Activiteit

Both protein-coding and noncoding RNAs can be decorated with a wealth of chemical modifications and such modifications coordinately orchestrate gene expression during normal hematopoietic differentiation and development. However, aberrant expression and/or dysfunction of the relevant RNA modification modulators/regulators (“writers”, “erasers”, and “readers”) drive the initiation and progression of hematopoietic malignancies, and targeting these dysregulated modulators holds potent therapeutic potential for the treatment of hematopoietic malignancies. In this review, we summarize current progress in the understanding of the biological functions and underlying mechanisms of RNA modifications in normal and malignant hematopoiesis, with a focus on the N6-methyladenosine (m6A) modification, and discuss the therapeutic potential of targeting RNA modifications for the treatment of hematopoietic malignancies, especially acute myeloid leukemia (AML).

To determine the potential impact of the presence of secondary variant histology on the gene expression profiles of muscle-invasive bladder cancer (MIBC) tumors.

For six tumors, revised samples were collected from urothelial and secondary variant components (cohort A). The commercial cohort (cohort B) consisted of the anonymized gene expression profiles of 173 patients with MIBC. Samples were obtained from the clinical use of the Decipher Bladder test that were available as part of the Decipher GRID prospective registry (NCT02609269). Secondary variant presence in cohort B was abstracted from institutional pathology reports. For the commercial cohort, only the urothelial carcinoma component was profiled.

Molecular subtyping of both urothelial and variant components found micropapillary and nested cases were classified as a luminal subtype. Conversely, the sarcomatoid and small cell cases were classified as basal/squamous or neuroendocrine-like, respectively. For cohort B, 50 (29%) of 173 cases had reported secondary variant histology. Cases with squamous variant had basal profiles, small cell cases expressed neuronal markers, and micropapillary cases were classified as luminal. CWI1-2 order Sarcomatoid tumors had robust epithelial-mesenchymal transition marker expression.

Our data suggest that in MIBC with secondary variant, the urothelial component can demonstrate an expression profile that closely resembles the variant component.

Our data suggest that in MIBC with secondary variant, the urothelial component can demonstrate an expression profile that closely resembles the variant component.Non-genetic heterogeneity, or gene expression stochasticity, is an important source of variability in biological systems. With the advent and improvement of single molecule resolution technologies, it has been shown that transcription dynamics and resultant transcript number fluctuations generate significant cell-to-cell variability that has important biological effects and may contribute substantially to both tissue homeostasis and disease. In this respect, the pathophysiology of stem cell-derived malignancies such as AML and MDS, which has historically been studied at the ensemble level, may require re-evaluation. To that end, it is our aim in this review to highlight the results of recent single-molecule, biophysical, and systems studies of gene expression dynamics, with the explicit purpose of demonstrating how the insights from these basic science studies may help inform and progress the field of leukemia biology and, ultimately, research into novel therapies.Diet is one of the most critical factors for inflammatory bowel disease (IBD). A whole dietary pattern should be considered when doing nutrient-based research to preserve the potential for synergism between nutrients. Dietary indices are important tools to evaluate diet quality, and we investigated the associations of it with IBD. Fourteen studies on the relation between index-based dietary patterns and IBD were included. 6 studies showed the relation between index-based dietary patterns and IBD risk, 7 studies explored the dietary indices and progression of IBD, and 1 study investigated the relationship between index and all-cause mortality in IBD patients. These results implied that a high score on the Mediterranean diet was negatively associated with risk and progression of IBD. However, a diet with high inflammatory potential could increase risk and aggravate disease activity in IBD. Dietary scores have the potential to evaluate the association between overall diet quality and risk and progression of IBD. Future randomized controlled trials are required to confirm the effect of the change in dietary score. This review was registered at http://www.crd.york.ac.uk/prospero/ as CRD42020220926.Washington State legalized recreational cannabis consumption in December 2012. We used data on all drivers involved in fatal crashes in Washington in years 2008-2019 (n=8,282) to estimate prevalence in fatal crashes of drivers with ∆9-tetrahydrocannabinol (THC, the main psychoactive compound in cannabis) in their blood before and after legalization. However, nearly half of the drivers were not tested for drugs; we used multiple imputation to estimate THC presence and concentration among them. We used logistic regression followed by marginal standardization to estimate the adjusted prevalence of THC-positive drivers after legalization relative to what would have been predicted without legalization. In the combined observed and imputed data, the proportion of drivers positive for THC was 9.3% before and 19.1% after legalization (adjusted Prevalence Ratio 2.3, 95% Confidence Interval 1.3, 4.1). The proportion of drivers with high THC concentrations increased substantially (adjusted Prevalence Ratio 4.7, 95% Confidence Interval 1.5, 15.1). Some of the increased prevalence of THC-positive drivers might have reflected cannabis use unassociated with driving; however, the increased prevalence of drivers with high THC concentrations suggests increased prevalence of driving shortly after using cannabis. Other jurisdictions should compile quantitative data on drug test results of drivers to enable surveillance and evaluation.