Corrigendum to“Nitrosamines crisis in pharmaceuticals-Insights on toxicological implications,root causes and risk assessment:A systematic review”[J.Pharm.Anal.14(2024)100919]

Original statement in the Section 2:2.Literature search Our primary screening of 180 articles yielded the relevant data for this study.2.1.Study selection A total of 180 articles spanning from 1960 to the present day,including original research,reviews,case reports and studies reporting nitrosamine impurities above the no-observed-adverse-effect levels(NOAEL)established by regulatory agencies,were initially screened.During the primary screening,we considered factors such as relevance,publication date,access to the full article text,and content.

Nitrosamines crisis in pharmaceuticals-Insights on toxicological implications,root causes and risk assessment:A systematic review

The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for nitrosamines.This review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological effects.Additionally,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk evaluation.This comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

Emerging targets for glioblastoma stem cell therapy

Glioblastoma multiforme（GBM）,designated as World Health Organization（WHO）grade IV astrocytoma,is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations,including GBM stem cells（GSCs）which are believed to contribute to tumor recurrence following initial response to therapies.Emerging evidence demonstrates that GBM tumors are initiated from GSCs.The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate sternness,proliferation and migration of GSCs,immunotherapy,and non-coding microRNAs may provide better means of treating GBM.Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs.Several signaling pathways including mTOR,AKT,maternal embryonic leucine zipper kinase（MELK）,NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133,CD44,Oct4,Sox2,Nanog,and ALDHlA1 maintain GSC properties.Moreover,the data published in the Cancer Genome Atlas（TCGA）specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis.Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy.Furthemore,recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs,but the differentiated GBM cells and the entire bulk of tumor cells.

Glioblastoma stem cells(GSCs)epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs

Cancer stem cells(CSCs)or cancer initiating cells(CICs)maintain self-renewal and multilineage differentiation properties of various tumors,as well as the cellular heterogeneity consisting of several subpopulations within tumors.CSCs display the malignant phenotype,self-renewal ability,altered genomic stability,specific epigenetic signature,and most of the time can be phenotyped by cell surface markers(e.g.,CD133,CD24,and CD44).Numerous studies support the concept that non-stem cancer cells(non-CSCs)are sensitive to cancer therapy while CSCs are relatively resistant to treatment.In glioblastoma stem cells(GSCs),there is clonal heterogeneity at the genetic level with distinct tumorigenic potential,and defined GSC marker expression resulting from clonal evolution which is likely to influence disease progression and response to treatment.Another level of complexity in glioblastoma multiforme(GBM)tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs,and the potential for non-GSCs to revert(dedifferentiate)to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell population.Moreover,exposure of the differentiated GBM cells to therapeutic doses of temozolomide(TMZ)or ionizing radiation(IR)increases the GSC pool both in vitro and in vivo.This review describes various subtypes of GBM,discusses the evolution of CSC models and epigenetic plasticity,as well as interconversion between GSCs and differentiated non-GSCs,and offers strategies to potentially eliminate GSCs.