The understanding of the pathogenesis of renal cell carcinoma led to the development of targeted therapies, which dramatically changed the overall survival rate. Nonetheless, despite innovative lines of therapy accessible to patients, the prognosis remains severe in most cases. Kidney cancer rarely shows mutations in the genes coding for proteins involved in programmed cell death, including p53. In this paper, we show that the molecular machinery responsible for different forms of cell death, such as apoptosis, ferroptosis, pyroptosis, and necroptosis, which are somehow impaired in kidney cancer to allow cancer cell growth and development, was reactivated by targeted pharmacological intervention. The aim of the present review was to summarize the modality of programmed cell death in the pathogenesis of renal cell carcinoma, showing in vitro and in vivo evidence of their potential role in controlling kidney cancer growth, and highlighting their possible therapeutic value.
Background: In doping control, the presence of the exon5 c.577del variant in the human erythropoietin gene may be a confounding factor in the interpretation of the results from the analytical method currently in force for the detection of human recombinant erythropoietin, based on immunoelectrophoresis on SDS-PAGE and/or SAR-PAGE. This variant, determining the transcription of a higher molecular weight protein, can erroneously suggest the presence of recombinant erythropoietin in a biological sample, causing the possibility of a false positive result. Although the variant was now identified only in East Asian populations and with a very low frequency, it can threaten the reliability of current anti-doping tests.Methods: We have implemented a genetic test to identify the presence of this variant in the biological samples that are presently collected for anti-doping analysis (whole blood, urine, and dried blood spots). The test is based on the Sanger sequencing of the human erythropoietin gene exon 5, where the c.577del variant falls.Results and Discussion: The method has a specificity of 100% and allows identification of the possible presence of the variant starting from 100 pg of genomic DNA extracted from each biological sample. The efficacy of the test has been confirmed by the analysis of real samples from subjects showing and not showing the exon c.577del variant.
Hematopoietic stem cells (HSC) are multipotent progenitor cells, resident primarily in human bone marrow. Their main function is the continuous renewal of all hematopoietic cells. A small fraction of HSC is also circulating in peripheral blood (cHSC) where they can be possibly detected thanks to the application of the new very sensitive flow cytometry methodologies. In recent times it has been debated whether the utilization of several different types of stem cells can be abused by athletes for doping purposes. Moreover, there is growing knowledge that the dynamic and turnover of circulating HSC may reflect changes affecting the physiologic processes at the erythropoietic level; also, cHSC and other circulating hematopoietic progenitors (cHP) resulted to give different responses in athletes engaged in endurance and maximal exercise sports. If it is true that the use of stem cells (mainly mesenchymal stem cells) to allow a rapid recover from an injury is not considered a doping practice, it is also true that the 2022 WADA list of prohibited substances and methods forbids “the use of normal or genetically modified cells” as well as “any form of intravascular manipulation of the blood or blood components by physical or chemical means”. In this context, HSC and hematopoietic erythroid progenitors may be a potential threat and the possibility of their abuse needs to be exploited in sport antidoping. In view of the above, we have preliminarily assessed the possibility of detecting circulating hematopoietic stem cells by flow cytofluorimetry. In details, we applied two flow cytofluorimetric protocols for the accurate and precise counting of circulating HSC, also discussing the potential applicability in a potential antidoping scenario. We concluded that i) flow cytofluorimetry is a pratical and rapid platform for the identification and the counting of cHSC and other erythroid progenitors in peripheral human whole blood, ii) the correlation between CD34+ circulating progenitors and standard haematological parameters may be an effective new tool to be exploited as in direct markers of blood doping and, iii) accurate baseline levels of HSC and erythroid progenitors need to be determined in order to identify abuses of HSC and/or conventional blood doping.
The inter‐individual variability, due to genetic polymorphisms, can significantly affect the levels of specific target analytes that are measured in the antidoping field as diagnostic biomarkers of the recourse to prohibited substances and methods. This variability could affect the reliability of the test, increasing the risk of both “false‐negative” and “false‐positive”results. In this work we are assessing whether, and if so, to what extent, some selected human genetic polymorphisms can affect the results of both direct and indirect doping analyses, with particular reference to those markers for which threshold values are fixed, therefore imposing their quantitative determination. In the field of anti‐doping research, the presence of polymorphisms involves a series of questions regarding the genetic influence on the susceptibility to both screening and confirmation analyses of prohibited substances. We have pre‐selected Single Nucleotide Polymorphisms (SNP) and Copy Number Variation (CNV) of genes of particular interest in anti‐doping: DNA was extracted from both urinary and blood matrix. The results of the individual genotyping have been utilized in order to determine the correlation with the basal values of specific biomarkers. Specifically, we have considered the CNV polymorphism of UGT2B17 and the SNP of UGT2B15, both of relevance for the levels of endogenous anabolic androgenic steroids; and the SNP rs1520220, rs6873545 and rs7703713, of relevance for the detection of doping by human growth hormone and insulin growth factor 1. Our results show that genetic variability may impact on the reliability of anti‐doping tests especially in the case of biomarkers for which population‐based threshold are in force to discriminate a negative result and an adverse analytical finding.
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