Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect ...mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor‐suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib‐desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low‐dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
What's new?
Sunitinib, a tyrosine kinase inhibitor, is one of the most commonly used targeted therapeutics for treatment of metastatic renal cell carcinoma (mRCC). However, the majority of patients who initially respond eventually develop acquired resistance. In the present study, by analyzing sequential tumor biopsies from an mRCC patient who developed acquired resistance to sunitinib, the authors identified mutations in genes whose loss of function conferred sunitinib resistance to tumor cell lines and xenografted mice and went on to identify critical downstream action mechanisms. The findings may be relevant for the development of predictive biomarkers and new therapeutic strategies in mRCC.
Highlights • Reduced 2 + 1 dose schedules of 4CMenB in infants were assessed. • Two catch-up doses of 4CMenB were administered 2 months apart in children 2–10 years. • ≥88% of vaccinated infants ...achieved seroprotective antibody levels for 4CMenB components. • ≥95% of children achieved seroprotective antibody levels for 4CMenB components. • No safety signals were identified during the study.
The virtualization of university teaching in Spain caused by the pandemic was a success, but the urgent nature of the transition from face-to-face teaching to online teaching meant that some ...peculiarities that should have been taken into account were omitted. Thus, in order to find out and analyze the factors causing the success of this virtualization and take measures to address the weak points of this process as teachers may want to maintain the use of online teaching as support for their face-to-face teaching, these factors were located through a literature review and were classified according to their level of importance in this success through a causal study carried out with the methodology of fuzzy cognitive maps. The results achieved indicated the determining factors in students, involving their attitude, aptitude and predisposition, which are factors where the work of the teacher is of main relevance (as it exerts the greatest influence on these factors). For this reason, technological attitude and aptitude, teaching style, and the creation and structuring of content should be reinforced in teachers.
Many fluorophores display interesting features that make them useful biological labels and chemosensors, in particular in Cell Biology. Changes in the absorption-emission spectra (ortho- and ...metachromasia) are accounted among them. Acridine orange (AO) is one such fluorochromes that shows a prototypical orthochromatic vs. metachromatic behavior depending on its concentration and binding mode to different cellular substrates. Here, we revisit the differential AO fluorescence that occurs in selected biological examples, which allows for the identification of single-stranded or double-stranded nucleic acids. Although known for long, the ultimate reason for this phenomenon has not been properly advanced. We provide a potential molecular mechanism that adequately accounts for the different aspects of the phenomenon. This theoretical mechanism implies a difference in the degree of overlap of excited state orbitals whenever AO molecules are interacting with a single-stranded or a double-stranded nucleic acid. In the first case, massive π-electron overlapping between bases and intercalated AO leads to a metachromatic red emission. On the contrary, no excited-state orbital overlapping in AO-intercalated DNA duplexes is possible due to excessive separation between AO molecules and compliancy to the nearest neighbor exclusion principle, which manifests as orthochromatic green fluorescence.
Analysis of the key performance variables in soccer is one of the most continuous and attractive research topics. Using global positioning devices (GPS), the primary aim of this study was to ...highlight the physiological response of a professional soccer team across competitive microcycles in-season according to the most influential contextual performance variables. Determining the training load (TL), a work ratio was established between all recorded data within the training sessions and the competitive profile (CP). Each microcycle was classified in accordance with the contextual variables: opponent level (high, medium, low), match location (home and away) and score (win, draw, lose). Results revealed that the team were significantly more successful (games won) in competitive games against high-level opponents and when played at home. Cumulative microcycle/weekly training load (WTL) was significantly lower when the team won. In addition to the opponent level and the match location, WTL could condition the athlete's performance in the competition. Competitive performance responses are the main source of information for the planning of training programs. The results of this study could be used as a reference to structure TL and WTL according to contextual variables in the competition. This study, which is the first of its kind, revealed that WTL effects the performance of the players in the competition.
Bioeconomic modelling in tilapia aquaculture: A review Dorantes‐de‐la‐O, Juan Carlos R.; Maeda‐Martínez, Alfonso N.; Espinosa‐Chaurand, Luis D. ...
Reviews in aquaculture,
09/2023, Letnik:
15, Številka:
4
Journal Article
Recenzirano
Abstract
The global production of aquatic resources is increasing at the rate of 3.3 million tons per year, main thanks to aquaculture. However, this industry is considered by financial institutions ...as high risk due to failures caused by epizootics, natural disasters and poor planning and monitoring. Bioeconomic modelling is a progressive branch of social science that seeks to integrate the disciplines of economics and biology to create theories that better explain economic events using a biological basis and vice versa. This should be used in aquaculture to plan, monitor, and determine cost‐effectiveness and risk, to reduce uncertainty and increase profits of ongoing or new projects. A meta‐analysis of the literature on bioeconomic modelling in aquaculture during 26 years (1994─2020) was performed, using four search engines. Sixty‐eight articles were published in 23 journals, on 25 groups of species or species. The most studied were shrimp, tilapia, seabream, salmon and carp. From these, 12 articles dealt with tilapia models that shared similar biological, management and economic sub‐models. In the 26‐year analysis, the global scientific productivity in this field is low (2.6 articles/year) in relation to the growth of world aquaculture. Bioeconomic modelling peaked during the decade from 2004 to 2014 with 5.6 papers/year, but then declined to only 0.83 articles/year from 2015 to 2020. This is possibly due to the low diffusion among producers, planners and financial institutions of the advantages of the models and the difficulty to use them if friendly and readily available software is lacking.
In this work, the mechanochemical synthesis method was used for the first time to produce powders of the nanocrystalline Nd1.1Fe10CoTi compound from Nd2O3, Fe2O3, Co and TiO2. High-energy-milled ...powders were heat treated at 1000 °C for 10 min to obtain the ThMn12-type structure. Volume fraction of the 1:12 phase was found to be as high as 95.7% with 4.3% of a bcc phase also present. The nitrogenation process of the sample was carried out at 350 °C during 3, 6, 9 and 12 h using a static pressure of 80 kPa of N2. The magnetic properties Mr, µ0Hc, and (BH)max were enhanced after nitrogenation, despite finding some residual nitrogen-free 1:12 phase. The magnetic values of a nitrogenated sample after 3 h were Mr = 75 Am2 kg–1, µ0Hc = 0.500 T and (BH)max = 58 kJ·m–3. Samples were aligned under an applied field of 2 T after washing and were measured in a direction parallel to the applied field. The best value of (BH)max ~ 114 kJ·m–3 was obtained for 3 h and the highest µ0Hc = 0.518 T for 6 h nitrogenation. SEM characterization revealed that the particles have a mean particle size around 360 nm and a rounded shape.
Drug-drug interactions (DDIs) detected in a patient may not be clinically apparent (potential DDIs), and when they occur, they produce adverse drug reactions (ADRs), toxicity or loss of treatment ...efficacy. In pediatrics, there are only few publications assessing potential DDIs and their risk factors. There are no studies in children admitted to emergency departments (ED). The present study estimates the prevalence and describes the characteristics of potential DDIs in patients admitted to an ED from a tertiary care hospital in Mexico; in addition, potential DDI-associated risk factors are investigated.
A secondary analysis of data from 915 patients admitted to the ED of the Hospital Infantil de México "Federico Gómez" was conducted. The Medscape Drug Interaction Checker software was used to identify potential DDIs. The results are expressed as number of cases (%), means (95% CI) and medians (25-75th percentiles). Count data regressions for number of total and severity-stratified potential DDIs were performed adjusting for patient characteristics, number of administered drugs, days of stay, presence of ADRs and diagnoses.
The prevalence of potential DDIs was 61%, with a median of 4 (2-8). A proportion of 0.2% of potential DDIs was "Contraindicated", 7.5% were classified as "Serious", 62.8% as "Significant" and 29.5% as "Minor". Female gender, age, days of stay, number of administered drugs and diagnoses of Neoplasms (C00-D48), Congenital malformations (Q00-Q99), Diseases of the Blood, Blood-forming Organs and Immunity (D50-D89) and Diseases of the nervous system (G00-G99) were significantly associated with potential DDIs.
The prevalence of potential DDIs in the ED is high, and strategies should therefore be established to monitor patients' safety during their stay, in addition to conducting investigations to estimate the real harm potential DDIs inflict on patients.
High-throughput sequencing has had an enormous impact on small RNA research during the past decade. However, sequencing only offers a one-dimensional view of the transcriptome and is often highly ...biased. Additionally, the 'sequence, map and annotate' approach, used widely in small RNA research, can lead to flawed interpretations of the data, lacking biological plausibility, due in part to database issues. Even in the absence of technical biases, the loss of three-dimensional information is a major limitation to understanding RNA stability, turnover and function. For example, noncoding RNA-derived fragments seem to exist mainly as dimers, tetramers or as nicked forms of their parental RNAs, contrary to widespread assumptions. In this perspective, we will discuss main sources of bias during small RNA-sequencing, present several useful bias-reducing strategies and provide guidance on the interpretation of small RNA-sequencing results, with emphasis on RNA fragmentomics. As sequencing offers a one-dimensional projection of a four-dimensional reality, prior structure-level knowledge is often needed to make sense of the data. Consequently, while less-biased sequencing methods are welcomed, integration of orthologous experimental techniques is also strongly recommended.
•Role allocation to partners is a relevant issue in Collaborative Networks.•A centralized matching approach is proposed to improve the allocation performance.•Incomplete preference lists with ties, ...and upper and lower quotas are considered.•Ad hoc arrangements are no longer necessary for role allocation to partners.
In the current constantly changing business and economic environment, partners (i.e., individuals and/or enterprises) create Collaborative Networks to join efforts and undertake new projects together, thus allowing them to face business opportunities that would not be possible if attempted by them individually. In this situation, an assignment problem arises, since these projects involve the performance of a group of tasks or processes (named roles) that have to be distributed among the partners. Specifically, this problem, called the Role-Partner Allocation (RPA) problem in Collaborative Networks is a two-sided matching problem with lower and upper quotas on the partner’s side, and incomplete and partially ordered preference lists on both sides. A matching problem, and thus also the RPA problem, should be solved by a centralized matching scheme. However, allocations in Collaborative Networks continue to be mainly created by ad hoc arrangements, which takes a long time and is hard work. Looking for a reliable and faster way of distributing roles among partners in a Collaborative Network, the existing centralized matching schemes expected to solve the RPA problem (e.g., DA algorithm, SOSM, CA-QL algorithm, and EADAM) are studied in this paper, concluding that none of them obtain a matching that properly meets the requirement of the RPA problem. Therefore, a new centralized matching scheme to solve the RPA problem is proposed, discussed and exemplified.
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