Summary
Recommended genetic categorization of acute myeloid leukaemias (AML) includes a favourable‐risk category, but not all these patients have good prognosis. Here, we used next‐generation ...sequencing to evaluate the mutational profile of 166 low‐risk AML patients: 30 core‐binding factor (CBF)‐AMLs, 33 nucleophosmin (NPM1)‐AMLs, 4 biCEBPα‐AMLs and 101 acute promyelocytic leukaemias (APLs). Functional categories of mutated genes differed among subgroups. NPM1‐AMLs showed frequent variations in DNA‐methylation genes (DNMT3A, TET2, IDH1/2) (79%), although without prognostic impact. Within this group, splicing‐gene mutations were an independent factor for relapse‐free (RFS) and overall survival (OS). In CBF‐AML, poor independent factors for RFS and OS were mutations in RAS pathway and cohesin genes, respectively. In APL, the mutational profile differed according to the risk groups. High‐risk APLs showed a high mutation rate in cell‐signalling genes (P = 0·002), highlighting an increased incidence of FLT3 internal tandem duplication (ITD) (65%, P < 0·0001). Remarkably, in low‐risk APLs (n = 28), NRAS mutations were strongly correlated with a shorter five‐year RFS (25% vs. 100%, P < 0·0001). Overall, a high number of mutations (≥3) was the worst prognostic factor RFS (HR = 2·6, P = 0·003). These results suggest that gene mutations may identify conventional low‐risk AML patients with poor prognosis and might be useful for better risk stratification and treatment decisions.
This paper introduces three methodologies to improve synthetic aperture radar (SAR)-based techniques used in ground-penetrating radar (GPR) systems. They consist of: 1) equalization of the frequency ...response of the transmitting (Tx) and receiving (Rx) antennas; 2) processing of SAR images using partially overlapped frequency subbands; and 3) imaging domain clustering. The goal is to combine ground penetration capabilities of lower frequency bands with the resolution achieved when increasing the overall frequency band, resulting in enhanced detection and imaging capabilities. Validation of these techniques has been done at three levels: first using simulations, next by means of measurements in a controlled scenario, and, finally, using a portable setup deployed in a realistic scenario.
PrimPol is a human primase/polymerase specialized in re-starting stalled forks by repriming beyond lesions such as pyrimidine dimers, and replication-perturbing structures including G-quadruplexes ...and R-loops. Unlike most conventional primases, PrimPol proficiently discriminates against ribonucleotides (NTPs), being able to start synthesis using deoxynucleotides (dNTPs), yet the structural basis and physiological implications for this discrimination are not understood. In silico analyses based on the three-dimensional structure of human PrimPol and related enzymes enabled us to predict a single residue, Tyr
, as the main effector of sugar discrimination in human PrimPol and a change of Tyr
to histidine to boost the efficiency of NTP incorporation. We show here that the Y100H mutation profoundly stimulates NTP incorporation by human PrimPol, with an efficiency similar to that for dNTP incorporation during both primase and polymerase reactions in vitro. As expected from the higher cellular concentration of NTPs relative to dNTPs, Y100H expression in mouse embryonic fibroblasts and U2OS osteosarcoma cells caused enhanced resistance to hydroxyurea, which decreases the dNTP pool levels in S-phase. Remarkably, the Y100H PrimPol mutation has been identified in cancer, suggesting that this mutation could be selected to promote survival at early stages of tumorigenesis, which is characterized by depleted dNTP pools.
This research study analysed the effect of adding fine—fMRA (0.25% and 50%)—and coarse—cMRA (0%, 25% and 50%)—mixed recycled aggregate both individually and simultaneously in the development of ...sustainable recycled concretes that require a lower consumption of natural resources. For this purpose, we first conducted a physical and mechanical characterisation of the new recycled raw materials and then analysed the effect of its addition on fresh and hardened new concretes. The results highlight that the addition of fMRA and/or cMRA does not cause a loss of workability in the new concrete but does increase the amount of entrained air. Regarding compressive strength, we observed that fMRA and/or cMRA cause a maximum increase of +12.4% compared with conventional concrete. Tensile strength increases with the addition of fMRA (between 8.7% and 5.5%) and decreases with the use of either cMRA or fMRA + cMRA (between 4.6% and 7%). The addition of fMRA mitigates the adverse effect that using cMRA has on tensile strength. Regarding watertightness, all designed concretes have a structure that is impermeable to water. Lastly, the results show the feasibility of using these concretes to design elements with a characteristic strength of 25 MPa and that the optimal percentage of fMRA replacement is 25%.
Cassia angustifolia is a species of plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines. Even though there are few ...documented drug–plant interactions, the use of C. angustifolia with different drugs may have additive effects, such as with other laxatives or potassium‐depleting diuretics. Its use also increases peristalsis which, may reduce drug absorption. The combination with digoxin has been associated with an increased risk of digoxin toxicity, probably due to an increase in plasma digoxin concentrations and hypokalaemia. We present a case with supratherapeutic trough concentration of tacrolimus, an immunosuppressive agent, and a herbal product in a liver transplant patient after concomitant intake of tacrolimus and a herbal product based on C. angustifolia, suggesting a possible drug–lant interaction through by P‐glycoprotein. We observed an increase in the patient’s blood concentration 2.8‐fold and the area under the curve at steady state 2.1‐fold. This interaction could be of clinical relevance, given the dose‐dependent side effects of tacrolimus, such as nephrotoxicity, neurotoxicity, hypertension, hyperglycaemia, or electrolyte alterations.
The relationship between homework and academic results has been widely researched. Most of that research has used English-speaking, European or Asian samples, and to date there have been no detailed ...studies into that relationship in Latin America and the Caribbean. The aim of this study is to examine the effect of quantitative homework characteristics on achievement in science. The sample comprised 61,938 students at 2,955 schools in the 15 Latin American countries (plus the Mexican state of New Leon) which participated in the Third Regional Comparative and Explanatory Study (TERCE), carried out by the Latin American Laboratory for Educational Quality (LLECE) in 2013. The mean age was 12.42 years old (±0.94). Within each country, three hierarchical-linear models were applied at two levels: student and school. The individual level considered time spent doing homework and the school level considered the amount and frequency of homework assignment. In addition, ten control variables were included in order to control the net effect of the characteristics of the homework on the result. The results confirmed that homework is widely assigned in the Latin American region. At the individual level, time spent on homework had little effect on academic performance, while in the quantitative homework characteristics it was the frequency of homework assignment which demonstrated a clearer effect rather than the amount of homework assigned.
The GAUDI study assessed safety and preliminary efficacy of induction therapy with obinutuzumab plus chemotherapy, followed by maintenance therapy with obinutuzumab alone, in previously untreated ...patients with follicular lymphoma. Assignment to chemotherapy was decided on a per-center basis before the patients' enrollment. Patients (n=81) received four to six cycles of obinutuzumab plus bendamustine every 4 weeks or six to eight cycles of obinutuzumab plus CHOP every 3 weeks. Patients with an end-of-treatment response were eligible for obinutuzumab maintenance therapy every 3 months for 2 years or until disease progression. Induction treatment was completed by 90% of patients in the obinutuzumab plus bendamustine group and 95% in the obinutuzumab plus CHOP group, while maintenance was completed by 81% and 72% of patients, respectively. All patients experienced at least one adverse event during induction, most commonly infusion-related reactions (58%), the majority of which were grade 1/2. The most common hematologic adverse event was grade 3/4 neutropenia (36% during induction and 7% during maintenance). One treatment-related death occurred during the maintenance phase. At the end of induction, 94% of patients had achieved an overall response, with complete response based on computed tomography in 36%. The progression-free survival rate at 36 months was 90% in the obinutuzumab plus bendamustine group and 84% in the obinutuzumab plus CHOP group. These results demonstrate that induction therapy with obinutuzumab plus bendamustine or obinutuzumab plus CHOP, followed by obinutuzumab maintenance, is associated with tolerable safety and promising efficacy. This study is registered at ClinicalTrials.gov as NCT00825149.
This review covers articles published in the period from 2010 to mid-2022 on synthetic advances in the formation of pyrimidine and related heterocyclic compounds. Special emphasis has been given to ...the different types of cycloadditions, taking into account the number of their components and leading to the formation of the pyrimidine ring. Due to the large number of publications on the Biginelli reaction and related reactions, this will be dealt with in a separate review in the near future.
Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, ...clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.
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