FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited FOXO3 variants with longevity was the result of partial protection against mortality risk posed by aging-related life-long stressors, particularly cardiometabolic disease. We then referred to the longevity-associated genotypes as conferring "mortality resilience.
View Article and Find Full Text PDFPediatr Dev Pathol
December 2022
Background: Workload measurement is important to help determine optimal staffing and workload distribution for pathology laboratories. The Level 4 Equivalent (L4E) System is the most widely used Anatomical Pathology (AP) workload measurement tool in Canada. However, it was initially not developed with subspecialties in mind.
View Article and Find Full Text PDFGlutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants.
View Article and Find Full Text PDFBackground: Obesity and its associated diseases are major health problems characterized by extensive metabolic disturbances. Understanding the causal connections between these phenotypes and variation in metabolite levels can uncover relevant biology and inform novel intervention strategies. Recent studies have combined metabolite profiling with genetic instrumental variable (IV) analysis (Mendelian randomization) to infer the direction of causality between metabolites and obesity, but often omitted a large portion of untargeted profiling data consisting of unknown, unidentified metabolite signals.
View Article and Find Full Text PDFAging (Albany NY)
September 2019
Glucuronic acid is a metabolite of glucose that is involved in the detoxification of xenobiotic compounds and the structure/remodeling of the extracellular matrix. We report for the first time that circulating glucuronic acid is a robust biomarker of mortality that is conserved across species. We find that glucuronic acid levels are significant predictors of all-cause mortality in three population-based cohorts from different countries with 4-20 years of follow-up (HR=1.
View Article and Find Full Text PDFMetabolomics is a powerful approach for discovering biomarkers and for characterizing the biochemical consequences of genetic variation. While untargeted metabolite profiling can measure thousands of signals in a single experiment, many biologically meaningful signals cannot be readily identified as known metabolites nor compared across datasets, making it difficult to infer biology and to conduct well-powered meta-analyses across studies. To overcome these challenges, we developed a suite of computational methods, PAIRUP-MS, to match metabolite signals across mass spectrometry-based profiling datasets and to generate metabolic pathway annotations for these signals.
View Article and Find Full Text PDFIntroduction: The placenta demonstrates a recognized sequence of histomorphologic maturation throughout pregnancy, and in some cases, shows abnormally advanced (AVM) or delayed (DVM) villous maturation. While AVM and DVM have important clinical implications, it is unknown whether they truly represent a state of accelerated/delayed normal maturation or a state of pathological maldevelopment. The purpose of our study is, therefore, to address this challenge via a genome-wide search for expression markers of normal villous maturation (NM) and the assessment of these genes in cases of maturational pathology.
View Article and Find Full Text PDFObjectives: While reference limits are foundational to interpreting clinical laboratory tests, they may not correspond to the actual values triggering clinical response. We propose to measure this using clinical action curves, which plot test values against an indicator of clinical action.
Methods: We selected repeat test ordering as a quantifiable, objective, useful measure that is readily calculable using available laboratory data.
Objectives: To identify inappropriate repeats of six common laboratory tests in a population sample of patients, using highly specific criteria based only on repeat time and test value.
Methods: We used a laboratory informatics database to conduct a retrospective cohort study using a population sample of 103,000 patients in the city of Calgary with an index test in 2010 and uniform follow-up of 1 year. We examined six tests (cholesterol, hemoglobin A1c, thyroid-stimulating hormone, vitamin B12, vitamin D, and ferritin) with consensus-based or easily justified criteria for inappropriate repeats based solely on time to repeat and the index test value.
Purpose: Cytogenetic analysis of solid tissue is indispensable in perinatal care, reproductive planning, and detection of gestational trophoblastic disease. Unfortunately, methods in common use suffer from drawbacks including culture artifact, low resolution, and high cost. We propose a new diagnostic algorithm based on direct genetic analysis of tissues (without cell culture) using QF-PCR and array CGH.
View Article and Find Full Text PDFCalorie restriction (CR) extends life span in mammals and delays the onset of age-related diseases, including cancer and diabetes. Drugs that target the same genes and pathways as CR may have enormous therapeutic potential. Recently, genome-scale data on the responses of human cell lines to over 1,000 drug treatments have become available.
View Article and Find Full Text PDFBackground: MIB-1 proliferation index (PI) has proven helpful for diagnosis and prognosis in non-Hodgkin lymphomas (NHLs). However, validated cutoff values for use in fine-needle aspiration (FNA) samples are not available. We investigated MIB-1 immunocytochemistry as an ancillary technique for stratifying NHL and attempted to establish PI cutpoints in cytologic samples.
View Article and Find Full Text PDFAims: To review the clinicopathological, cytomorphological and immunophenotyping data from new cases and published series of thyroid lymphoma diagnosed by fine-needle aspiration (FNA), in order to identify useful diagnostic features.
Methods: Cases from 1988 to 2009 with an FNA diagnosis of thyroid lymphoma were selected from hospital records. An electronic MEDLINE and EMBASE search retrieved published series from 1980 to 2009.