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We previously established a hepatocellular carcinoma (HCC) targeting system of conditionally replicative adenovirus (CRAd) delivered by human umbilical cord-derived mesenchymal stem cells (HUMSCs). However, this system needed to be developed further to enhance the antitumor effect and overcome the limitations caused by the alpha-fetoprotein (AFP) heterogeneity of HCC. In this study, a bispecific T cell engager (BiTE) targeting programmed death ligand 1 controlled by the human telomerase reverse transcriptase promoter was armed on the CRAd of the old system. It was demonstrated on orthotopic transplantation model mice that the new system had a better anti-tumor effect with no more damage to extrahepatic organs and less liver injury, and the infiltration and activation of T cells were significantly enhanced in the tumor tissues of the model mice treated with the new system. Importantly, we confirmed that the new system eliminated the AFP-negative cells on AFP heterogeneous tumor models efficiently. Conclusion: Compared with the old system, the new system provided a more effective and safer strategy against HCC. [ABSTRACT FROM AUTHOR]

Over-expression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To explore chemical inhibitors against TNFα activity, we applied computer-aided drug design (CADD) combined with in vitro and cell-based assays and identified a lead chemical compound, (E)-4-(2-(4-chloro-3-nitrophenyl) (named as C87 thereafter), which directly binds to TNFα, potently inhibits TNFα-induced cytotoxicity \((IC_{50}=8.73\mu M)\) and effectively blocks TNFα-triggered signaling activities. Furthermore, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα-mediated inflammatory diseases.

The SARS-CoV-2 Omicron variant evades most currently approved neutralizing antibodies (nAbs) and caused drastic decrease of plasma neutralizing activity elicited by vaccination or prior infection, urging the need for the development of pan-variant antivirals. Breakthrough infection induces a hybrid immunological response with potentially broad, potent and durable protection against variants, therefore, convalescent plasma from breakthrough infection may provide a broadened repertoire for identifying elite nAbs. We performed single-cell RNA sequencing (scRNA-seq) and BCR sequencing (scBCR-seq) of B cells from BA.1 breakthrough-infected patients who received 2 or 3 previous doses of inactivated vaccine. Elite nAbs, mainly derived from the IGHV2-5 and IGHV3-66/53 germlines, showed potent neutralizing activity across Wuhan-Hu-1, Delta, Omicron sublineages BA.1 and BA.2 at picomolar NT 50 values. Cryo-EM analysis revealed diverse modes of spike recognition and guides the design of cocktail therapy. A single injection of paired antibodies cocktail provided potent protection in the K18-hACE2 transgenic female mouse model of SARS-CoV-2 infection., (© 2023. The Author(s).)

Cognitive impairment is one of the three primary symptoms of schizophrenic patients and shows important value in early detection and warning for high-risk individuals. To study the specifics of electroencephalogram (EEG) in patients with schizophrenia under the cognitive load, we collected EEG signals from 17 schizophrenic patients and 19 healthy controls, extracted signals of each band based on wavelet transform, calculated the characteristics of nonlinear dynamic and functional brain networks, and automatically classified the two groups of people by using a machine learning algorithm. Experimental results indicated that the correlation dimension and sample entropy showed significant differences in α, β, θ, and γ rhythm of the Fp1 and Fp2 electrodes between groups under the cognitive load. These results implied that the functional disruptions in the frontal lobe might be the important factors of cognitive impairments in schizophrenic patients. Further results of the automatic classification analysis indicated that the combination of nonlinear dynamics and functional brain network properties as the input characteristics of the classifier showed the best performance, with the accuracy of 76.77%, sensitivity of 72.09%, and specificity of 80.36%. The results of this study demonstrated that the combination of nonlinear dynamics and function brain network properties may be potential biomarkers for early screening and auxiliary diagnosis of schizophrenia.

Recent studies have demonstrated mesenchymal stem cells (MSCs) are able to migrate specifically to tumors and their metastatic sites when administered intravenously. This characteristic tumor tropism has opened up an emerging field to utilize MSCs as vectors to deliver anti-cancer agents for targeted therapies. Genetically engineered MSCs can specifically migrate to various tumors and locally secrete therapeutic proteins, such as interferon β (IFN-β) and IFN-γ, interleukin 12 and 24, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or suicide gene/enzyme prodrug. In addition, MSCs have also been engineered to deliver oncolytic viruses and drug-loaded nanoparticles. Here, we present the characteristics of MSCs, the current progress on MSC mediated anti-cancer agents delivery systems and the interaction between MSCs and tumors.

Background: Increasing evidence suggests that aberrant activation of PI3K/Akt is involved in many human cancers, and that inhibition of the PI3K/Akt pathway might be a promising strategy for cancer therapy. The aims of this study is to evaluate the effects of combined therapy of Phosphatidylinositol 3-Kinase inhibitor (LY294002 ) and Paclitaxel in athymic mice xenogeneic transplant model of lung cancer and to reveal the possible mechanisms involved., Methods: Eighteen athymic mice were randomly divided into 3 groups (control, paclitaxel alone and paclitaxel plus LY294002), and were treated respectively. Athymic mice xenogeneic transplant model was established by inoculation (sc) with A549 lung cancer cells. Body mass (BM) and diameter of tumor mass were measured. Furthermore, the protein expressions of CyclinD1,bcl-2 and bax in tumor tissues were analyzed with immunohistochemistry., Results: The tumor-inhibiting rate of paclitaxel plus LY294002 (92.47%) was significantly higher than the paclitaxel alone (65.59%)(P <0.05).The protein expression of bcl-2 in paclitaxel plus LY294002 group were significantly higher, while bax was significantly lower than that in the other two groups (P <0.05). The protein expression of CyclinD1 was significantly lower than the control group (P <0.05)., Conclusions: LY294002 can enhance the effects of paclitaxel in the treatment of lung cancer and CyclinD1, bcl-2 and bax may be involved in its inhibitory effects.

Background: Metastasis is the main cause of cancer related mortality, and identification of genes involved in tumor metastasis is important for effective therapies. The membrane cytoskeletal crosslinker participated in several functions including cell adhersion, motility and cell survival, and there is increasing evidence that it regulates tumor progression. However, the role played by ezrin in lung cancer metastasis has not been clearly delineated. The aims of this study are to investigate the ezrin expression pattern in human lung carcinoma and the correlation with clinicopathologic characteristics., Methods: Ezrin expression was detected by two- step immunohistochemical staining technique in tumor tissues from 75 lung cancer cases and in normal lung tissues from 16 cases with benign disease and analyzed by the lung cancer clinicopathologic characteristics. The gene and protein level expression of Ezrin in lung cancer cell lines was also detected by Confocal Laser Scanning Microscope (CLSM) and RT-PCR., Results: The positive incidence of ezrin expression (77.3%) was significantly lower in lung cancer tissues than that in normal tissues (100%) (P<0.05), and the down-regulated of ezrin expression was significantly correlated with lymph node metastasis and distant metastasis (P<0.05) and was not correlated with gender, age, tumor size, pathological type, the degree of differentiation of tissue and clinical stage. Otherwise, the subcellular redistribution of ezrin from cell membrane to cell plasma was significantly correlated with lymph node metastasis (P< 0.05), in consistance with in vitro experimental result. High metastasis cell line BE1 had the lowest expression of ezrin under CLSM, similar to RT-PCR, and ezrin was mainly located in cell plasma under CLSM., Conclusions: Ezrin expression is down-regulated in lung cancer tissue and lung cancer cell line, and the locational change from cell membrane to cell plasma may be associated with the oncogenesis and development of lung cancer.