Contribution value of akt, c-myc, cip2a, and pp2a genes expression in leukemogenesis: A bright perspective on the molecular pattern of patients with acute myeloid leukemia (aml)

Background: The heterogeneous nature of acute myeloid leukemia (AML) and the hurdle to find a suitable treatment strategy for this malignancy put this type of leukemia at the top of the list of the priorities for finding a valuable biomarker to improve its treatment and predict the outcome of the patients. Objectives: Given the involvement of the variety of signaling pathways, foremost the PI3K axis in the pathogenesis of human can-cers, we aimed to investigate the expression of the most important downstream targets of this pathway to propose a plausible mechanism underlying AML pathogenesis. Methods: In this case-control study, the blood samples from 30 patients diagnosed with AML were collected and after extracting their RNAs, the expression levels of Akt, c-Myc, CIP2A, and PP2A were evaluated using qRT-PCR analysis. For the control group, we also collected blood samples from 10 healthy volunteers. Afterward, by applying statistical analysis, we determined the probable correlation between the expressions of the aforementioned genes. Results: There was a significant elevation in the expression levels of Akt, c-Myc, and CIP2A coupled with the meaningful reduction in the expression level of PP2A in AML samples. However, we failed to find any significant association between the expression level of the indicated genes and age, sex, and the percentage of the blasts. Conclusions: As the most straightforward interpretation of our results, we propose that probably the association between PI3K and c-Myc which is built through the interaction between CIP2A and PP2A may play a pivotal role in the pathogenies of AML and any component of this axis could serve as a potential new target for more profound treatment strategy. However, further detailed inves-tigations in this field are required to clarify the exact role of this interesting testis-specific pathway in the context of hematological malignancies, in particular AML. © 2020, Author(s)

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. Methods We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. Findings Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. Interpretation As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. Funding Bill & Melinda Gates Foundation

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Anti-Cancer Effect of Aprepitant on Nb4 Leukemic Cells

BACKGROUND AND OBJECTIVE: Genetic studies have demonstrated that the neurokini-1 Receptor (NK1R (is frequently involved in the pathogenesis of wide assortment of human malignancies, including acute promyelocytic leukemia (APL). The activity of this pathway in leukemic cells results in an excessive cell proliferation and evade from apoptosis. In this study, we aimed to investigate the effect of Aprepitant (NK1R antagonist) on the survival rate of APL cells. METHODS: This experimental study is conducted on APL-derived NB4 cells (Institute Pasteur). To determine the anti-tumor effect of Aprepitant, NB4 cells were divided into 6 groups: control and 1-, 2-, 3-, 4- and 5 µM-drug treated groups. Then the cell viability, metabolic activity, induction of apoptosis and transcriptional alteration of Bax and Bcl-2 genes were investigated after 24 and 36 h treatment using trypan blue assay, MTT assay, Annexin-V/PI staining and RQ-PCR analysis, respectively. FINDINGS: 36 h treatment with the highest concentration of Aprepitant (5 µM) resulted in an approximately 50% reduction in the viability (assessed by trypan blue) and metabolic activity (assessed by MTT assay) of NB4 cells (p<0.001) in comparison with control group. Moreover, Aprepitant is able to increase the proportion apoptotic cells from 1.4% in control group to 10.6% in 5 µM drug-treated cells though up-regulating Bax/Bcl-2 molecular ratio (p≤0.05). CONCLUSION: Aprepitant exerted both cytotoxic and anti-proliferative effects in NB4 cells

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