👤 Michel Polak

Aim: To summarise current knowledge on the effects of intermittent fasting on cognitive functions and neuroprotective mechanisms, with particular attention to Alzheimer's disease and Parkinson's disease. Materials and Methods: A narrative review based on twelve peer-reviewed publications on the effects of intermittent fasting on cognitive function, neuroprotection, and circadian rhythms. Preclinical data and selected clinical studies indicate that intermittent fasting improves memory, attention, and executive functions, which is associated with activation of autophagy, reduction of oxidative stress, improved mitochondrial function, and increased levels of brain-derived neurotrophic factor. In Parkinson's disease, intermittent fasting limits alpha-synuclein aggregation and protects dopaminergic neurons, whereas in Alzheimer's disease it reduces beta-amyloid deposition and enhances synaptic plasticity. Intermittent fasting also influences the gut-brain axis and circadian rhythm alignment, which may further support neuroprotection. Conclusions: Intermittent fasting is a promising adjunct strategy in the management of neurodegenerative diseases. However, well-designed, randomised clinical trials are needed to confirm its effectiveness and safety. Show less

In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor-positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy. Show less

To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994-2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients' age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0-53.2) years for patients born before 2007 and 0.4 (0-9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males. Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less

Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial-mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC. Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC. Show less

Subclinical atherosclerosis (sCVD), measured by coronary artery calcium (CAC) and carotid intima media thickness (CIMT) is associated with cardiovascular disease (CVD). Genome-Wide Association Studies (GWAS) of sCVD and CVD have focused primarily on Caucasian populations. We hypothesized that these associations may differ in populations from distinct genetic backgrounds. The associations between sCVD and 66 single nucleotide polymorphisms (SNPs) from published GWAS of sCVD and CVD were tested in 8224 Multi-Ethnic Study of Atherosclerosis (MESA) and MESA Family participants [2329 Caucasians (EUA), 691 Chinese (CHN), 2482 African Americans (AFA), and 2012 Hispanic (HIS)] using an additive model adjusting for CVD risk factors, with SNP significance defined by a Bonferroni-corrected p < 7.6 × 10(-4) (0.05/66). In EUA there were significant associations for CAC with SNPs in 9p21 (rs1333049, P = 2 × 10(-9); rs4977574, P = 4 × 10(-9)), COL4A1 (rs9515203, P = 9 × 10(-6)), and PHACTR1 (rs9349379, P = 4 × 10(-4)). In HIS, CAC was associated with SNPs in 9p21 (rs1333049, P = 8 × 10(-5); rs4977574, P = 5 × 10(-5)), APOA5 (rs964184, P = 2 × 10(-4)), and ADAMTS7 (rs7173743, P = 4 × 10(-4)). There were no associations between CAC and 9p21 SNPs for AFA and CHN. Fine mapping of the 9p21 region revealed SNPs with robust associations with CAC in EUA and HIS but no significant associations in AFA and CHN. Our results suggest some shared genetic architecture for sCVD across ethnic groups, while also underscoring the possibility of novel variants and/or pathways in risk of CVD in ethnically diverse populations. Show less

Genetic variation at the apolipoprotein A5 gene (APOA5) is associated with increased triglyceride concentrations, a risk factor for atherosclerosis. Carotid intimal medial thickness (IMT) is a surrogate measure of atherosclerosis burden. We sought to determine the association of common APOA5 genetic variants with carotid IMT and stenosis. A total of 2,273 Framingham Offspring Study participants underwent carotid ultrasound and had data on at least one of the five APOA5 variants (-1131T>C, -3A>G, 56C>G, IVS3+476G >A, and 1259T>C). Although none of the individual variants was significantly associated with carotid measures, the haplotype defined by the presence of the rare allele of the 56C>G variant was associated with a higher common carotid artery (CCA) IMT compared with the wild-type haplotype (0.75 vs. 0.73 mm; P < 0.05). The rare allele of each of the -1131T >C, -3A>G, IVS3+476G>A, and 1259T>C variants and the haplotype defined by the presence of the rare alleles in these four variants were each significantly associated with CCA IMT in obese participants. These associations remained significant even after adjustment for triglycerides. APOA5 variants were associated with CCA IMT, particularly in obese participants. The mechanism of these associations and the effect modification by obesity are independent of fasting triglyceride levels. Show less