NF-κB-dependent mechanism of action of c-Myc inhibitor 10058-F4: Highlighting a promising effect of c-Myc inhibition in Leukemia cells, irrespective of p53 status

Due to the frequent contribution in the pathogenesis of different human malignancies, c-Myc is among those transcription factors that are believed to be pharmacologically targeted for cancer therapeutic approaches. In the present study, we examined the anti-leukemic effect of a well-known c-Myc inhibitor 10058-F4 on a panel of hematologic malignant cells harboring either mutant or wild-type p53. Notably, we found that the suppression of c-Myc was coupled with the reduction in the survival of all the tested leukemic cells; however, as far as we are aware, this study suggests for the first time that the cytotoxic effect of 10058-F4 was not significantly affected by the molecular status of p53. Delving into the molecular mechanisms of the inhibitor in the most sensitive cell line revealed that 10058-F4 could induce apoptotic cell death in mutant p53-expressing NB4 cells through the suppression of NF-κB pathway coupled with a significant induction of intracellular reactive oxygen species (ROS). In addition, we found that the anti-leukemic effect of 10058-F4 was overshadowed, at least partially, through the compensatory activation of the PI3K signaling pathway; highlighting a plausible attenuating role of this axis on 10058-F4 cytotoxicity. In conclusion, the results of the present study shed light on the favorable anti-leukemic effect of 10058-F4, especially in combination with PI3K inhibitors in acute promyelocytic leukemia; however, further investigations should be accomplished to determine the efficacy of the inhibitor, either as a single agent or in a combined-modal strategy, in leukemia treatment. © 2020, Iranian Journal of Pharmaceutical Research. All rights reserved

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020–June 19, 2020) and late 2020 (June 20, 2020–December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p <.001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46–0.98, p =.016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p <.001 and 50/571 [8.8%] vs. 213/402 [52.2%], p <.001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p <.001 and 73/571 [12.8%] vs. 5/402 [1.2%], p <.001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study

COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: A comparative analysis from a multicenter study

Lung transplant recipients (LTR) with coronavirus disease 2019 (COVID-19) may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with COVID-19 to compare mortality by 28 days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with COVID-19, 1,081 (66%) were hospitalized including 120/159 (75%) LTR and 961/1457 (66%) non-lung SOTR (p =.02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p =.032), and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0–2.6, p =.04). Among LTR, chronic lung allograft dysfunction (aOR 3.3, 95% CI 1.0–11.3, p =.05) was the only independent risk factor for mortality and age >65 years, heart failure and obesity were not independently associated with death. Among SOTR hospitalized for COVID-19, LTR had higher mortality than non-lung SOTR. In LTR, chronic allograft dysfunction was independently associated with mortality

Cohort Profile: Burden of Obstructive Lung Disease (BOLD) study

The Burden of Obstructive Lung Disease (BOLD) study was established to assess the prevalence of chronic airflow obstruction, a key characteristic of chronic obstructive pulmonary disease, and its risk factors in adults (≥40 years) from general populations across the world. The baseline study was conducted between 2003 and 2016, in 41 sites across Africa, Asia, Europe, North America, the Caribbean and Oceania, and collected high-quality pre- and post-bronchodilator spirometry from 28 828 participants. The follow-up study was conducted between 2019 and 2021, in 18 sites across Africa, Asia, Europe and the Caribbean. At baseline, there were in these sites 12 502 participants with high-quality spirometry. A total of 6452 were followed up, with 5936 completing the study core questionnaire. Of these, 4044 also provided high-quality pre- and post-bronchodilator spirometry. On both occasions, the core questionnaire covered information on respiratory symptoms, doctor diagnoses, health care use, medication use and ealth status, as well as potential risk factors. Information on occupation, environmental exposures and diet was also collected

Low grade cerebral tumors : development of in vitro and in vivo models for designing innovative therapeutic approaches

Les gliomes diffus de bas grades sont des tumeurs qui affectent des régions fonctionnelles du cerveau chez des jeunes patients. Malgré leur faible taux de prolifération ces tumeurs peuvent dégénérer en des tumeurs plus agressives après leurs exérèses. Le gène IDH1 est très fréquemment muté dans les DLGG. Cette mutation confère à l’enzyme isocitratedeshydrogénase (IDH1) la propriété de produire du 2-OH-glutarate (2-HG) au lieu de l’α-cétoglutarate (α-KG). L’oncométabolite 2HG rentre alors en compétition avec l’α-KG pour les enzymes de déméthylation conduisant à une hyperméthylation de l’ADN et de l’histone H3 concourant à un blocage de la différenciation cellulaire. Mon projet de thèse consiste à la caractérisation des cellules tumorales et la compréhension des voies de signalisation impliquées dans la progression tumorale ainsi que l’identité du microenvironnement tumoral. Les récepteurs tyrosine kinase, PDGFRα et EGFR, sont abondamment exprimés par les cellules tumorales mais ne sont pas activés. En revanche, une forte phosphorylation de la protéine Erk p42/44 a été détectée dans les tumeurs. Cette phosphorylation a une double origine : les cellules tumorales et leur environnement. L’utilisation d’une série de marqueurs m’a permis de mieux définir l’état de différenciation des cellules tumorales et de mettre en évidence une préférence pour l’expression de Sox8 dans les oligodendrogliomes tandis que Sox9 est prédominant dans les astrocytomes. Dans une seconde partie, j’ai mis au point des méthodes pour la culture des gliomes diffus de bas grade et isolé cinq lignées de gliomes portant la mutation récurente IDH1 R132H. Récemment, la société Agios a identifié des inhibiteurs très spécifiques (notamment l’AGI-5198) de l’enzyme mutée IDH1 qui, utilisés dans un modèle de gliome murin, provoquent une déméthylation des histones H3K9me3 associées à une augmentation de l’expression de gènes de différenciation ainsi qu’à une réduction de la masse tumorale. A contrario, j’ai montré que l’AGI-5198 augmente la croissance cellulaire sur les lignée de patients, modifie la migration cellulaire ainsi que différentes voies de signalisation.Ces travaux apportent un nouvel éclairage sur le phénotype des cellules tumorales, leur diversité et les mécanismes moléculaires régissant leur prolifération.Low grade gliomas are low proliferating tumors affecting functional regions of young patients. In most cases, they tend to transform into a more malignant state following surgery. These tumors carry a key mutation in isocitrate dehydrogenase (70-80% of DLGG). Gliomas with IDH1 mutation have improved prognosis compared togliomaswith wild type IDH1. IDH1 protein acquires the ability to convert α-Ketoglutarate (α-KG) to 2-OH-glutarate (2-HG). The new onco-metabolite can interfere with the normal function of α-KG, leading to a general hypermethylation of the genome, thus inducing a blockage of the cellular differentiation. Very good reviews on the molecular mechanisms underlying high grade glioma invasion already exist but little is known about the cellular and molecular mechanisms in diffuse low grade gliomas. To that end, I characterized the profile of IDH1 mutated cells in the different types of DLGG. I have demonstrated that the tyrosine kinase, PDGFRα and EGFR receptors are abundantly expressed by tumor cells eventhough they are not activated. In contrast, a strong phosphorylation of Erk p42 / 44 proteins was detected in these tumors. This phosphorylation has a dual origin: tumor cells and their environment. The use of a series of markers allowed me to better define the state of differentiation of cancerous cells and to demonstrate a preferential expression of Sox8 in oligodendrogliomas while Sox9 is predominant in astrocytomas. In a second time, I have developed a method for the culture of low-grade diffuse gliomas and isolated five cell lines carrying the recurrent mutation IDH1 R132H. Recently Agios has identified very specific inhibitors (particularly AGI-5198) of the mutated IDH1 enzyme which, used in a murine glioma model, contributed to the demethylation of H3K9me3 histones with an increased expression of differentiation related genes as well as a reduction of the tumor mass. On the contrary, I have shown that AGI-5198 increases cell growth of patient cell lines, modifies the cellular migration and various signaling pathways.These studies shed new light on the phenotype of tumor cells, their diversity and The molecular mechanisms governing their proliferation

Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: A novel therapeutic potential for aprepitant

Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies. Copyright © 2018 Wolters Kluwer Health, Inc

Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: A novel therapeutic potential for aprepitant

Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies. Copyright © 2018 Wolters Kluwer Health, Inc

Suppression of c-Myc using 10058-F4 exerts caspase-3-dependent apoptosis and intensifies the antileukemic effect of vincristine in pre-B acute lymphoblastic leukemia cells

Despite an old history behind the identification of the leading role of c-Myc in leukemogenesis, the road to constructing a therapeutic perspective for this molecule in acute lymphoblastic leukemia (ALL) is yet mesmerizing. This study was designed to provide a better outlook for the anticancer property of 10058-F4, an appealing inhibitor of c-Myc, in pre-B ALL cell lines either in the context of monotherapy or in combination with chemotherapeutic drugs. Our results declared that abrogation of c-Myc decreased the proliferative capacity of pre-B ALL-derived cells through halting the transition of the cells from G1 phase, and reducing the replicative potential of both REH and Nalm-6 cells, at least partly, through c-Myc-mediated suppression of human telomerase reverse transcriptase. Moreover, 10058-F4 potently induced a caspase-3-dependent apoptosis in pre-B ALL cells via shifting the balance between pro- and anti-apoptotic target genes. Although the inhibition of PI3Kδ using Idelalisib upregulated the messenger RNA expression of autophagy-related genes in 10058-F4-treated cells, treatment with autophagy inhibitor chloroquine decreased viability of the cells, either as a single agent or in combination with Idelalisib and/or 10058-F4; suggesting that the activation of autophagy in pre-B ALL cells could blunt apoptotic events and attenuate anticancer effect of both c-Myc and PI3K inhibitors. Finally, the results of our synergistic experiments delineated that 10058-F4 produced a synergistic effect with vincristine and provided an enhanced therapeutic efficacy in ALL cells, highlighting that c-Myc oncoprotein could be a bona fide target for the treatment of ALL. © 2019 Wiley Periodicals, Inc

Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation

International audienceTertiary lymphoid structures (TLS) are lymphoid organs present in inflammatory non-lymphoid tissues. Studies have linked TLS to favorable outcomes for patients with cancers or infectious diseases, but the mechanisms underlying their formation are not fully understood. In particular, secondary lymphoid organs innervation raises the question of sympathetic nerve fibers involvement in TLS organogenesis. We established a model of pulmonary inflammation based on 5 daily intranasal instillations of lipopolysaccharide (LPS) in immunocompetent mice. In this setting, lung lymphoid aggregates formed transiently, evolving toward mature TLS and disappearing when inflammation resolved. Sympathetic nerve fibers were then depleted using 6-hydroxydopamine. TLS quantification by immunohistochemistry showed a decrease in LPS-induced TLS number and surface in denervated mouse lungs. Although a reduction in alveolar space was observed, it did not impair overall pulmonary content of transcripts encoding TNF-α, IL-1β and IFN-γ inflammation molecules whose expression was induced by LPS instillations. Immunofluorescence analysis of immune infiltrates in lungs of LPS-treated mice showed a drop in the proportion of CD23+ naive cells among CD19+ B220+ B cells in denervated mice whereas the proportion of other cell subsets remained unchanged. These data support the existence of neuroimmune crosstalk impacting lung TLS neogenesis and local naive B cell pool

A Machine Learning and Blockchain Based Efficient Fraud Detection Mechanism

In this paper, we address the problems of fraud and anomalies in the Bitcoin network. These are common problems in e-banking and online transactions. However, as the financial sector evolves, so do the methods for fraud and anomalies. Moreover, blockchain technology is being introduced as the most secure method integrated into finance. However, along with these advanced technologies, many frauds are also increasing every year. Therefore, we propose a secure fraud detection model based on machine learning and blockchain. There are two machine learning algorithms—XGboost and random forest (RF)—used for transaction classification. The machine learning techniques train the dataset based on the fraudulent and integrated transaction patterns and predict the new incoming transactions. The blockchain technology is integrated with machine learning algorithms to detect fraudulent transactions in the Bitcoin network. In the proposed model, XGboost and random forest (RF) algorithms are used to classify transactions and predict transaction patterns. We also calculate the precision and AUC of the models to measure the accuracy. A security analysis of the proposed smart contract is also performed to show the robustness of our system. In addition, an attacker model is also proposed to protect the proposed system from attacks and vulnerabilities