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Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation. This review traces the main milestones in the treatment of ALK-positive metastatic patients and the survival outcomes in the first-line and second-line settings with different ALK inhibitors. It presents the two options available for first-line treatment at the present time: sequencing different ALK inhibitors versus using the most potent inhibitor in front-line treatment. The efficacy outcomes of different ALK inhibitors in the first-line setting; the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations; and patients' co-morbidities and inhibitor toxicities should be taken into account to address the choice of the first-line treatment, as suggested in this review.

Objective: To create and evaluate the content validity of educational videos on self-management of fluid restriction and thirst for individuals with heart failure (HF)., Method: A psychometric study was conducted in three stages: (1) an integrative literature review to identify strategies for self-management of fluid restriction and thirst by individuals with HF; (2) creation of animated videos about strategies for self-management of fluid restriction and thirst; and (3) analysis of the content validity of the educational videos by 11 experts. For each criterion, the content validity ratio (CVR) was calculated; it was considered adequate when <0.636. Suggestions were evaluated by the researchers, and the videos were modified., Results: Ten scripts and videos were created, averaging 30 s each. The videos' contents were based on 11 studies retrieved from the review and one specialized website. The videos were evaluated by experts, and adjustments were made when CVR < 0.636 and when allowed by the video production platform., Conclusions: Educational videos were developed and have satisfactory content validity evidence according to expert opinions., Implications for Nursing Practice: These videos are expected to be used as educational strategies in clinical practice to prevent episodes of decompensation due to excessive fluid volume., (© 2024 NANDA International, Inc.)

Background: To date, measurement of intracellular cystine is used for the therapeutic monitoring of patients affected by cystinosis in treatment with cysteamine. Since this method is time and sample consuming, development of a faster method to quantify cysteamine would be extremely useful in order to help clinicians to adjust dosages of cysteamine and to define better the pharmacokinetic profile of this drug. The aim of the study was to develop a liquid chromatography tandem mass spectrometry method for the quantification of cysteamine in plasma samples and to test its applicability on plasma samples derived from patients with nephropathic infantile cystinosis in treatment with cysteamine., Results: The percentage of accuracy of the developed method varied between 97.80 and 106.00% and CV% between 0.90 and 6.93%. There was no carry over. The calibration curves were built from 2.5 to 50 µM. The limit of detection and the lower limit of quantification occurred at 0.25 and 1.25 µM respectively. Cysteamine was stable up to 2 months at -20 °C. Concentrations of cysteamine and intracellular cystine of 4 patients were in line with data previously reported., Conclusion: The proposed method showed an appropriate selectivity, specificity, linearity, sensibility, accuracy, precision and good applicability to samples., (© 2022. The Author(s).)

Previous work has suggested that highly positively charged protein segments coded by rare codons or poly (A) stretches induce ribosome stalling and translational arrest through electrostatic interactions with the negatively charged ribosome exit tunnel, leading to inefficient elongation. This arrest leads to the activation of the Ribosome Quality Control (RQC) pathway and results in low expression of these reporter proteins. However, the only endogenous yeast proteins known to activate the RQC are Rqc1, a protein essential for RQC function, and Sdd1, a protein with unknown function, both of which contain polybasic sequences. To explore the generality of this phenomenon, we investigated whether the RQC complex controls the expression of other proteins with polybasic sequences. We showed by ribosome profiling data analysis and western blot that proteins containing polybasic sequences similar to, or even more positively charged than those of Rqc1 and Sdd1, were not targeted by the RQC complex. We also observed that the previously reported Ltn1-dependent regulation of Rqc1 is posttranslational, independent of the RQC activity. Taken together, our results suggest that RQC should not be regarded as a general regulatory pathway for the expression of highly positively charged proteins in yeast., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Capsid proteins often present a positively charged arginine-rich sequence at their terminal regions, which has a fundamental role in genome packaging and particle stability for some icosahedral viruses. These sequences show little to no conservation and are structurally dynamic such that they cannot be easily detected by common sequence or structure comparisons. As a result, the occurrence and distribution of positively charged domains across the viral universe are unknown. Based on the net charge calculation of discrete protein segments, we identified proteins containing amino acid stretches with a notably high net charge (Q > + 17), which are enriched in icosahedral viruses with a distinctive bias towards arginine over lysine. We used viral particle structural data to calculate the total electrostatic charge derived from the most positively charged protein segment of capsid proteins and correlated these values with genome charges arising from the phosphates of each nucleotide. We obtained a positive correlation (r = 0.91, p-value <0001) for a group of 17 viral families, corresponding to 40% of all families with icosahedral structures described to date. These data indicated that unrelated viruses with diverse genome types adopt a common underlying mechanism for capsid assembly based on R-arms.

Translation initiation is a critical step in the regulation of protein synthesis, and it is subjected to different control mechanisms, such as 5' UTR secondary structure and initiation codon context, that can influence the rates at which initiation and consequentially translation occur. For some genes, translation elongation also affects the rate of protein synthesis. With a GFP library containing nearly all possible combinations of nucleotides from the 3 rd to the 5 th codon positions in the protein coding region of the mRNA, it was previously demonstrated that some nucleotide combinations increased GFP expression up to four orders of magnitude. While it is clear that the codon region from positions 3 to 5 can influence protein expression levels of artificial constructs, its impact on endogenous proteins is still unknown. Through bioinformatics analysis, we identified the nucleotide combinations of the GFP library in Escherichia coli genes and examined the correlation between the expected levels of translation according to the GFP data with the experimental measures of protein expression. We observed that E. coli genes were enriched with the nucleotide compositions that enhanced protein expression in the GFP library, but surprisingly, it seemed to affect the translation efficiency only marginally. Nevertheless, our data indicate that different enterobacteria present similar nucleotide composition enrichment as E. coli , suggesting an evolutionary pressure towards the conservation of short translational enhancer sequences.

The codon stabilization coefficient (CSC) is derived from the correlation between each codon frequency in transcripts and mRNA half-life experimental data. In this work, we used this metric as a reference to compare previously published Saccharomyces cerevisiae mRNA half-life datasets and investigate how codon composition related to protein levels. We generated CSCs derived from nine studies. Four datasets produced similar CSCs, which also correlated with other independent parameters that reflected codon optimality, such as the tRNA abundance and ribosome residence time. By calculating the average CSC for each gene, we found that most mRNAs tended to have more non-optimal codons. Conversely, a high proportion of optimal codons was found for genes coding highly abundant proteins, including proteins that were only transiently overexpressed in response to stress conditions. We also used CSCs to identify and locate mRNA regions enriched in non-optimal codons. We found that these stretches were usually located close to the initiation codon and were sufficient to slow ribosome movement. However, in contrast to observations from reporter systems, we found no position-dependent effect on the mRNA half-life. These analyses underscore the value of CSCs in studies of mRNA stability and codon bias and their relationships with protein expression., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Bone conduction implants based on abutment-driven acoustic transmission result in good hearing outcomes; however, skin complications impact the quality of life (QOL) and possibly the viability of the device for many patients. The transcutaneous magnetic Baha ® Attract technology was developed with the goal of minimising skin complications., Objectives: To analyse surgical, auditory and QOL outcomes for patients implanted with the Baha ® Attract., Design: Prospective multicentre cohort study., Setting: Four French tertiary referral centres., Participants: Thirty-two patients implanted with the Baha ® Attract, including 25 with conductive and mixed hearing loss and 7 with single-sided deafness., Main Outcome Measures: Postoperative follow-up involved the visual analysis of soft tissue adaptation and sound processor magnet strength measurement. The audiometric outcomes were evaluated in quiet and noise, and the QOL was assessed using three different questionnaires., Results: After 12 months of use, soft tissue was thinner, and mean magnet strength was significantly decreased (3.7-3.1, P < 0.05) relative to measures during surgery. The speech recognition threshold in quiet significantly improved compared to unaided situation (73-44 dB HL respectively, P < 0.001) as did functional gain in noise (+2.8). All QOL scores improved, and the APHAB questionnaire score correlated with the audiometric outcomes., Conclusions: The Baha ® Attract technology results in significant hearing gain and improves QOL. Skin complications were not observed, although surgeons, audiologists and patients should be aware of soft tissue evolution during the first postoperative year. The reversibility of this implant is a major advantage that allows switching to another system if hearing degrades., (© 2018 John Wiley & Sons Ltd.)

As proteins are synthesized, the nascent polypeptide must pass through a negatively charged exit tunnel. During this stage, positively charged stretches can interact with the ribosome walls and slow the translation. Therefore, charged polypeptides may be important factors that affect protein expression. To determine the frequency and distribution of positively and negatively charged stretches in different proteomes, the net charge was calculated for every 30 consecutive amino acid residues, which corresponds to the length of the ribosome exit tunnel. The following annotated and reviewed proteins in the UniProt database (Swiss-Prot) were analyzed: 551,705 proteins from different organisms and a total of 180 million protein segments. We observed that there were more negative than positive stretches and that super-charged positive sequences (i.e., net charges ≥ 14) were underrepresented in the proteomes. Overall, the proteins were more positively charged at their N-termini and C-termini, and this feature was present in most organisms and subcellular localizations. To investigate whether the N-terminal charges affect the elongation rates, previously published ribosomal profiling data obtained from S. cerevisiae, without translation-interfering drugs, were analyzed. We observed a nonlinear effect of the charge on the ribosome occupancy in which values ≥ +5 and ≤ -6 showed increased and reduced ribosome densities, respectively. These groups also showed different distributions across 80S monosomes and polysomes. Basic polypeptides are more common within short proteins that are translated by monosomes, whereas negative stretches are more abundant in polysome-translated proteins. These findings suggest that the nascent peptide charge impacts translation and can be one of the factors that regulate translation efficiency and protein expression.

It has been proposed that polybasic peptides cause slower movement of ribosomes through an electrostatic interaction with the highly negative ribosome exit tunnel. Ribosome profiling data-the sequencing of short ribosome-bound fragments of mRNA-is a powerful tool for the analysis of mRNA translation. Using the yeast Saccharomyces cerevisiae as a model, we showed that reduced translation efficiency associated with polybasic protein sequences could be inferred from ribosome profiling. However, an increase in ribosome density at polybasic sequences was evident only when the commonly used translational inhibitors cycloheximide and anisomycin were omitted during mRNA isolation. Since ribosome profiling performed without inhibitors agrees with experimental evidence obtained by other methods, we conclude that cycloheximide and anisomycin must be avoided in ribosome profiling experiments.

Garcinia cambogia seems to promote weight reduction and improvement on lipid profile by its major compound, hydroxycitric acid (HCA), blocking ATP-citratelyase, potentially inhibiting lipogenesis. Furthermore, it is suggested that its extract is able to change the adipokine levels. Thus, the aim of this study was to analyse the effect of G. cambogia on the lipid profile, endocrine, calorimetric and anthropometric parameters of obese women. The women (BMI > 25 kg/m(2) ; age 25-60 years), divided in treated (n = 30) and control (n = 13) groups, received 2.4 g (800 mg 3×/day) of garcinia extract (50% of HCA) or placebo during 60 days, respectively, as well as dietary control. Weight, BMI, waist-hip ratio and percentage of fat mass, resting metabolic rate, respiratory coefficient, triglycerides (TG), total cholesterol, HDL and LDL, leptin and insulin serum levels were evaluated. TG was significantly reduced in the treated group (p = 0.0002) and the post-treatment variation was different compared to the placebo group (p = 0.04). No significant response was observed on other variables of the lipid profile, or on the anthropometric and calorimetric parameters. Leptin and insulin levels did not change significantly after the treatment. The short-term treatment with G. cambogia demonstrated a hypotriglyceridemic effect, which does not appear to be related to changes in leptinemia., (Copyright © 2013 John Wiley & Sons, Ltd.)

Bilirubin has been considered an antioxidant, with capacity to remove reactive species of oxygen. Studies have suggested that an increased bilirubin level promotes protection against atherosclerosis. The case group was composed of 100 patients with coronary artery disease and the control group 100 patients with normal coronaries. Blood samples were collected to determine bilirubin concentrations. Bivariate analysis, multiple logistic regression models, and Spearman's correlation index were performed. A P value < 0.05 was considered to be significant. The case group was predominantly composed of men and the control group of women, with a mean age of 60 +/- 8.8 versus 56 +/- 10.9 (P = 0.015). The total bilirubin average was significantly higher in the control group than in the case group (0.76 mg/dL versus 0.39 mg/dL, P < 0.001). The level of ultrasensitive C reactive protein (us-CRP) was increased in the case group (3.63 mg/L versus 0.93 mg/L, P < 0.001). Although the correlation index for this inverse association has been weak, both are independently associated with a higher prevalence of coronary artery disease, total bilirubin 3 mg/L (OR: 1.17; IC: 1.04-1.33; P = 0.009). Reduced serum levels of bilirubin were shown to be associated with a higher prevalence of coronary artery disease emerging as a new potential risk factor marker. Additional studies are still necessary to confirm and demonstrate the association of these findings with clinical outcomes.

Introduction: Cigarette smoking is highly prevalent among men. Many studies have evaluated the effect of cigarette smoking on levels of male reproductive hormones; however, the findings still remain controversial., Aim: To evaluate the influence of cigarette smoking on serum levels of total testosterone (TT), free testosterone (FT), bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)., Methods: A total of 255 men (90 smokers and 165 nonsmokers), aged 30 to 70 years, were investigated. Weight and height were obtained and body mass index (BMI) was calculated. Also, waist circumference and hip circumference were measured and waist-to-hip ratio was obtained. Fasting blood samples were drawn for determination of plasmatic glucose levels and serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-c), triglycerides, albumin, prolactin, TT, SHBG, LH, and FSH. The values of low-density lipoprotein cholesterol (LDL-c) were determined by Friedwald equation and the values of FT and BT were calculated from TT, SHBG, and albumin. Statistical significance was set at P < or = 0.05., Main Outcome Measures: The influence of smoking on levels of TT, FT, and BT., Results: No significant difference was observed in the mean values of TT (P = 0.580), FT (P = 0.869), BT (P = 0.933), SHBG (P = 0.279), LH (P = 0.573), and FSH (P = 0.693) in the different levels of pack-years when compared to nonsmokers. Moreover, after multivariate logistic regression, no association between increased pack-years of smoking and increased odds ratio for occurrence of low hormones and SHBG levels was observed., Conclusion: In this study, smokers and nonsmokers had similar mean values of androgens, gonadotropins and SHBG. However, it is necessary to standardize pack-years of smoking in order to elucidate the influence of cigarette smoking on sex hormone levels, as well as to minimize differences among studies and to confirm our results.