Meta-Analysis of Doxorubicin-Eluting Beads via Transcatheter Arterial Chemoembolization in the Treatment of Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIMS: To evaluate the efficacy and safety of doxorubicin-eluting beads combined with transcatheter arterial chemoembolization (DEB-TACE) compared with conventional TACE (cTACE). METHODOLOGY: PubMed, EMBASE, MEDLINE and Cochrane Controlled Trials Register were searched for articles published to identify randomized controlled trials evaluating efficacy and side effects between DEB-TACE and cTACE. The RR (relative risk) with a 95% confidence interval (CI) was calculated by the Revman 5.0 software. RESULTS: Totally 4 studies, including 527 patients, compared the efficacy and safety of DEB-TACE with cTACE. The DEB-TACE achieved fewer side effects in alopecia (p = 0.0002, RR = 0.05, 95% CI: 0.01-0.24) and myelosuppression (p = 0.009, RR = 0.32, 95% CI: 0.14-0.75). Meanwhile, there was no significant difference in efficacy evaluation including complete response (p = 0.16, RR = 1.36, 95% CI: 0.89-2.08), partial response (p = 0.48, RR = 1.14, 95% CI: 0.80-1.62), stable disease (p = 0.73, RR = 0.93,95% CI: 0.60-1.40), progressive disease (p 0.19, RR = 0.80, 95% CI: 0.56-1.12), objective response (p = 0.26, RR 0.91, 95% CI: 0.48-1.72) and disease control (p = 0.05, RR = 1.18, 95% CI: 1.00-1.39). CONCLUSIONS: DEB-TACE shows similar therapeutic efficacy to cTACE method and fewer adverse events.

Engineered Bacillus subtilis alleviates intestinal oxidative injury through Nrf2-Keap1 pathway in enterotoxigenic Escherichia coli (ETEC) K88-infected piglet / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Engineered probiotics can serve as therapeutics based on their ability of produce recombinant immune-stimulating properties. In this study, we built the recombinant Bacillus subtilis WB800 expressing antimicrobial peptide KR32 (WB800-KR32) using genetic engineering methods and investigated its protective effects of nuclear factor-E2-related factor 2 (Nrf2)‍-Kelch-like ECH-associated protein 1 (Keap1) pathway activation in intestinal oxidative disturbance induced by enterotoxigenic Escherichia coli (ETEC) K88 in weaned piglets. Twenty-eight weaned piglets were randomly distributed into four treatment groups with seven replicates fed with a basal diet. The feed of the control group (CON) was infused with normal sterilized saline; meanwhile, the ETEC, ETEC+WB800, and ETEC+WB800-KR32 groups were orally administered normal sterilized saline, 5×1010 CFU (CFU: colony forming units) WB800, and 5×1010 CFU WB800-KR32, respectively, on Days 1‍‒‍14 and all infused with ETEC K88 1×1010 CFU on Days 15‍‒‍17. The results showed that pretreatment with WB800-KR32 attenuated ETEC-induced intestinal disturbance, improved the mucosal activity of antioxidant enzyme (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)) and decreased the content of malondialdehyde (MDA). More importantly, WB800-KR32 downregulated genes involved in antioxidant defense (GPx and SOD1). Interestingly, WB800-KR32 upregulated the protein expression of Nrf2 and downregulated the protein expression of Keap1 in the ileum. WB800-KR32 markedly changed the richness estimators (Ace and Chao) of gut microbiota and increased the abundance of Eubacterium_rectale_ATCC_33656 in the feces. The results suggested that WB800-KR32 may alleviate ETEC-induced intestinal oxidative injury through the Nrf2-Keap1 pathway, providing a new perspective for WB800-KR32 as potential therapeutics to regulate intestinal oxidative disturbance in ETEC K88 infection.

Biomechanical Response of Macrophages/Microglia Cells to Blast Shock Injury in Mice / 医用生物力学

Objective To establish a blast injury experimental model using a shock tube at lateral lying position of C57BL/6 mice, investigate biomechanical responses of macrophages/microglia cells in the heart, lung and brain tissues to mechanical damage by shock wave within 24 hours. Methods Shock tube was employed to generate a shock wave to C57BL/6 mice. Firstly, the weight changes of mice were measured at different time points after the shock. Then the cardiac, pulmonary and whole brain tissue samples were dissected after anesthesia. Pathological sections were stained with HE staining to detect structural damage; the TUNEL staining method was used to mark and count the proportion of dead cells in each tissue. Microglial cells were labeled with fluorescent antibody, while responses and changes of macrophages/microglia after shock loading were analyzed. Results The shock tube exerted 179 kPa overpressure shock wave upon sideway of the mouse, and lethal rate of the mouse was 3.33%. Compared with normal control group, the mice in experimental group had a significant weight loss within 24 hours after loading shock. Pathological sections showed rupture of lung tissues after shock, accompanied by alveolar protein deposition, pulmonary bulla and other diseases. Fluorescence staining showed that lung tissue was recruited and activated in a large amount within 24 hours. The proportion of dead cells cleared rebounded to normal level within 24 hours. The heart was highly tolerant to shock, and macrophages appeared near the large blood vessels. The brain showed unilateral aggregation of microglia due to the impact posture, mainly due to prolonged inflammation and a higher proportion of dead cells at the junction of gray and white matter. Conclusions A blast shock model at lateral lying position of the mouse was established. Within 24 hours, macrophages/microglia were recruited quickly to the injury site after being impacted, which mediated strong immune stress, and might participate in the immune response to trigger a second long-term inflammatory injury. The results of the study provide experimental basis for the evaluation of primary impact injury, such as dose-effect relationship and tissue damage difference.

Effects of Intensive Lower Extremity Motor Control Training on Function of Lower Extremitis in Stroke Patients / 中国康复理论与实践

Objective To observe the effects of intensive lower extremity motor control training on the motor function of lower extremi-ty, balance and walking capability of stroke patients. Methods 40 stroke patients were randomized into the intervention group (n=20) and control group (n=20). Both groups received the routine rehabilitation, while the intervention group accepted the lower extremity motor con-trol training in addition for 6 weeks. Before and after 6 weeks of treatments, they were assessed with Fugl-Meyer Assessment of lower ex-tremity (FMA-L), Berg Balance Scale (BBS), Holden Functional Ambulation Category (FAC);their gaits were analysesd with footprint. Re-sults Both groups improved significantly in scores of FMA-L, BBS, FAC and average step length, stride width, walking velocity (P<0.01) after treatment, and improved more in the intervention group than in the control group (P<0.05). Conclusion Intensive motor control train-ing of lower extremity may promote the recovery of motor function of lower extremities, balance and walking ability of stroke patients.

Effects of Intensive Lower Extremity Motor Control Training on Function of Lower Extremitis in Stroke Patients / 中国康复理论与实践

@#Objective To observe the effects of intensive lower extremity motor control training on the motor function of lower extremity, balance and walking capability of stroke patients. Methods 40 stroke patients were randomized into the intervention group (n=20) and control group (n=20). Both groups received the routine rehabilitation, while the intervention group accepted the lower extremity motor control training in addition for 6 weeks. Before and after 6 weeks of treatments, they were assessed with Fugl-Meyer Assessment of lower extremity (FMA-L), Berg Balance Scale (BBS), Holden Functional Ambulation Category (FAC); their gaits were analysesd with footprint. Results Both groups improved significantly in scores of FMA-L, BBS, FAC and average step length, stride width, walking velocity (P<0.01) after treatment, and improved more in the intervention group than in the control group (P<0.05). Conclusion Intensive motor control training of lower extremity may promote the recovery of motor function of lower extremities, balance and walking ability of stroke patients.

Effect of propofol on interleukin-1β-induced increase in monolayer permeability of human umbilical vein endothelial cells / 中华麻醉学杂志

Objective To evaluate the effect of propofol on interleukin-1β (IL-1β)-induced increase in monolayer permeability of human umbilical vein endothelial cells (HUVECs).Methods Primary HUVECs were cultured and purified by immuno-magnetic separation.The expression of VE-cadherin in endothelial cells was determined by immunofluorescence.The HUVEC monolayer permeability was detected by the Transwell system.The cells were seeded on the upper chamber (2 × 105 cells/well) and cultured for 3 days after confluence.The cells were treated in two ways.The cells were randomly divided into 6 groups (n =36 each) and 5 of the 6 groups treated with 1,2,5,10 and 20 ng/ml IL-1β for 24 h except for control group.The cells were also randomly divided into 5 groups (n =30 each) and 4 of the 5 groups were pretreated with 0,10,50 and 100 μmol/L propofol for 30 min,and then treated with 10 ng/ml IL-1β for 24 h except for control group.The cells were radomly divided into 3 groups (n =18 each) and 2 of the 3 groups were pretreated with 50 μmol/L propofol for 30 min,and then treated with 10 ng/ml IL-1β for 24 h or 30 min.The expression of occludin protien,p38 mitogen activiated protienkinase (p38 MAPK) and phosphorylated p38 MAPK (p-p38 MAPK) was determined by Western blot.Results Compared with control group,5,10 and 20 ng/ml IL-1β significantly increased HUVEC monolayer permeability in a concentration-dependent manner (P ＜ 0.05 or 0.01).10,50 and 100 μmol/L propofol inhibited IL-1 β-induced increase in the permeability of HUVEC monolayer permeability in a concentration-dependent manner (P ＜ 0.01).IL-1β could down-regulate HUVEC occludin protein expression,and activate p38MAPK signaling pathway,and propofol inhibited IL-1β-induced down-regulation of HUVEC occludin protein expression and activation of p38 MAPK signaling pathway (P ＜ 0.01).Conclusion Propofol can alleviate IL-1β-induced increase in the permeability of HUVEC monolayer via inhibiting activation of p38 MAPK signaling pathway.

An ultra-high affinity synthetic nanobody blocks SARS-CoV-2 infection by locking Spike into an inactive conformation

Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.