Interação de derivados de benzenossulfonamida com Smyd3 usando um modelo teórico

Cancer is a serious public health problem worldwide. This clinical pathology is associated with the activation/release of several biomolecules, including the Smyd proteins family. In this way, some studies indicate that Smyd3 is associated with cancer cells growth. It is important to mention that some drugs act as Smyd3 inhibitors in the treat some cancers. However, their interaction is very confusing; for this reason, the aim of this research was to evaluate the theoretical interaction of benzenesulfonamide and their derivatives (compounds 2 to 28) using 7o2c protein, novobiocin, BAY-6035, EPZ031686 and BCI-121 drugs as theoretical tools in DockingServer program. The results showed differences in the aminoacid residues involved in the interaction of benzenesulfonamide and their derivatives with 7o2c protein surface compared with novobiocin, BAY-6035, EPZ031686 and BCI-121 drugs. In additions, the inhibition constant (Ki) for benzenesulfonamide derivatives 2, 7, 8, 13, 14, 17, 20, 21, 24 and 28 was very lower compared to benzenesulfonamide, novobiocin, BAY-6035, EPZ031686 and BCI-121. In conclusion, the benzenesulfonamide derivatives 2, 7, 8, 13, 14, 17, 20, 21, 24 and 28 could be a good alternative as Smyd3 inhibitors to decrease cancer cells growth.El cáncer es un grave problema de salud pública a nivel mundial. Esta patología clínica está asociada a la activación/liberación de varias biomoléculas, entre ellas las proteínas de la familia Smyd. De esta forma, algunos estudios indican que Smyd3 está asociado con el crecimiento de células cancerosas. Es importante mencionar que algunos medicamentos actúan como inhibidores de Smyd3 en el tratamiento de algunos tipos de cáncer. Sin embargo, su interacción es muy confusa; por tal motivo, el objetivo de esta investigación fue evaluar la interacción teórica de la bencenosulfonamida y sus derivados (compuestos 2 al 28) utilizando como herramientas teóricas en el programa DockingServer la proteína 7o2c, novobiocina, BAY-6035, EPZ031686 y BCI-121. . Los resultados mostraron diferencias en los residuos de aminoácidos involucrados en la interacción de la bencenosulfonamida y sus derivados con la superficie de la proteína 7o2c en comparación con los fármacos novobiocina, BAY-6035, EPZ031686 y BCI-121. Además, la constante de inhibición (Ki) para los derivados de bencenosulfonamida 2, 7, 8, 13, 14, 17, 20, 21, 24 y 28 fue mucho menor en comparación con bencenosulfonamida, novobiocina, BAY-6035, EPZ031686 y BCI-121. En conclusión, los derivados de bencenosulfonamida 2, 7, 8, 13, 14, 17, 20, 21, 24 y 28 pueden ser una buena alternativa como inhibidores de Smyd3 para disminuir el crecimiento de células cancerosas.O câncer é um grave problema de saúde pública em todo o mundo. Esta patologia clínica está associada à ativação/liberação de várias biomoléculas, incluindo as proteínas da família Smyd. Desta forma, alguns estudos indicam que o Smyd3 está associado ao crescimento de células cancerígenas. É importante mencionar que algumas drogas atuam como inibidores de Smyd3 no tratamento de alguns tipos de câncer. No entanto, sua interação é muito confusa; por esta razão, o objetivo desta pesquisa foi avaliar a interação teórica de benzenossulfonamida e seus derivados (compostos 2 a 28) usando a proteína 7o2c, novobiocina, BAY-6035, EPZ031686 e drogas BCI-121 como ferramentas teóricas no programa DockingServer. Os resultados mostraram diferenças nos resíduos de aminoácidos envolvidos na interação da benzenossulfonamida e seus derivados com a superfície da proteína 7o2c em comparação com as drogas novobiocina, BAY-6035, EPZ031686 e BCI-121. Além disso, a constante de inibição (Ki) para os derivados de benzenossulfonamida 2, 7, 8, 13, 14, 17, 20, 21, 24 e 28 foi muito menor em comparação com benzenossulfonamida, novobiocina, BAY-6035, EPZ031686 e BCI-121. Em conclusão, os derivados de benzenossulfonamida 2, 7, 8, 13, 14, 17, 20, 21, 24 e 28 podem ser uma boa alternativa como inibidores de Smyd3 para diminuir o crescimento de células cancerígenas

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Ghrelin

This work was supported by grants from the NIH (DP2DK105570-01 and 2P30DK046200 to MLA, DK21397 to HJG, K01DK098319 to KMH, K01MH091222 to LH, DK093848 to RJS, R01DK082590 to LS, R01DK097550 to JT, RO1 DK 076037 to MOT, R01DA024680 and R01MH085298 to JMZ, R01AG019230 and R01AG029740 to RGS) The Wellcome Trust (MK), Science Foundation Ireland (12/YI/B2480 to CWL), the Alexander von Humboldt Foundation (MHT), the Deutsches Zentrum für Diabetesforschung (MHT), the Helmholtz Alliance ICEMED e Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association (MHT), and the Helmholtz cross-program topic “Metabolic Dysfunction” (MHT). Allan Geliebter was sponsored by NIH grants R01DK80153; R01DK074046; R03DK068603; P30DK26687

The Cherenkov Telescope Array: layout, design and performance

The Cherenkov Telescope Array (CTA) will be the next generation very-high-energy gamma-ray observatory. CTA is expected to provide substantial improvement in accuracy and sensitivity with respect to existing instruments thanks to a tenfold increase in the number of telescopes and their state-of-the-art design. Detailed Monte Carlo simulations are used to further optimise the number of telescopes and the array layout, and to estimate the observatory performance using updated models of the selected telescope designs. These studies are presented in this contribution for the two CTA stations located on the island of La Palma (Spain) and near Paranal (Chile) and for different operation and observation conditions

Performance of the Cherenkov Telescope Array in the presence of clouds

The Cherenkov Telescope Array (CTA) is the future ground-based observatory for gamma-ray astronomy at very high energies. The atmosphere is an integral part of every Cherenkov telescope. Different atmospheric conditions, such as clouds, can reduce the fraction of Cherenkov photons produced in air showers that reach ground-based telescopes, which may affect the performance. Decreased sensitivity of the telescopes may lead to misconstructed energies and spectra. This study presents the impact of various atmospheric conditions on CTA performance. The atmospheric transmission in a cloudy atmosphere in the wavelength range from 203 nm to 1000 nm was simulated for different cloud bases and different optical depths using the MODerate resolution atmospheric TRANsmission (MODTRAN) code. MODTRAN output files were used as inputs for generic Monte Carlo simulations. The analysis was performed using the MAGIC Analysis and Reconstruction Software (MARS) adapted for CTA. As expected, the effects of clouds are most evident at low energies, near the energy threshold. Even in the presence of dense clouds, high-energy gamma rays may still trigger the telescopes if the first interaction occurs lower in the atmosphere, below the cloud base. A method to analyze very high-energy data obtained in the presence of clouds is presented. The systematic uncertainties of the method are evaluated. These studies help to gain more precise knowledge about the CTA response to cloudy conditions and give insights on how to proceed with data obtained in such conditions. This may prove crucial for alert-based observations and time-critical studies of transient phenomena

Sensitivity of the Cherenkov Telescope Array to emission from the gamma-ray counterparts of neutrino events

We investigate the possibility of detection of the VHE gamma-ray counterparts to the neutrino astrophysical sources within the Neutrino Target of Opportunity (NToO) program of CTA using the populations simulated by the FIRESONG software to resemble the diffuse astrophysical neutrino flux measured by IceCube. We derive the detection probability for different zenith angles and geomagnetic field configurations. The difference in detectability of sources between CTA-North and CTA-South for the average geomagnetic field is not substantial. We investigate the effect of a higher night-sky background and the preliminary CTA Alpha layout on the detection probability

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

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century