5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

Background:Colorectal cancer(CRC)is one of the most frequently diagnosed cancers.In many cases,the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil(5-FU).The epithelial-to-mesenchymal transition(EMT)and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many cancers.This study looked into the effect of 5-FU dose escalation on EMT and protein methylation in CRC.Materials and Methods:HCT-116,Caco-2,and DLD-1 CRC cell lines were exposed to dose escalation treatment of 5-FU.The motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion assays.This was followed by aWestern blot which analyzed the protein expressions of the epithelial marker E-cadherin,mesenchymal marker vimentin,and the EMT transcription factor(EMTTF),the snail family transcriptional repressor 1(Snail)in the parental and desensitized cells.Western blotting was also conducted to study the protein expressions of the protein methyltransferases(PMTs),Euchromatic histone lysine methyltransferase 2(EHMT2/G9A),protein arginine methyltransferase(PRMT5),and SET domain containing 7/9(SETD7/9)along with the global lysine and arginine methylation profiles.Results:The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of 5-FU.The 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental cells.This was reflected in the observed reduction in E-cadherin,vimentin,and Snail in the desensitized cell lines.Additionally,the protein expressions of EHMT2/G9A,PRMT5,and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU treatment.Conclusion:This study showed that continuous,dose-escalation treatment of 5-FU in CRC cells generated 5-FU desensitized cancer cells that seemed to be less aggressive than parental cells.

Palliative care with adequate pain relief challenges the need for euthanasia legislation

Background:In today’s society the ongoing discussion about euthanasia triggers emotionally charged debates surrounding the delicate balance between valuing life and respecting an individual’s autonomy.With the persistence of this debate,there has been the emergence of the concept of the so-called alternative:palliative care.Positioned as a substitute for euthanasia,palliative care aims to alleviate suffering in terminally ill patients without engaging in the ethical dilemmas associated with euthanasia.Methods:This paper explores the facets of palliative care highlighting its core objectives such as providing adequate pain relief as a compassionate alternative to euthanasia.Results:By examining palliative care as a comprehensive approach to end of life support,this study challenges the perceived necessity of euthanasia and advocates,for compassionate and dignified end of life experiences.Conclusion:In conclusion,palliative care emerges as a viable and ethically sound alternative to euthanasia,emphasizing the importance of compassionate end-of-life care and pain management.

Exploring euthanasia in Malta: an intersectional analysis of medical, legal, and ethical perspectives

This paper provides a comprehensive examination of euthanasia from various perspectives,including medical,legal,religious,philosophical,and moral.The study also explores the public perceptions and trends in Malta.The medical perspective analyses the benefits and risks of euthanasia and its impact on the healthcare system.The legal perspective discusses the legality of euthanasia in Malta and the potential legal implications of legalizing the practice.The religious perspective explores the beliefs of various religious groups in Malta,particularly Catholicism,on euthanasia.The philosophical perspective discusses the ethical and moral considerations of euthanasia.The paper also analyses the results of surveys conducted in Malta,examining the public’s attitudes towards euthanasia.Overall,the study provides a thorough analysis of euthanasia from various angles,shedding light on the complex and controversial nature of the topic.

SCFD1 in amyotrophic lateral sclerosis:reconciling a genetic association with in vivo functional analysis

Amyotrophic lateral sclerosis(ALS)is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons,resulting in muscle weakness and spasticity,eventually leading to death due to respiratory failure.Analyses by our group of a casecontrol cohort from an isolated island population have found that genetics plays a significant role in disease etiology(Farrugia Wismayer et al.,2023).

Overview of microRNAs as liquid biopsy biomarkers for colorectal cancer sub-type profiling and chemoresistance

Colorectal cancer(CRC)is the third most common cancer worldwide.It has also been demonstrated that over the last ten years the incidence of CRC among younger people below the age of 50 is also increasing.Screening for colorectal cancer is of utmost importance;the rationale behind screening is to target the malignancy and reduce the incidence and mortality of the disease.Diagnostic methods to screen for incidence or relapse are therefore a requisite to detect cancer as early as possible.Scientific findings demonstrate that many deaths are due to lack of screening and therefore early identification will lead to greater survivability.In colorectal cancer,diagnostic tests include liquid biopsy biomarkers.Since the discovery of microRNAs(miRNAs),many studies have demonstrated the relationship between miRNAs and the various sub-types of CRC.Several miRNAs have been identified after analysing serum or plasma samples in patients,and such miRNAs were found to be significantly dysregulated.Such findings place the possibility of miRNAs to be at the epicentre of novel diagnostic techniques for CRC identification and sub-type stratification,including other characteristics associated with CRC development such as patient prognosis.The following review serves to underline the latest findings for miRNAs with such potential for routine diagnostic employment in CRC diagnostics and treatments.