Overexpressed CXCR4 and CCR7 on the surface of NK92 cell have improved migration and anti-tumor activity in human colon tumor model.

Successive infusion of natural killer cells is increasingly being explored as a treatment for cancer patients. The inadequate homing of natural killer cells into the tumor site resulted in the poor efficacy of natural killer cells on solid tumors. For the adoptive transfer of tumor-directed natural killer cell has been proved effective, it is hypothesized that there must be more association between the tumor-produced chemokines and the natural killer cells-expressed chemokine receptors. Increased CXCL12 and CCL21 could ameliorated colorectal cancer via generating an anti-tumor environment by preferentially attracting natural killer cells which expressed the chemokine receptor CXCR4 and CCR7. This study demonstrated that overexpressed CXCR4 and CCR7 on the surface of NK92 cell enhanced their migration to human colon cells. Moreover, the administration of such natural killer cells resulted in tumor shrinkage and a significantly increased survival of experimental mice when compared to ones undergoing the treatment of xenografts with natural killer cells expressing only the mock control. These suggested that chemokine receptor engineered natural killer cells could be a promising tool to improve adoptive tumor immunotherapy.

Impact of diabetes on outcomes of cardiogenic shock: A systematic review and meta-analysis.

To provide synthesized evidence on the association of diabetes with clinical outcomes of patients with acute myocardial infarction (AMI) and associated cardiogenic shock (CS). We analyzed observational studies on patients with AMI and CS, identified through a systematic search using PubMed and Scopus databases. The main outcome was mortality and other outcomes of interest were risk of major bleeding, re-infarction, cerebrovascular adverse events, and need for revascularization. We conducted the meta-analysis with data from 15 studies. Compared to patients without diabetes, those with diabetes had an increased risk of in-hospital mortality (OR, 1.34; 95% CI, 1.17-1.54) and cerebrovascular complications (OR, 1.28; 95% CI, 1.11-1.48). We found similar risk of major bleeding (OR, 0.68; 95% CI, 0.43-1.09), re-infarction (OR, 0.98; 95% CI, 0.48-1.98) and need for re-vascularization (OR, 0.96; 95% CI, 0.75-1.22) as well as hospital stay lengths (in days) (WMD 0.00; 95% CI, -0.27-0.28; n = 4; I2 = 99.7%) in the two groups of patients. Patients with diabetes, acute MI and associated cardiogenic shock have increased risks of mortality and adverse cerebrovascular events than those without diabetes.

Engineering NK-92 Cell by Upregulating CXCR2 and IL-2 Via CRISPR-Cas9 Improves Its Antitumor Effects as Cellular Immunotherapy for Human Colon Cancer.

Natural killer (NK) cells have shown good application prospects in adoptive cellular immunotherapy against cancer. However, due to its insufficient infiltration and low activity, the therapeutic effect of infused NK cells has been limited in solid tumors, such as colorectal cancer. It has been proved that tumor-produced chemokines regulate the migration of NK cells expressing corresponding chemokine receptors, and cytokines could enhance the antitumor activity of NK cells. In this study, we innovatively upregulated the expression of chemokine receptor CXC chemokine receptor 2 (CXCR2) and cytokine interleukin (IL)-2 on NK-92 cells using CRISPR-Cas9 gene-editing technology. We demonstrated that overexpressing CXCR2 and IL-2 promotes NK-92 cells to increasingly transfer into tumor sites and achieve stronger cell-killing and proliferation activity. Moreover, the inhibitory effects of gene-edited NK-92 cells on the growth of human colon cancer in vivo were also improved. The tumor burden of tumor-bearing mice was reduced, and their survival time was significantly prolonged. Gene-editing modification NK cells are expected to become a novel and promising tumor treatment strategy.

Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides.

BACKGROUND: The present study aimed to explore residues' properties interacting with HLA-A*02-restricted peptides on T-cell receptors (TCRs) and their effects on bond types of interaction and binding free energy. METHODS: We searched the crystal structures of HLA-A*02-restricted peptide-TCR complexes from the Protein Data Bank (PDB) database and subsequently collected relevant parameters. We then employed Schrodinger to analyze the bond types of interaction and Gromacs 2019 to evaluate the TCR-antigen peptide complex's molecular dynamics simulation. Finally, we compared the changes of bond types of interaction and binding free energy before and after residue substitution to ensure consistency of the conditions before and after residue substitution. RESULTS: The main sites on the antigen peptides that formed the intermolecular interaction [hydrogen bond (HB) and pi stack] with TCRs were P4, P8, P2, and P6. The hydrophobicity of the amino acids inside or outside the disulfide bond of TCRs may be related to the intermolecular interaction and binding free energy between TCRs and peptides. Residues located outside the disulfide bond of TCR α or ß chains and forming pi stack force played favorable roles in the complex intermolecular interaction and binding free energy. The residues of the TCR α or ß chains that interacted with peptides were replaced by alanine (Ala) or glycine (Gly), and their intermolecular binding free energy of the complex had been improved. However, it had nothing to do with the formation of HB. CONCLUSIONS: The findings of this study suggest that the hydrophobic nature of the amino acids inside or outside the disulfide bonds on the TCR may be associated with the intermolecular interaction and binding between the TCR and polypeptide. The residues located outside the TCR α or ß single-chain disulfide bond and forming the pi-stack force showed a beneficial effect on the intermolecular interaction and binding of the complex. In addition, the part of the residues on the TCR α or ß single chain that produced bond types of interaction with the polypeptide after being replaced by Ala or Gly, the intermolecular binding free energy of the complex was increased, regardless of whether HB was formed.