Irinotecan dosing and pharmacogenomics: a comprehensive exploration based on UGT1A1 variants and emerging insights.

Irinotecan is a critical anticancer drug used to treat metastatic colorectal cancer and advanced pancreatic ductal adenocarcinoma by obstructing topoisomerase 1; however, it can cause minor-to-severe and life-threatening adverse effects. UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms increase the risk of irinotecan-induced neutropenia and diarrhea. Hence, screening for UGT1A1 polymorphisms before irinotecan-based chemotherapy is recommended to minimize toxicity, whereas liposomes offer the potential to deliver irinotecan with fewer side effects in patients with pancreatic ductal adenocarcinoma. This review presents a comprehensive overview of the effects of genotype-guided dosing of irinotecan on UGT1A1*28 and UGT1A1*6 variants, incorporating pharmacogenomic research, optimal regimens for metastatic colorectal and pancreatic cancer treatment using irinotecan, guidelines for toxicity reduction, and an evaluation of the cost-effectiveness of UGT1A1 genotype testing.

Orchestration of Genetic Alterations in PSEN1 and PSEN2 Genes in Development of Alzheimer's Disease through Computational Analysis.

Dementia is a syndrome that can cause a number of progressive illnesses that affect memory, thinking, and ability to perform everyday tasks. Alzheimer's disease (AD) is the most common cause of dementia and represents a major public health problem. AD is a progressive disease, where in early stages there is mild memory loss and in late-stage patient loses the ability to carry on a conversation. AD (for which there is no exact cause and cure known so far) is the sixth leading cause of deaths in the United States. Every 68 second someone develops AD. This study focuses on protein structure modeling of genes presenilin 1 and 2 ( PSEN1 and PSEN2 ) and their mutated forms (Asn141Tyr found in Chinese family, Gly34Ser identified in a Japanese patient, and Arg62Cys & Val214Leu identified in the Korean patients). It also involves wild and mutant type comparison, protein interaction studies, docking and phylogenetic history based on representative ortholog species and also sheds insight into the comparative evolutionary rates of coding sequence across various orthologs. This study gives a time and cost-effective analysis of genes ( PSEN1 and PSEN2 ) underlying AD and genetic alterations that drive development and causes of disease.

Undetermined and accidental mortality rates as possible sources of underreported suicides: population-based study comparing Islamic countries and traditionally religious Western countries.

BACKGROUND: Four Western countries (Greece, Ireland, Italy and Portugal) with strong Orthodox and Catholic traditions have been associated with the underreporting of death by suicide, and underreported suicides are sometimes found among deaths recorded as 'undetermined' or 'accidental'. AIMS: This population-based study tests whether there are any significant difference in patterns of suicides, undetermined deaths and accidental deaths between these four Western countries and 21 predominately Islamic countries. METHOD: World Health Organization age-standardised death rates per million population were used to compare suicide rates with combined undetermined death and accidental death (UnD+AccD) rates, from which odds ratios were calculated. Substantial odds ratios (OR > 2.0) were taken as indicative of likely underreporting of suicides. The Islamic countries come from four different historico-cultural regions, described as: less-traditional Islamic countries; former USSR countries; Gulf Arab states; and Middle Eastern and North African countries. χ2-tests were used to determine any significant differences between the Western comparator countries and the Islamic regions. RESULTS: For the Western comparator countries, the average suicide rate was 66 per million population, the average undetermined death rate 56 per million and the average accidental death rate 58 per million, yielding a suicide:UnD+AccD odds ratio (OR) of 1.73. The average values for the other three groups were as follows. Less-traditional Islamic countries: suicide rate, 31 per million; UnD+AccD rate, 101 per million; suicide:UnD+AccD OR = 3.3. Former USSR countries: suicide rate, 61 per million; UnD+AccD rate, 221 per million; suicide:UnD+AccD OR = 3.6. Gulf Arab states: suicide rate, 10 per million; UnD+AccD rate, 76 per million; suicide:UnD+AccD OR = 8.6. Middle Eastern and North African countries: suicide rate, 6 per million; UnD+AccD rate, 151 per million; suicide:UnD+AccD OR = 25.2. The patterns of these mortalities in the Islamic countries was significantly different from Western comparator countries. CONCLUSIONS: The results indicate underreporting of suicides in Islamic countries. This might inadvertently lead to reduced access to mental health preventive services in both Western and Islamic countries.