Beskyd Fryčovice (Czechia)

Aggressive and metastatic cancers show enhanced metabolic plasticity, but the precise underlying mechanisms for this remain unclear. Here, we reveal how two NSUN3-dependent RNA modifications, 5-methylcytosine (m⁵C) and its derivative 5-formylcytosine (f⁵C), drive mitochondrial mRNA translation to power metastasis. Translation of mitochondrial-encoded subunits of the oxidative phosphorylation (OXPHOS) complex depends on the formation of m⁵C at position 34 in mitochondrial tRNA^Met. m⁵C-deficient human oral cancer cells enhance glycolysis and adapt mitochondrial function without affecting cell viability or primary tumour growth <em>in vivo</em>; however, metabolic plasticity is severely impaired as mitochondrial m⁵C-deficient tumours fail to efficiently metastasize. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m⁵C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in head and neck cancer patients is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch allowing tumour cell metastasis can be pharmacologically targeted through inhibition of mitochondrial mRNA translation <em>in vivo</em>. Together, our results reveal site-specific mitochondrial RNA modifications as novel therapeutic targets to fight metastasis. This Script was made to analyze the RNAseq data from VDH15 cell line infected with shRNA control (Ctr) or targeting NSUN3 (sh#1, sh#2), injected in mice, tumors collected 21days after infection, and cancer cell lines sorted.

To determine if single nucleotide polymorphisms (SNPs) in interleukin (IL) IL-1A, IL-1B, IL-1RN, IL-2, IL-9, and IL-9R were associated with chronic beryllium disease (CBD) and beryllium sensitization (BeS). Forty SNPs in six IL genes were evaluated in 85 individuals with CBD, 61 individuals with BeS, and 730 individuals without BeS or CBD (nonsensitized) using a 5' nuclease polymerase chain reaction assay. Logistic regression was used to evaluate the association between IL SNPs, CBD, and BeS, adjusting for plant-site and HLA-DPB1Glu69 in additive, dominant, and recessive inheritance models. IL-1A-1142, IL-1A-3769, and IL-1A-4697 were significantly associated with CBD in both the additive and dominant models compared to individuals with BeS or the nonsensitized. These results indicate that genetic variations in the IL-1A gene may play a role in the development of CBD but not BeS.

The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of trials needed to properly evaluate them. The majority of patients treated today, many of whom could be eligible for participation in these studies, are seen in community hospitals and medical practices that are not affiliated with an academic medical center. Thus, there is a demonstrable need for physicians in private practice to enlist as investigators in these trials. This article is intended to encourage those physicians by describing the need and providing the rationale for their participation. It covers basic requirements for participating in clinical trials and outlines ethical, regulatory, financial, and other logistical issues of importance for the potential investigator and provides an algorithm for selecting a study for participation. Finally, the appendices review basic elements of study design and statistical principles, which may be of interest to a potential investigator.

The peak rate of systolic wall thickening (p +/- dTw/dt) in regions of the left ventricle (LV) was determined preoperatively by biplane roentgen videometry in 18 patients before and after sublingual administration of nitroglycerin (NTG) and 3-23 months (median 12) after aortocoronary bypass surgery. The regional LV response to NTG was a reliable predictor for postoperative improvement in regional wall dynamics after successful aortocoronary bypass grafting. The ejection fraction response to NTG or surgery will not predict the regional myocardial response to NTG or surgery, nor will the regional response predict the global response. Subendocardial myocardial infarction is another cause of unimproved regional myocardial function after NTG and aortocoronary bypass surgery.