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Sparking and Sustaining the Essential Functions of Research
Published in Thomas S. Inui, Richard M. Frankel, Enhancing the Professional Culture of Academic Health Science Centers, 2022
Eric B. Larson, Christine Tachibana, Edward H. Wagner
A 1995 population-based, case-control study and resulting intervention at Group Health illustrates the translational efficiency that is possible in a learning health system in collaboration with an academic health science center. Bruce Psaty and UW colleagues found that use of short-acting calcium channel blockers such as nifedipine in hypertensive patients is associated with an increased risk of heart attack.27 This led to a 1996 US FDA recommendation to discourage use of nifedipine for treating high blood pressure. A few months later, Group Health began providing physicians with a summary of evidence about nifedipine, current guidelines about hypertension medication, and patient letters to distribute, advising either a new medication or a physician visit. In a follow-up study of the intervention, Psaty and colleagues found that almost 80% of patients taking short-acting nifedipine had discontinued use within 6 months.28 Within a year of publication, evidence from a Group Health-UW study influenced national recommendations and led to safer drug use in its member population.
Resistance Exercise Training and The Regulation of Muscle Protein Synthesis
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Nathan Hodson, Daniel R. Moore, Chris McGlory
Broadly speaking, the processes underlying an increase in rates of MPS at the molecular level can be separated into two processes: that of translational efficiency and translational capacity. Translational efficiency refers to the amount of protein yield per unit of mRNA/ribosome, whereas translational capacity typically means the amount of translational machinery (i.e., mRNA/ribosome abundance) available to build more muscle protein (27). In the previous section we primarily focused on how resistance exercise and AA feeding affect signalling events that regulate translational efficiency. However, there is recent evidence that translational capacity also may play a crucial role in resistance exercise–induced hypertrophy (27, 36).
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Remarkably, Walter Fiers and Henri Grosjean (1979) were the first to comment on the total nucleotide sequence of the lac repressor gene I of 361 codons (Farabaugh 1978), where the codon usage was quite different from that of the MS2 and φX174 genomes. It was emphasized in this comment that the MS2 genome had optimized translational efficiency, especially of the coat gene, which needed the proper choice of degenerate code words, in contrast to the lacI gene, where lac repressor protein was made at very low levels. Thus, the possible relation of selective pattern of the codon usage to a difference in translational efficiency was proposed. Continuing this idea, general principles of the preferential codon usage in highly-expressed prokaryotic genes were postulated (Grosjean and Fiers 1982). The authors hypothesized that both the optimization of codon-anticodon interaction energy and the adaptation of the population to codon frequency, or vice versa, in highly expressed genes were part of a strategy that optimized the efficiency of translation. Conversely, codon usage in weakly expressed genes, such as repressor genes, followed exactly the opposite rules. It was concluded therefore that, in addition to the need for coding an amino acid sequence, the energetic consideration for the codon-anticodon pairing, as well as the adaptation of codons to the tRNA population, might have been important evolutionary constraints on the selection of the optimal nucleotide sequence.
From animal studies into clinical trials: the relevance of animal models to develop vaccines and therapies to reduce disease severity and prevent hRSV infection
Published in Expert Opinion on Drug Discovery, 2022
J.A Soto, N.M.S Galvez, D.B Rivera, F.E Díaz, C.A Riedel, S.M Bueno, A.M Kalergis
The limited availability of therapeutic and prophylactic tools to prevent severe hRSV infection in high-risk populations continues to challenge researchers, more than six decades after hRSV was first reported [43]. Since hRSV is highly specific to the human host, the development of antiviral molecules, monoclonal antibodies, and vaccines has required extensive testing in preclinical models. Considering the pros and cons of each animal model, which have been recently reviewed [35,41,53,129], it is clear that no single animal model is enough to comprehend all aspects a drug or vaccine against hRSV can have on humans. These aspects consider, but are not limited to, administration route, dosage, mechanisms of action, efficacy, and translational efficiency. Furthermore, we will benefit from the refinement of already established and the generation of new animal models to increase confidence in the success of potential treatments in clinical trials. A successful example of this point is the licensing of palivizumab for human use, highlighting the vast contribution of rodents in the early testing of this therapy and many others, such as vaccines or antiviral molecules. Along these lines, we highlight the relevance of the cotton rat as a model, which should be more routinely employed in comparison to mice. This is due to its higher permissiveness for viral replication and high versatility as a model, which makes it suitable for antibody, and antiviral drug testing, VED exploration, and evaluation of mechanistic studies, as we reported in this review.
CDH1 Gene rs1801552 C/T Polymorphism Increases Susceptibility to Esophageal Squamous Cell Carcinoma but Not to Gastric Cardiac Adenocarcinoma
Published in Cancer Investigation, 2021
Xi Huang, Yan Li, Rong-Miao Zhou, Sai-Jin Cui, Shi-Ru Cao, Xiang-Ran Huo, Na Wang
Amino acids are encoded by multiple synonymous codons, but the synonymous codons are used in different frequency, which called codon usage bias (28,29). Different synonymous codons have different translational efficiency (TE), in other words, the speed of translation between different synonymous codons is different (26,30). Various factors have been revealed to affect TE, the most important of which is the abundance of the transfer RNAs (tRNAs) (31,32). Higher tRNAs abundance leads to faster ribosomal translation, and then results in higher protein levels (24,33,34). E-cadherin protein is a tumor suppressor protein by inhibiting tumor invasion and metastasis. So the person with the T/T genotype may have fewer E-cadherin protein levels, which resulting in high risk of ESCC. There have been some reports on the association between the rs1801552 C/T polymorphism and gastric cancer susceptibility. Caggiari et al. (35) have done a study to improve information of the E-cadherin alterations and the HER2 in the context of gastric cancer to characterize subtypes of patients that could better benefit from targeted therapy. They found that the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T), with better prognosis of gastric cancer. Zhan et al. (36) have genotyped four functional polymorphisms, which including the rs1801552 C/T polymorphism in the CDH1 gene in a case–control study of 387 gastric cancer cases and 392 healthy controls. They found no significant association between the risk of gastric cancer and the variant alleles of the SNP.
Tackling pharmacological response heterogeneity by PBPK modeling to advance precision medicine productivity of nanotechnology and genomics therapeutics
Published in Expert Review of Precision Medicine and Drug Development, 2019
Ioannis S. Vizirianakis, Androulla N. Miliotou, George A. Mystridis, Eleftherios G. Andriotis, Ioannis I. Andreadis, Lefkothea C. Papadopoulou, Dimitrios G. Fatouros
In the first delivery procedure, despite the benefits of self-adjuvating activity, the direct translation into the cytoplasm, the low risk of insertional mutagenesis, as well as the simple and inexpensive manufacturing procedure, the control of IVT-mRNA’s translational efficiency remains challenging. IVT-mRNA, in naked formation, may be spontaneously translocated into any cell type’s cytoplasm through scavenger receptor-mediated endocytosis. Thus, there is no specificity, and only a small amount can be captured by antigen-presenting cells (APCs) to be translated into antigens and presented. Direct ultrasound-guided percutaneous injection of IVT-mRNA into the lymph nodes allows the maximum translocation into APCs [76]. Sahin et al. [77] demonstrated (during a clinical study in melanoma patients) that IVT-mRNA encoding poly-neoantigens, through intranodal injection, was remarkably stable and efficiently translated and finally presented via major histocompatibility complex (MHC) class I and II molecules on DCs. The limitation of the use of intranodal injection method is the need of repeated percutaneous injections (up to 20), a not so practical administration route.