Changes in Polypharmacy and Psychotropic Medication Use After Diagnosis of Major Neurocognitive Disorders: A Population-based Study in Québec, Canada.

BACKGROUND: Older adults with major neurocognitive disorder (MNCD) are often exposed to polypharmacy. We aimed to assess the prescribing and discontinuation patterns of medications following diagnosis of MNCD among community-dwelling older adults. METHODS: Using the Quebec Integrated Chronic Disease Surveillance System, we conducted a population-based cohort study comparing 1-year prediagnosis and postdiagnosis use of medications between a group of individuals older than 65 years newly diagnosed with MNCD in 2016-2017 and a control group without MNCD. The difference-in-difference method was used to estimate the prediagnosis and postdiagnosis variation in the number of medications prescribed and in the proportion of psychotropic and anticholinergic medication users. RESULTS: In the MNCD group, the mean number of medications used (excluding Alzheimer disease treatments) increased by 1.25 in the year after the diagnosis. The respective increase was 0.45 in the control group, yielding an adjusted difference-in-differences of 0.81 (95% confidence interval: 0.74; 0.87) between groups. The adjusted difference-in-differences in the proportions of antipsychotic, antidepressant, and anticholinergic medication users was 13.2% (12.5; 13.9), 7.1% (6.5; 7.7), and 3.8% (3.1; 4.6), respectively. CONCLUSIONS: The medication burden among older adults tends to increase in the year following a diagnosis of MNCD. The use of antipsychotics and antidepressants may explain a part of the observed increase.

Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect.

The mammalian genome contains two mitogen-activated protein kinase (MAPK) kinase (MEK)-encoding genes, Mek1 and Mek2. MEKs phosphorylate and activate the two extracellular signal-regulated kinase (ERK) isoforms ERK1 and ERK2. Mek1(-/-) embryos die due to placental defects, whereas Mek2(-/-) mice survive with a normal life span and fertility, suggesting that MEK1 has functions not shared by MEK2. However, most Mek1(+/-)Mek2(+/-) embryos also die from placental defects, indicating that both Mek genes contribute to placental development. To assess the functional specificity of the Mek1 and Mek2 genes, we produced a Mek1 knock-in allele in which the Mek2 coding sequences were placed under the control of Mek1 regulatory sequences (Mek1(2) allele). Mek1(2/2) mice were viable with no apparent phenotype, indicating rescue by MEK2 and functional redundancy between the two MEK proteins. However, Mek1(2/-) embryos with Mek2 in only one of the Mek1 alleles and the other Mek1 allele null died from abnormal placenta, suggesting a dosage effect. Analysis of mice from a Mek1 Mek2 allelic series revealed that the occurrence of the placenta phenotype correlated with the amount of MEK protein independently of which MEK isoform was produced. Thus, although MEK1 and MEK2 can substitute for each other, a minimum amount of MEK is critical for placenta development and embryo survival.

A 12-gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5-fluorouracil or FOLFIRI.

Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5-fluorouracil (5-FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5-FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5-FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5-FU response signature. We refined this signature using a clinically relevant DNA microarray-based dataset of 359 formalin-fixed and paraffin-embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray-based dataset of 316 stage III FFPE samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5-FU resistant patients using our signature. We confirmed using the PETACC-3 dataset that the overall survival of subjects responding well to 5-FU did not improve with the addition of irinotecan (FOLFIRI; two-sided log-rank test p = 0.795). Conversely, patients who responded poorly to 5-FU based on our 12-gene signature were associated with better survival on FOLFIRI therapy (one-sided log-rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5-FU treatment alone.

The AF2 domain of the orphan nuclear receptor TEC is essential for the transcriptional activity of the oncogenic fusion protein EWS/TEC.

The EWS/TEC fusion protein encoded by the t(9:22) chromosomal translocation in human extraskeletal myxoid chondrosarcoma tumors is thought to participate in the tumoral process at least in part by deregulating the expression of specific target genes involved in the control of cell proliferation. In this work we show that the activation function-2 (AF2) domain of TEC is essential for the transcriptional activity of the EWS/TEC fusion protein. Significantly, deleting only the last 15 amino acids of the fusion protein, which contains 949 amino acids in its full form, results in a loss of over 70% of its transcriptional activity in transfected human chondrocyte cell lines. Point mutation analyses indicate that within the AF2 domain, amino acid residues I939, D940 and F943 all play a crucial role in the activity of EWS/TEC. Comparable results were obtained with the native TEC receptor. These results suggest that EWS/TEC interacts at least in part with the same transcriptional coactivators as the native TEC receptor, and that these coactivators may be involved in the tumoral process leading to human chondrosarcoma tumors.