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Normal tissues are essential for studying disease-specific differential gene expression. However, healthy human controls are typically available only in postmortal/autopsy settings. In cancer research, fragments of pathologically normal tissue adjacent to tumor site are frequently used as the controls. However, it is largely underexplored how cancers can systematically influence gene expression of the neighboring tissues. Here we performed a comprehensive pan-cancer comparison of molecular profiles of solid tumor-adjacent and autopsy-derived healthy normal tissues. We found a number of systemic molecular differences related to activation of the immune cells, intracellular transport and autophagy, cellular respiration, telomerase activation, p38 signaling, cytoskeleton remodeling, and reorganization of the extracellular matrix. The tumor-adjacent tissues were deficient in apoptotic signaling and negative regulation of cell growth including G2/M cell cycle transition checkpoint. We also detected an extensive rearrangement of the chemical perception network. Molecular targets of 32 and 37 cancer drugs were over- or underexpressed, respectively, in the tumor-adjacent norms. These processes may be driven by molecular events that are correlated between the paired cancer and adjacent normal tissues, that mostly relate to inflammation and regulation of intracellular molecular pathways such as the p38, MAPK, Notch, and IGF1 signaling. However, using a model of macaque postmortal tissues we showed that for the 30 min - 24-hour time frame at 4ºC, an RNA degradation pattern in lung biosamples resulted in an artifact differential expression profile for 1140 genes, although no differences could be detected in liver. Thus, such concerns should be addressed in practice.

Dynamic changes in genomic DNA methylation patterns govern the epigenetic developmental programs and accompany the organism's aging. Epigenetic clock (eAge) algorithms utilize DNA methylation to estimate the age and risk factors for diseases as well as analyze the impact of various interventions. High-throughput bisulfite sequencing methods, such as reduced-representation bisulfite sequencing (RRBS) or whole genome bisulfite sequencing (WGBS), provide an opportunity to identify the genomic regions of disordered or heterogeneous DNA methylation, which might be associated with cell-type heterogeneity, DNA methylation erosion, and allele-specific methylation. We systematically evaluated the applicability of five scores assessing the variability of methylation patterns by evaluating within-sample heterogeneity (WSH) to construct human blood epigenetic clock models using RRBS data. The best performance was demonstrated by the model based on a metric designed to assess DNA methylation erosion with an MAE of 3.686 years. We also trained a prediction model that uses the average methylation level over genomic regions. Although this region-based model was relatively more efficient than the WSH-based model, the latter required the analysis of just a few short genomic regions and, therefore, could be a useful tool to design a reduced epigenetic clock that is analyzed by targeted next-generation sequencing. [ABSTRACT FROM AUTHOR]

Cancer virotherapy is an alternative therapeutic approach based on the viruses that selectively infect and kill tumor cells. Vaccinia virus (VV) is a member of the Poxviridae, a family of enveloped viruses with a large linear double-stranded DNA genome. The proven safety of the VV strains as well as considerable transgene capacity of the viral genome, make VV an excellent platform for creating recombinant oncolytic viruses for cancer therapy. Furthermore, various genetic modifications can increase tumor selectivity and therapeutic efficacy of VV by arming it with the immune-modulatory genes or proapoptotic molecules, boosting the host immune system, and increasing cross-priming recognition of the tumor cells by T-cells or NK cells. In this review, we summarized the data on bioengineering approaches to develop recombinant VV strains for enhanced cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied in COVID-19. This work aimed to analyze the activation and differentiation of both circulating NKT-like cells and CD56− T cells during COVID-19 among intensive care unit (ICU) patients, moderate severity (MS) patients, and convalescents. A decreased proportion of CD56+ T cells was found in ICU patients with fatal outcome. Severe COVID-19 was accompanied by a decrease in the proportion of CD8+ T cells, mainly due to the CD56− cell death, and a redistribution of the NKT-like cell subset composition with a predominance of more differentiated cytotoxic CD8+ T cells. The differentiation process was accompanied by an increase in the proportions of KIR2DL2/3+ and NKp30+ cells in the CD56+ T cell subset of COVID-19 patients and convalescents. Decreased percentages of NKG2D+ and NKG2A+ cells and increased PD-1 and HLA-DR expression levels were found in both CD56− and CD56+ T cells, and can be considered as indicators of COVID-19 progression. In the CD56− T cell fraction, increased CD16 levels were observed in MS patients and in ICU patients with lethal outcome, suggesting a negative role for CD56−CD16+ T cells in COVID-19. Overall, our findings suggest an antiviral role of CD56+ T cells in COVID-19. [ABSTRACT FROM AUTHOR]

Oncolytic viral therapy is a promising novel approach to cancer treatment. Oncolytic viruses cause tumor regression through direct cytolysis on the one hand and recruiting and activating immune cells on the other. In this study, to enhance the antitumor efficacy of the thymidine kinase-deficient vaccinia virus (VV, Lister strain), recombinant variants encoding bacterial flagellin (subunit B) of Vibrio vulnificus (LIVP-FlaB-RFP), firefly luciferase (LIVP-Fluc-RFP) or red fluorescent protein (LIVP-RFP) were developed. The LIVP-FLuc-RFP strain demonstrated exceptional onco-specificity in tumor-bearing mice, detected by the in vivo imaging system (IVIS). The antitumor efficacy of these variants was explored in syngeneic murine tumor models (B16 melanoma, CT26 colon cancer and 4T1 breast cancer). After intravenous treatment with LIVP-FlaB-RFP or LIVP-RFP, all mice tumor models exhibited tumor regression, with a prolonged survival rate in comparison with the control mice. However, superior oncolytic activity was observed in the B16 melanoma models treated with LIVP-FlaB-RFP. Tumor-infiltrated lymphocytes and the cytokine analysis of the serum and tumor samples from the melanoma-xenografted mice treated with these virus variants demonstrated activation of the host's immune response. Thus, the expression of bacterial flagellin by VV can enhance its oncolytic efficacy against immunosuppressive solid tumors. [ABSTRACT FROM AUTHOR]

The data is obtained on the effect of high‐intensity pulses of terahertz (THz) radiation with a broad spectrum (0.2–3 THz) on cell cultures. We have evaluated the threshold exposure parameters of THz radiation causing genotoxic effects in fibroblasts. Phosphorylation of histone H2AX at Ser 139 (γH2AX) was chosen as a marker for genotoxicity and a quantitative estimation of γH2AX foci number in fibroblasts was performed after cell irradiation with THz pulses for 30 min. No genotoxic effects of THz radiation were observed in fibroblasts unless peak intensity and electric field strength exceeded 21 GW cm−2 and 2.8 MV cm−1, respectively. In tumor cell lines (neuroblastoma (SK‐N‐BE (2)) and glioblastoma (U87)), exposure to THz pulses with peak intensity of 21 GW cm−2 for 30 min caused no morphological changes as well as no statistically significant increase in histone phosphorylation foci number. [ABSTRACT FROM AUTHOR]

Objective: Race disparities exist in bone metastasis (BM) development and survival in lung cancer (LC) patients. The Surveillance, Epidemiology, and End Results (SEER) database was used to investigate different patterns of BM development and survival in different races. Design: LC patients with BM were identified from the database from 2010 to 2014. Risk factors were investigated by univariable and multivariable logistic regression. Potential factors for prognosis were evaluated by univariable and multivariable Cox regression. Results: Asian and Pacific Islander (API) patients presented the highest prevalence of BM (24.6%), followed by white (20.7%) and black patients (19.9%) (χ2 = 78.74; p <.001). After adjusting for the demographic and clinical factors, API race was independently associated with a high risk of BM development. The median survival times for the API, white and black LC patients with BM were 16 months (95% CI: 15.2–16.8), 11 months (95% CI: 10.9–11.1) and 10 months (95% CI: 9.7–10.3), respectively, with significant differences (p <.001). Multivariable Cox regression showed that API race was positively associated with greater overall survival compared with white and black patients. Male gender, larger tumor size, lymph node involvement, lower tumor differentiated grade, and the presence of lung, liver and brain metastases were independently associated with a high risk of developing BM and worse survival with LC across all races. Age, income, insurance and histological types had different impacts on BM among different races. Conclusion: Homogeneous and heterogeneous associated factors for BM were revealed among different races. Individualized screening and treatment should be performed race-specifically. [ABSTRACT FROM AUTHOR]

The level of troponins after cardiac surgery always exceeds the reference values, however, the interpretation of these changes is difficult. Aim: to determine the relationship between high-sensitivity cardiac troponin I and troponin T levels and the risk of developing heart failure (HF) within 24 hours after heart surgery. A prospective, observational, single-center study included 70 patients undergoing elective heart surgery. Patients were retrospectively divided into two groups based on the development of HF in the first 12 hours after surgery. The levels of highly sensitive Troponin I (HsTI) in patients who underwent elective heart surgery without complications (n=57) were 61 times higher than the upper reference limit, with HF (n=13) - 111 times higher than the upper reference limit. The levels of highly sensitive Troponin T (HsTT) are 25.5 and 51 times higher, respectively. The level of HsTI at the end of the surgery can be a predictor of the development of HF, regardless of the use of cardiopulmonary bypass (threshold value 1483 ng/l), as well as a predictor of the need for inotropic support for 2 days or more, regardless of the type of operation (threshold value 1573 ng/l). There was a direct moderate correlation of HsTI at the end of the operation and 6 hours after the operation with cumulative hemohydrobalance for 24 hours, which was 60% higher in patients with HF than in patients without complications. In this study, we conducted a comparative assessment of troponin concentration with and without CVI. The HsTI levels in patients who underwent elective heart surgery without complications were 61 times higher than the upper limit of normal, whereas with CVI development, these were 111 times higher than the upper limit of normal, and the HsTT levels were 25.5 and 51 times higher, respectively. Threshold values for the prognosis of CVI after heart surgery (with/without CPB) is perhaps the level of HsTI of 1483 ng/L at the end of surgery and the HsTT level of 178 pg/mL 24 h after surgery with CPB. Elevated HsTI level predicts the need for catecholamine support and the probability of a complicated postoperative period earlier than HsTT. In the present study, we revealed the predictive ability of HsTI at the end of surgery and 6 and 24 h after surgery in determining the risk of CVI development and the need for inotropic support for 2 days or more. In the present study, in addition to trying to determine the "signal" level of troponin in cardiac surgery, we identified factors associated with an increase in troponin level and CVI development postoperatively, namely, CPB duration and perioperative infusion volume. Given the relationship between the rise in troponin levels and CPB duration, but not the period of myocardial ischemia, the systemic inflammatory response may influence the level of troponins. A factor in the increase in troponins was a significant positive perioperative hemohydrobalance. [ABSTRACT FROM AUTHOR]

Immunotherapy based on adoptive transfer of genetically engineered T‐ and NK‐cells is an area of active ongoing research and has proven highly efficacious for patients with certain B‐cell malignancies. Use of NK cells and NK cell lines as carriers of chimeric antigen receptors (CARs) appears particularly promising, as this opens an opportunity for moving the therapy from autologous to the allogeneic (universal) format. This "off‐the‐shelf" approach is thought to significantly reduce the price of the treatment and make it available to many more patients in need. Yet, the efficacy of CAR‐NK cells in vivo presently remains low, and boosting the activity of CAR NK cells via stronger tumor homing, resistance to tumor microenvironment, as well as greater cytotoxicity may translate into improved patient outcomes. Here, we established a derivative of a human NK cell line YT overexpressing a positive regulator of cytotoxicity, VAV1. Activity of YT‐VAV1 cells obtained was assayed in vitro against several cancer cell lines and primary patient‐derived cancer cells. YT‐VAV1 cells outperform parental YT cells in terms of cytotoxicity. [ABSTRACT FROM AUTHOR]

Cancer virotherapy is an alternative therapeutic approach based on the viruses that selectively infect and kill tumor cells. Vaccinia virus (VV) is a member of the Poxviridae, a family of enveloped viruses with a large linear double-stranded DNA genome. The proven safety of the VV strains as well as considerable transgene capacity of the viral genome, make VV an excellent platform for creating recombinant oncolytic viruses for cancer therapy. Furthermore, various genetic modifications can increase tumor selectivity and therapeutic efficacy of VV by arming it with the immune-modulatory genes or proapoptotic molecules, boosting the host immune system, and increasing cross-priming recognition of the tumor cells by T-cells or NK cells. In this review, we summarized the data on bioengineering approaches to develop recombinant VV strains for enhanced cancer immunotherapy.

The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied in COVID-19. This work aimed to analyze the activation and differentiation of both circulating NKT-like cells and CD56 - T cells during COVID-19 among intensive care unit (ICU) patients, moderate severity (MS) patients, and convalescents. A decreased proportion of CD56 + T cells was found in ICU patients with fatal outcome. Severe COVID-19 was accompanied by a decrease in the proportion of CD8 + T cells, mainly due to the CD56 - cell death, and a redistribution of the NKT-like cell subset composition with a predominance of more differentiated cytotoxic CD8 + T cells. The differentiation process was accompanied by an increase in the proportions of KIR2DL2/3 + and NKp30 + cells in the CD56 + T cell subset of COVID-19 patients and convalescents. Decreased percentages of NKG2D + and NKG2A + cells and increased PD-1 and HLA-DR expression levels were found in both CD56 - and CD56 + T cells, and can be considered as indicators of COVID-19 progression. In the CD56 - T cell fraction, increased CD16 levels were observed in MS patients and in ICU patients with lethal outcome, suggesting a negative role for CD56 - CD16 + T cells in COVID-19. Overall, our findings suggest an antiviral role of CD56 + T cells in COVID-19.