Oxidation Of Adenosine And Inosine: The Chemistry Of 8-oxo-7,8-dihydropurines, Purine Iminoquinones, And Purine Quinones As Observed By Ultrafast Spectroscopy

Oxidative damage to purine nucleic acid bases proceeds through quinoidal intermediates derived from their corresponding 8-oxo-7,8-dihydropurine bases. Oxidation studies of 8-oxo-7,8-dihyroadenosine and 8-oxo-7,8-dihydroinosine indicate that these quinoidal species can produce stable cross links with a wide variety of nucleophiles in the 2-positions of the purines. An azide precursor for the adenosine iminoquinone has been synthesized and applied in ultrafast transient absorption spectroscopic studies. Thus, the adenosine iminoquinone can be observed directly, and its susceptibility to nudeophilic attack with various nucleophiles as well as the stability of the resulting cross linked species have been evaluated Finally, these observations indicate that this azide might be a very useful photoaffurity labeling agent, because the reactive intermediate, adenosine iminoquinone, is such a good mimic for the universal purine base adenosine

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Graphene Oxide Chemistry Management via the Use of KMnO4/K2Cr2O7 Oxidizing Agents

In this paper, we propose a facile approach to the management of graphene oxide (GO) chemistry via its synthesis using KMnO4/K2Cr2O7 oxidizing agents at different ratios. Using Fourier Transformed Infrared Spectroscopy, X-ray Photoelectron Spectroscopy, and X-ray Absorption Spectroscopy, we show that the number of basal-plane and edge-located oxygenic groups can be controllably tuned by altering the KMnO4/K2Cr2O7 ratio. The linear two-fold reduction in the number of the hydroxyls and epoxides with the simultaneous three-fold rise in the content of carbonyls and carboxyls is indicated upon the transition from KMnO4 to K2Cr2O7 as a predominant oxidizing agent. The effect of the oxidation mixture’s composition on the structure of the synthesized GOs is also comprehensively studied by means of X-ray diffraction, Raman spectroscopy, transmission electron microscopy, atomic-force microscopy, optical microscopy, and the laser diffraction method. The nanoscale corrugation of the GO platelets with the increase of the K2Cr2O7 content is signified, whereas the 10–100 μm lateral size, lamellar, and defect-free structure is demonstrated for all of the synthesized GOs regardless of the KMnO4/K2Cr2O7 ratio. The proposed method for the synthesis of GO with the desired chemistry opens up new horizons for the development of graphene-based materials with tunable functional properties

Revaccination in Age-Risk Groups with Sputnik V Is Immunologically Effective and Depends on the Initial Neutralizing SARS-CoV-2 IgG Antibodies Level

Vaccination against COVID-19 has occurred in Russia for more than two years. According to the Russian official clinical guidelines to maintain tense immunity in the conditions of the ongoing COVID-19 pandemic, it is necessary to use booster immunization six months after primary vaccination or a previous COVID-19 contraction. It is especially important to ensure the maintenance of protective immunity in the elderly, who are at risk of severe courses of COVID-19. Meanwhile, the immunological effectiveness of the booster doses has not been sufficiently substantiated. To investigate the immunogenicity of Sputnik V within the recommended revaccination regimen and evaluate the effectiveness of booster doses, we conducted this study on 3983 samples obtained from individuals previously vaccinated with Sputnik V in Moscow. We analyzed the level of antibodies in BAU/mL three times: (i) six months after primary immunization immediately before the booster (RV), (ii) 3 weeks after the introduction of the first component of the booster (RV1), and (iii) 3 weeks after the introduction of the second component of the booster (RV2). Six months after the primary vaccination with Sputnik V, 95.5% of patients maintained a positive level of IgG antibodies to the receptor-binding domain (RBD) of SARS-CoV-2. The degree of increase in the specific virus-neutralizing antibodies level after revaccination increased with a decrease in their initial level just before the booster dose application. In the group of people with the level of antibodies up to 100 BAU/mL six months after the vaccination, a more than eightfold increase (p p p p < 0.05), regardless of the previous COVID-19 infection. Thus, revaccination is most effective in individuals with an antibody level below 500 BAU/mL, regardless of the vaccinee age and COVID-19 contraction. For the first time, it has been shown that a single booster dose of the Sputnik vaccine is sufficient to form a protective immunity in most vaccinees regardless of age and preexisting antibody level

DataSheet_1_Estimation of anti-orthopoxvirus immunity in Moscow residents and potential risks of spreading Monkeypox virus.docx

WHO has declared the outbreak of monkeypox as a public health emergency of international concern. In less than three months, monkeypox was detected in more than 30 000 people and spread to more than 80 countries around the world. It is believed that the immunity formed to smallpox vaccine can protect from monkeypox infection with high efficiency. The widespread use of Vaccinia virus has not been carried out since the 1980s, which raises the question of the level of residual immunity among the population and the identification of groups requiring priority vaccination. We conducted a cross-sectional serological study of remaining immunity among Moscow residents. To do this, a collection of blood serum samples of age group over 30 years old was formed, an in-house ELISA test system was developed, and a virus neutralization protocol was set up. Serum samples were examined for the presence of IgG antibodies against Vaccinia virus (n=2908), as well as for the ability to neutralize plaque formation with a Vaccinia virus MNIIVP-10 strain (n=299). The results indicate the presence of neutralizing antibody titer of 1/20 or more in 33.3 to 53.2% of people older than 45 years. Among people 30-45 years old who probably have not been vaccinated, the proportion with virus neutralizing antibodies ranged from 3.2 to 6.7%. Despite the higher level of antibodies in age group older than 66 years, the proportion of positive samples in this group was slightly lower than in people aged 46-65 years. The results indicate the priority of vaccination in groups younger than 45, and possibly older than 66 years to ensure the protection of the population in case of spread of monkeypox among Moscow residents. The herd immunity level needed to stop the circulation of the virus should be at least 50.25 – 65.28%.</p