Effect of Cold Adaptation on the State of Cardiovascular System and Cardiac Tolerance to Ischemia/Reperfusion Injury.

Despite the unconditional success achieved in the treatment and prevention of AMI over the past 40 years, mortality in this disease remains high. Hence, it is necessary to develop novel drugs with mechanism of action different from those currently used in clinical practices. Studying the molecular mechanisms involved in the cardioprotective effect of adapting to cold could contribute to the development of drugs that increase cardiac tolerance to the impact of ischemia/reperfusion. An analysis of the published data shows that the long-term human stay in the Far North contributes to the occurrence of cardiovascular diseases. At the same time, chronic and continuous exposure to cold increases tolerance of the rat heart to ischemia/ reperfusion. It has been demonstrated that the cardioprotective effect of cold adaptation depends on the activation of ROS production, stimulation of the ß2-adrenergic receptor and protein kinase C, MPT pore closing, and KATP channel.

Assessment of Safety and Prophylactic Efficacy of the EpiVacCorona Peptide Vaccine for COVID-19 Prevention (Phase III).

The State Research Center of Virology and Biotechnology "VECTOR" of the Federal Service for the Oversight of Consumer Protection and Welfare (Rospotrebnadzor) has developed the peptide-based EpiVacCorona vaccine, which is the first synthetic peptide-based antiviral vaccine for mass immunization in international vaccinology. An early clinical trial (Phase I-II) demonstrated that the EpiVacCorona vaccine is a safe product. The "Multicenter double-blind, placebo-controlled, comparative, randomized trial to assess the tolerability, safety, immunogenicity and prophylactic efficacy of the EpiVacCorona COVID-19 vaccine based on peptide antigens in 3000 volunteers aged 18 years and older" was performed regarding vaccine safety. The key objectives of the study were to evaluate the safety and prophylactic efficacy of the two-dose EpiVacCorona vaccine administered via the intramuscular route. The results of the clinical study (Phase III) demonstrated the safety of the EpiVacCorona vaccine. Vaccine administration was accompanied by mild local reactions in ≤27% of cases and mild systemic reactions in ≤14% of cases. The prophylactic efficacy of the EpiVacCorona COVID-19 vaccine after the completion of the vaccination series was 82.5% (CI95 = 75.3-87.6%). The high safety and efficacy of the vaccine give grounds for recommending this vaccine for regular seasonal prevention of COVID-19 as a safe and effective medicinal product.

Blue Light and Temperature Actigraphy Measures Predicting Metabolic Health Are Linked to Melatonin Receptor Polymorphism.

This study explores the relationship between the light features of the Arctic spring equinox and circadian rhythms, sleep and metabolic health. Residents (N = 62) provided week-long actigraphy measures, including light exposure, which were related to body mass index (BMI), leptin and cortisol. Lower wrist temperature (wT) and higher evening blue light exposure (BLE), expressed as a novel index, the nocturnal excess index (NEIbl), were the most sensitive actigraphy measures associated with BMI. A higher BMI was linked to nocturnal BLE within distinct time windows. These associations were present specifically in carriers of the MTNR1B rs10830963 G-allele. A larger wake-after-sleep onset (WASO), smaller 24 h amplitude and earlier phase of the activity rhythm were associated with higher leptin. Higher cortisol was associated with an earlier M10 onset of BLE and with our other novel index, the Daylight Deficit Index of blue light, DDIbl. We also found sex-, age- and population-dependent differences in the parametric and non-parametric indices of BLE, wT and physical activity, while there were no differences in any sleep characteristics. Overall, this study determined sensitive actigraphy markers of light exposure and wT predictive of metabolic health and showed that these markers are linked to melatonin receptor polymorphism.

Tumor Colonization and Therapy by Escherichia coli Nissle 1917 Strain in Syngeneic Tumor-Bearing Mice Is Strongly Affected by the Gut Microbiome.

In the past, different bacterial species have been tested for cancer therapy in preclinical and clinical studies. The success of bacterial cancer therapy is mainly dependent on the ability of the utilized bacteria to overcome the host immune defense system to colonize the tumors and to initiate tumor-specific immunity. In recent years, several groups have demonstrated that the gut microbiome plays an important role of modulation of the host immune response and has an impact on therapeutic responses in murine models and in cohorts of human cancer patients. Here we analyzed the impact of the gut microbiome on tumor colonization and tumor therapy by the Escherichia coli Nissle 1917 (EcN) strain. This EcN strain is a promising cancer therapy candidate with probiotic properties. In our study, we observed significantly better tumor colonization by EcN after antibiotic-induced temporal depletion of the gut microbiome and after two intranasal applications of the EcN derivate (EcN/pMUT-gfp Knr) in 4T1 tumor-bearing syngeneic BALB/c mice. In addition, we demonstrated significant reduction in tumor growth and extended survival of the EcN-treated mice in contrast to phosphate-buffered saline (PBS)-treated tumor-bearing control animals. Multispectral imaging of immune cells revealed that depletion of the gut microbiome led to significantly lower infiltration of cytotoxic and helper T cells (CD4 and CD8 cells) in PBS tumors of mice pretreated with antibiotics in comparison with antibiotic untreated PBS-or EcN treated mice. These findings may help in the future advancement of cancer treatment strategies using E. coli Nissle 1917.

Interplay of Obesity, Ethanol, and Contaminant Mixture on Clinical Profiles of Cardiovascular and Metabolic Diseases: Evidence from an Animal Study.

Obesity, ethanol, and contaminants are known risk factors of cardiovascular and metabolic diseases (CMD). However, their interplay on clinical profiles of these diseases remains unclear, and thus were investigated in this study. Male lean or obese JCR rats were given water or 10% ethanol and orally treated with or without a contaminant mixture (CM) dissolved in corn oil and loaded on two cookies at 0, 1.6, or 16 mg/kg BW/day dose levels for 4 weeks. The CM consisted 22 environmental contaminants found in human blood or serum of Northern populations. Over 60 parameters related to CMD were examined. The results revealed that obesity in JCR rats resembles the clinical profiles of non-alcoholic fatty liver disease in humans. Obesity was also associated with increased serum and organ retention of mercury, one of the chemical components of CM. Exposure to ethanol lightened hyperlipidemia, increased liver retention of mercury, and increased risk for hypertension in the obese rats. CM lessened hyperlipidemia and hyperenzymemia, worsened systemic inflammation and increased the risk for hypertension in the obese rats. CM markedly increased serum ethanol levels with or without ethanol exposure. Tissue total mercury contents significantly correlated with clinical parameters with altered profiles by both ethanol and obesity. These results suggest that obese individuals may be more prone to contaminant accumulation. Ethanol and CM exposure can alter clinical profiles associated with obesity, which may lead to misdiagnosis of CMD associated with obesity. CM can alter endogenous production and/or metabolism of ethanol, further complicating disease progression, diagnosis, and treatment.

Association between food addiction and time perspective during COVID-19 isolation.

PURPOSE: The concept of time perspective (TP) implies that a mental focus on past, present, or future affect a person makes decisions and take action. Inability to plan their life for a sufficiently long time perspective due to the COVID-19 pandemic appeared to have a pronounced impact on a human's lifestyle influencing their thoughts, feelings, and behaviors, including eating behavior. This study tested two hypotheses: (a) that during COVID-19 isolation, the incidence rate of food addiction is increased, and (b) people with present TP are more likely exhibited signs of food addiction (FA). METHODS: The final study sample included 949 people, mean age 21.8 ± 7.8 years (range: 17-71 years, women: 78.3%). Each participant indicated their personal data and completed Yale Food Addiction Scale and the Zimbardo Time Perspective Inventory. RESULTS: There was an increased incidence rate of FA (OR = 1.678, 95% CI = 1.324, 2.148, p = 0.000) during COVID-19 isolation. Individuals with balanced, future, and past positive TP were less likely to exhibit symptoms of FA. Persons with past negative, and present hedonistic TP were more likely to exhibit signs of FA. CONCLUSION: There was an increased incidence rate of FA during COVID-19 isolation. Persons with shortened time horizon are more likely to exhibit symptoms of FA. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

Asymmetric Adaptive LDPC-Based Information Reconciliation for Industrial Quantum Key Distribution.

We develop a new approach for asymmetric LDPC-based information reconciliation in order to adapt to the current channel state and achieve better performance and scalability in practical resource-constrained QKD systems. The new scheme combines the advantages of LDPC codes, a priori error rate estimation, rate-adaptive and blind information reconciliation techniques. We compare the performance of several asymmetric and symmetric error correction schemes using a real industrial QKD setup. The proposed asymmetric algorithm achieves significantly higher throughput, providing a secret key rate that is close to the symmetric one in a wide range of error rates. Thus, our approach is found to be particularly efficient for applications with high key rates, limited classical channel capacity and asymmetric computational resource allocation.

Canine Adipose-Derived Mesenchymal Stem Cells (cAdMSCs) as a "Trojan Horse" in Vaccinia Virus Mediated Oncolytic Therapy against Canine Soft Tissue Sarcomas.

Several oncolytic viruses (OVs) including various human and canine adenoviruses, canine distemper virus, herpes-simplex virus, reovirus, and members of the poxvirus family, such as vaccinia virus and myxoma virus, have been successfully tested for canine cancer therapy in preclinical and clinical settings. The success of the cancer virotherapy is dependent on the ability of oncolytic viruses to overcome the attacks of the host immune system, to preferentially infect and lyse cancer cells, and to initiate tumor-specific immunity. To date, several different strategies have been developed to overcome the antiviral host defense barriers. In our study, we used canine adipose-derived mesenchymal stem cells (cAdMSCs) as a "Trojan horse" for the delivery of oncolytic vaccinia virus Copenhagen strain to achieve maximum oncolysis against canine soft tissue sarcoma (CSTS) tumors. A single systemic administration of vaccinia virus-loaded cAdMSCs was found to be safe and led to the significant reduction and substantial inhibition of tumor growth in a CSTS xenograft mouse model. This is the first example that vaccinia virus-loaded cAdMSCs could serve as a therapeutic agent against CSTS tumors.

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology.

Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen major cancer types, we compared heterogeneities at the levels of mutations and gene expression with the repertoires of targeted therapeutics and their molecular targets accepted by the current guidelines in oncology. Totally, 85 drugs were investigated, collectively covering 82 individual molecular targets. For the first time, we showed that the repertoires of molecular targets of accepted drugs did not correlate with molecular heterogeneities of different cancer types. On the other hand, we found that the clinical recommendations for the available cancer drugs were strongly congruent with the gene expression but not gene mutation patterns. We detected the best match among the drugs usage recommendations and molecular patterns for the kidney, stomach, bladder, ovarian and endometrial cancers. In contrast, brain tumors, prostate and colorectal cancers showed the lowest match. These findings provide a theoretical basis for reconsidering usage of targeted therapeutics and intensifying drug repurposing efforts.

Hypereosinophilic Syndrome, Cardiomyopathies, and Sudden Cardiac Death in Superinvasive Opisthorchiasis.

Cardiovascular pathology in patients with superinvasive opisthorchiasis is characterized by severe changes in haemodynamics and myocardial metabolism, impaired automatism, excitability, and conduction of the heart muscle. An analysis of 578 cases (medical and outpatient records and reports of pathoanatomical and forensic autopsies) recorded in healthcare facilities treating opisthorchiasis patients with a hyperendemic focus was carried out. We identified a set of cardiac changes in patients with hypereosinophilic syndrome associated with superinvasive opisthorchiasis infection, classified the pathological processes in accordance with ICD-10, and described their pathogenesis.

Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers.

BACKGROUND: Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties. METHODS: To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations. RESULTS: Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor. CONCLUSIONS: Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.

Circular Dichroism in Fluorescence Emission Following the C 1s→π* Excitation and Resonant Auger Decay of Carbon Monoxide.

Dichroism in angle-resolved spectra of circularly polarized fluorescence from freely-rotating CO molecules was studied experimentally and theoretically. For this purpose, carbon monoxide in the gas phase was exposed to circularly polarized soft X-ray synchrotron radiation. The photon energy was tuned across the C 1s→π* resonant excitation, which decayed via the participator Auger transition into the CO⁺ A ²Π state. The dichroic parameter ß1 of the subsequent CO⁺ (A ²Π → X ²Σ⁺) visible fluorescence was measured by photon-induced fluorescence spectroscopy. Present experimental results are explained with the ab initio electronic structure and dynamics calculations performed by the single center method. Our results confirm the possibility to perform partial wave analysis of the emitted photoelectrons in closed-shell molecules.

Enhanced Ti0.84Ta0.16N diffusion barriers, grown by a hybrid sputtering technique with no substrate heating, between Si(001) wafers and Cu overlayers.

We compare the performance of conventional DC magnetron sputter-deposited (DCMS) TiN diffusion barriers between Cu overlayers and Si(001) substrates with Ti0.84Ta0.16N barriers grown by hybrid DCMS/high-power impulse magnetron sputtering (HiPIMS) with substrate bias synchronized to the metal-rich portion of each pulse. DCMS power is applied to a Ti target, and HiPIMS applied to Ta. No external substrate heating is used in either the DCMS or hybrid DCMS/HiPIMS process in order to meet future industrial thermal-budget requirements. Barrier efficiency in inhibiting Cu diffusion into Si(001) while annealing for 1 hour at temperatures between 700 and 900 °C is investigated using scanning electron microscopy, X-ray diffraction, four-point-probe sheet resistance measurements, transmission electron microscopy, and energy-dispersive X-ray spectroscopy profiling. Ti0.84Ta0.16N barriers are shown to prevent large-scale Cu diffusion at temperatures up to 900 °C, while conventional TiN barriers fail at ≤700 °C. The improved performance of the Ti0.84Ta0.16N barrier is due to film densification resulting from HiPIMS pulsed irradiation of the growing film with synchronized Ta ions. The heavy ion bombardment dynamically enhances near-surface atomic mixing during barrier-layer deposition.

Gene expression and molecular pathway activation signatures of MYCN-amplified neuroblastomas.

Neuroblastoma is a pediatric cancer arising from sympathetic nervous system. Remarkable heterogeneity in outcomes is one of its widely known features. One of the traits strongly associated with the unfavorable subtype is the amplification of oncogene MYCN. Here, we performed cross-platform biomarker detection by comparing gene expression and pathway activation patterns from the two literature reports and from our experimental dataset, combining profiles for the 761 neuroblastoma patients with known MYCN amplification status. We identified 109 / 25 gene expression / pathway activation biomarkers strongly linked with the MYCN amplification. The marker genes/pathways are involved in the processes of purine nucleotide biosynthesis, ATP-binding, tetrahydrofolate metabolism, building mitochondrial matrix, biosynthesis of amino acids, tRNA aminoacylation and NADP-linked oxidation-reduction processes, as well as in the tyrosine phosphatase activity, p53 signaling, cell cycle progression and the G1/S and G2/M checkpoints. To connect molecular functions of the genes involved in MYCN-amplified phenotype, we built a new molecular pathway using known intracellular protein interaction networks. The activation of this pathway was highly selective in discriminating MYCN-amplified neuroblastomas in all three datasets. Our data also suggest that the phosphoinositide 3-kinase (PI3K) inhibitors may provide new opportunities for the treatment of the MYCN-amplified neuroblastoma subtype.

Differentially expressed proteins in glioblastoma multiforme identified with a nanobody-based anti-proteome approach and confirmed by OncoFinder as possible tumor-class predictive biomarker candidates.

Glioblastoma multiforme is the most frequent primary malignancy of the central nervous system. Despite remarkable progress towards an understanding of tumor biology, there is no efficient treatment and patient outcome remains poor. Here, we present a unique anti-proteomic approach for selection of nanobodies specific for overexpressed glioblastoma proteins. A phage-displayed nanobody library was enriched in protein extracts from NCH644 and NCH421K glioblastoma cell lines. Differential ELISA screenings revealed seven nanobodies that target the following antigens: the ACTB/NUCL complex, VIM, NAP1L1, TUFM, DPYSL2, CRMP1, and ALYREF. Western blots showed highest protein up-regulation for ALYREF, CRMP1, and VIM. Moreover, bioinformatic analysis with the OncoFinder software against the complete "Cancer Genome Atlas" brain tumor gene expression dataset suggests the involvement of different proteins in the WNT and ATM pathways, and in Aurora B, Sem3A, and E-cadherin signaling. We demonstrate the potential use of NAP1L1, NUCL, CRMP1, ACTB, and VIM for differentiation between glioblastoma and lower grade gliomas, with DPYSL2 as a promising "glioma versus reference" biomarker. A small scale validation study confirmed significant changes in mRNA expression levels of VIM, DPYSL2, ACTB and TRIM28. This work helps to fill the information gap in this field by defining novel differences in biochemical profiles between gliomas and reference samples. Thus, selected genes can be used to distinguish glioblastoma from lower grade gliomas, and from reference samples. These findings should be valuable for glioblastoma patients once they are validated on a larger sample size.

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells.

Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro.

BACKGROUND: Tumour resistance to a wide range of drugs (multiple drug resistant, MDR) acquired after intensive chemotherapy is considered to be the main obstacle of the curative treatment of cancer patients. Recent work has shown that oncolytic viruses demonstrated prominent potential for effective treatment of diverse cancers. Here, we evaluated whether genetically modified vaccinia virus (LIVP-GFP) may be effective in treatment of cancers displaying MDR phenotype. METHODS: LIVP-GFP replication, transgene expression and cytopathic effects were analysed in human cervical carcinomas KB-3-1 (MDR-), KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), murine lymphosarcomas RLS and RLS-40 (MDR+). To investigate the efficacy of this therapy in vivo, we treated immunocompetent mice bearing murine lymphosarcoma RLS-40 (MDR+) (6- to 8-week-old female CBA mice; n = 10/group) or melanoma B-16 (MDR-) (6- to 8-week-old female C57Bl mice; n = 6/group) with LIVP-GFP (5 × 10(7) PFU of virus in 0.1 mL of IMDM immediately and 4 days after tumour implantation). RESULTS: We demonstrated that LIVP-GFP replication was effective in human cervical carcinomas KB-3-1 (MDR-) and KB-8-5 (MDR+) and in murine melanoma B-16 (MDR-), whereas active viral production was not detected in murine lymphosarcomas RLS and RLS-40 (MDR+). Additionally, it was found that in tumour models in immunocompetent mice under the optimized regimen intratumoural injections of LIVP-GFP significantly inhibited melanoma B16 (33 % of mice were with complete response after 90 days) and RLS-40 tumour growth (fourfold increase in tumour doubling time) as well as metastasis. CONCLUSION: The anti-tumour activity of LIVP-GFP is a result of direct oncolysis of tumour cells in case of melanoma B-16 because the virus effectively replicates and destroys these cells, and virus-mediated activation of the host immune system followed by immunologically mediated destruction of of tumour cells in case of lymphosarcoma RLS-40. Thus, the recombinant vaccinia virus LIVP-GFP is able to inhibit the growth of malignant cells with the MDR phenotype and tumour metastasis when administered in the early stages of tumour development.

A Northern contaminant mixture impairs pancreas function in obese and lean JCR rats and inhibits insulin secretion in MIN6 cells.

Rates of obesity and diabetes mellitus of Arctic populations are increasing due to multiple reasons including a departure from traditional lifestyles and alcohol consumption patterns. These populations are also exposed to a variety of anthropogenic contaminants through consumption of contaminated country foods. We have previously shown that a Northern contaminant mixture (NCM), containing 22 organic and inorganic contaminants found in the blood of Canadian Arctic populations, induces endothelial cell dysfunction and exacerbates development of non-alcoholic fatty liver disease in experimental models. In order to determine if these contaminants affect pancreas function and physiology and if obesity and alcohol can influence contaminant toxicity and the development of diabetes, lean and obese JCR rats were orally treated with NCM at 0 (vehicle), 1.6 or 16mg/kg BW for four weeks in the presence or absence of 10% (v/v) alcohol. NCM treatment altered islet morphology, increased iron deposit in pancreas, and reduced circulating and pancreatic insulin levels and circulating glucagon levels as a result of direct islet injury with ß and α cell loss with or without exposure to alcohol. Studies conducted with cultured mouse insulin-secreting (MIN6) ß cells further demonstrated that NCM inhibited insulin release and induced cell death through oxidative stress and mitochondrial dysfunction. 2,3,4,6-Tetrabromophenol, a minor component of the NCM, alone also inhibited insulin release from MIN6 cells after 10min of exposure. These results suggest that Northern contaminants may contribute to pancreatic dysfunction, and possibly development of diabetes, in some of the highly exposed Arctic populations. The implications and relevance of these findings to Northern populations remains to be confirmed through epidemiological studies.