–approved small-molecule HCV-NS3 inhibitors have been successfully adapted to design novel safety switches for CAR T cells (28, 29).The RNA (30–33) together with ribonucleases (RNases) (34, 35) was shown to possess a broad therapeutic potential. RNases are a large family of bacterial or eukaryotic enzymes that has a natural protein partner that can form a tight and specific complex—RNase inhibitor. The RNase superfamily is an excellent source of proteins for generating regulated CAR T cells. The barnase-barstar toxin-antitoxin system is orchestrated by the RNase toxin barnase and inactivated by the cognate barstar antitoxin, representing an outstanding example of molecular switching based on the extraordinary affinity of the barnase-barstar complex (K_D ∼10⁻¹⁴) (36–39). Here, the barnase–barstar interaction was applied to guide barstar-modified CAR (BsCAR) T cells to tumor cells by barnase-based molecular switches. Barnase was fused with designed ankyrin repeat proteins (DARPins) that are specific to tumor antigens HER2 (human epidermal growth factor receptor 2) and EpCAM. The resulting DARPin-barnase (DARPin-Bn) proteins enabled specific targeting of tumor cells by T cells modified with universal BsCAR. The high affinity of barnase-barstar binding provide a unique regulatory potential of CAR T therapeutics in vivo. This approach can reinforce the CAR technology with therapeutic modes, including the redirection of T cell cytotoxicity toward combinations of multiple tumor antigens.     

Evaluation of the Role of the Activating Application Method in the Cold Sintering Process of ZnO Ceramics Using Ammonium Chloride

The influence of the method of applying the activating additive ammonium chloride and its concentration on the density and microstructure of zinc oxide ceramic obtained by cold sintering at 244 °C was investigated. The activating agent was applied by two methods: impregnation and subsequent autoclave treatment. When the powder was activated by the impregnation method, the crystal sizes remained at the initial level of 0.17–0.19 μm. After the autoclave treatment, the crystal sizes increased to 0.31–0.53 μm. Samples of cold sintering ZnO with relative density up to 0.96 and average grain sizes 0.29–0.86 μm were obtained. ZnO powders and ceramic samples were analyzed using SEM, TGA/DSC, and XRD to reveal the effect of the powder activation method and cold sintering conditions on the material microstructure. The effect of ammonium chloride concentration on grain growth and microstructure of ceramic samples is shown. It was found that the average grain size of ceramic samples with an increase in additive concentration passes through a minimum. In cold sintering of the autoclave activated powder, the effect of reducing the average grain size was observed. The results of this work are discussed on the basis of the idea of the solid-phase mobility of the crystal structure arising when interacting with an aqueous medium.     

Choroidal neovascularization in a patient after resolution of multiple evanescent white dot syndrome: A case report

Choroidal neovascularization (CNV) is a rare complication of the Multiple Evanescent White Dot Syndrome (MEWDS). It can develop after resolving of the disease when there is already no evident inflammatory activity. Therefore, a long‐term follow‐up of such patients is important.