Uptake of novel therapies into first-line treatment for acute myeloid leukemia patients: EU4 + UK perspective.

Aim: To explore the incorporation of novel agents in the first-line setting for acute myeloid leukemia patients. Materials & methods: Observational study based on data from a multi-country cross-sectional retrospective web-based survey sent to 518 physicians in Europe between 2020 and 2021. Information from 2040 patients was analyzed. Results: 604 patients (29.6%) received novel agents in both intensive and non-intensive setting. Comorbidities were not a barrier for the use of novel agents. The presence of tumor mutations was observed to be an important element for treatment decision. Conclusion: There is a progressive incorporation of novel agents for newly diagnosed acute myeloid leukemia patients.

What is this article about? We now have new treatments for patients suffering from a type of blood cancer called acute myeloid leukemia (acronym AML). They are available as the first choice of therapy. In this study we explored how these new treatments are included in daily patient care. What were the results? We reviewed the data of 2040 patients in Europe, obtained from an online survey sent to physicians in two waves (between 2020 and 2021). The use of these new AML treatments was more frequent in patients who presented some specific gene alterations (changes in their DNA sequence) and were in worse health due to other diseases and old age. Most of the new treatments were administered together with other milder chemotherapies. What do the results of the study mean? The results of this study help us understand how new AML treatments are being used.

Genome wide association in Spanish bread wheat landraces identifies six key genomic regions that constitute potential targets for improving grain yield related traits.

KEY MESSAGE: Association mapping conducted in 189 Spanish bread wheat landraces revealed six key genomic regions that constitute stable QTLs for yield and include 15 candidate genes. Genetically diverse landraces provide an ideal population to conduct association analysis. In this study, association mapping was conducted in a collection of 189 Spanish bread wheat landraces whose genomic diversity had been previously assessed. These genomic data were combined with characterization for yield-related traits, including grain size and shape, and phenological traits screened across five seasons. The association analysis revealed a total of 881 significant marker trait associations, involving 434 markers across the genome, that could be grouped in 366 QTLs based on linkage disequilibrium. After accounting for days to heading, we defined 33 high density QTL genomic regions associated to at least four traits. Considering the importance of detecting stable QTLs, 6 regions associated to several grain traits and thousand kernel weight in at least three environments were selected as the most promising ones to harbour targets for breeding. To dissect the genetic cause of the observed associations, we studied the function and in silico expression of the 413 genes located inside these six regions. This identified 15 candidate genes that provide a starting point for future analysis aimed at the identification and validation of wheat yield related genes.

Development and marker-trait relationships of functional markers for glutamine synthetase GS1 and GS2 homoeogenes in bread wheat.

GS1 and GS2 genes encode, respectively, the main cytosolic and the plastidic isoforms of glutamine synthetase (GS). In the present study, the wheat GS1 and GS2 homoeogenes located in the A, B and D genome chromosomes have been sequenced in a group of 15 bread wheat varieties including landraces, old commercial varieties and modern cultivars. Phenotypic characterization by multi-environment field trials detected significant effects of specific GS homoeogenes on three of the seven agronomic and grain quality traits analyzed. Based on the gene sequence polymorphisms found, biallelic molecular markers that could facilitate marker-assisted breeding were developed for genes GS1A, GS2A and GS2D. The remaining genes encoding main wheat GS were excluded because of being monomorphic (GS1D) or too polymorphic (GS1B and GS2B) in the sequencing panel varieties. A collection of 187 Spanish bread wheat landraces was genotyped for these gene-based molecular markers. Data analyses conducted with phenotypic records reported for this germplasm collection in López-Fernández et al. (Plants-Basel 10: 620, 2021) have revealed the beneficial influence of some individual alleles on thousand-kernel weight (TKW), kernels per spike (KS) and grain protein content. Furthermore, genetic interactions between GS1A, a cytosolic GS isoform coding gene, and GS2A or GS2D, plastidic GS enzyme coding genes, were found to affect TKW and KS. The finding that some alleles at one locus may mask the effect of positive alleles at hypostatic GS loci should be kept in mind if gene pyramiding strategies are attempted for the improvement of N-use efficiency-related traits. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-022-01354-0.

Application of Machine Learning to the Prediction of Cancer-Associated Venous Thromboembolism.

Venous thromboembolism (VTE) is a common and impactful complication of cancer. Several clinical prediction rules have been devised to estimate the risk of a thrombotic event in this patient population, however they are associated with limitations. We aimed to develop a predictive model of cancer-associated VTE using machine learning as a means to better integrate all available data, improve prediction accuracy and allow applicability regardless of timing for systemic therapy administration. A retrospective cohort was used to fit and validate the models, consisting of adult patients who had next generation sequencing performed on their solid tumor for the years 2014 to 2019. A deep learning survival model limited to demographic, cancer-specific, laboratory and pharmacological predictors was selected based on results from training data for 23,800 individuals and was evaluated on an internal validation set including 5,951 individuals, yielding a time-dependent concordance index of 0.72 (95% CI = 0.70-0.74) for the first 6 months of observation. Adapted models also performed well overall compared to the Khorana Score (KS) in two external cohorts of individuals starting systemic therapy; in an external validation set of 1,250 patients, the C-index was 0.71 (95% CI = 0.65-0.77) for the deep learning model vs 0.66 (95% CI = 0.59-0.72) for the KS and in a smaller external cohort of 358 patients the C-index was 0.59 (95% CI = 0.50-0.69) for the deep learning model vs 0.56 (95% CI = 0.48-0.64) for the KS. The proportions of patients accurately reclassified by the deep learning model were 25% and 26% respectively. In this large cohort of patients with a broad range of solid malignancies and at different phases of systemic therapy, the use of deep learning resulted in improved accuracy for VTE incidence predictions. Additional studies are needed to further assess the validity of this model.

Exploring the End-Use Quality Potential of a Collection of Spanish Bread Wheat Landraces.

Modern plant-breeding practices have narrowed the genetic base of wheat, such that there is a need to introduce new germplasms with underexploited diversity into breeding programs. Wheat landraces are a very valuable resource when searching for genetic variation, which not only possess increased adaptability, but also quality-related traits. Several studies have shown a wide genetic diversity in Spanish wheat landraces compared to other germplasm collections; therefore, the main objective of this study is to analyze the variability in a collection of 189 landraces from the Spanish National Plant Genetic Resources Centre (Centro de Recursos Fitogenéticos, CRF-INIA, Alcalá de Henares), in relation to end-use quality traits. We characterized the whole collection for high-molecular-weight glutenin and puroindoline allelic composition, and for gluten strength. In addition, grain protein content, grains per spike, and thousand kernel weight were evaluated in samples from four-year field trials. The relationship between glutenin composition and quality was evaluated, and some alleles strongly associated with high quality were identified in the collection, some of them specific for Iberian landraces. The results also show the presence of novel variability within high-molecular-weight glutenin and puroindolines, which needs to be characterized further in order to assess its influence on wheat quality. In addition, a set of landraces showing outstanding values for gluten quality and a good agronomic performance was selected for testing in field trials in order to evaluate the suitability of their direct use in cropping systems.

Genomic analysis of Spanish wheat landraces reveals their variability and potential for breeding.

BACKGROUND: One of the main goals of the plant breeding in the twenty-first century is the development of crop cultivars that can maintain current yields in unfavorable environments. Landraces that have been grown under varying local conditions include genetic diversity that will be essential to achieve this objective. The Center of Plant Genetic Resources of the Spanish Institute for Agriculture Research maintains a broad collection of wheat landraces. These accessions, which are locally adapted to diverse eco-climatic conditions, represent highly valuable materials for breeding. However, their efficient use requires an exhaustive genetic characterization. The overall aim of this study was to assess the diversity and population structure of a selected set of 380 Spanish landraces and 52 reference varieties of bread and durum wheat by high-throughput genotyping. RESULTS: The DArTseq GBS approach generated 10 K SNPs and 40 K high-quality DArT markers, which were located against the currently available bread and durum wheat reference genomes. The markers with known locations were distributed across all chromosomes with relatively well-balanced genome-wide coverage. The genetic analysis showed that the Spanish wheat landraces were clustered in different groups, thus representing genetic pools providing a range of allelic variation. The subspecies had a major impact on the population structure of the durum wheat landraces, with three distinct clusters that corresponded to subsp. durum, turgidum and dicoccon being identified. The population structure of bread wheat landraces was mainly biased by geographic origin. CONCLUSIONS: The results showed broader genetic diversity in the landraces compared to a reference set that included commercial varieties, and higher divergence between the landraces and the reference set in durum wheat than in bread wheat. The analyses revealed genomic regions whose patterns of variation were markedly different in the landraces and reference varieties, indicating loci that have been under selection during crop improvement, which could help to target breeding efforts. The results obtained from this work will provide a basis for future genome-wide association studies.

Osteotomy as a treatment option in dysplasia epiphyseal hemimelica of the distal radius: a case report.

Dysplasia epiphysialis hemimelica (DEH), also known as Trevor disease, is a very rare disease characterized by an overgrowth of the osteocartilaginous epiphyseal caused by unknown factors. The medial side of the epiphysis is affected twice as often as the lateral side and more than one epiphysis was affected in two-thirds of the cases. Only a few cases of DEH in the upper extremities have been published, as the lower limb is usually the most affected, especially in the bones of the ankle joint. The symptoms vary from little significant deformities to symptomatic cases, pain, and decreased function depending on the location and the size of the lesion. When surgery is indicated, the complete excision of the lesion is the procedure of choice. If this is not possible, because of the location or size of the lesion, a realignment osteotomy may be necessary. We report the case of a 12-year-old patient with a distal epiphysis DEH on the left radius, treated by wedge osteotomy realignment at the level of the lesion with Kirschner wires. The clinical outcome of realignment osteotomy of the radial epiphysis has been the correction of the deformity with a normal and painless function of the wrist and hand. The case reported was an extremely rare location in the distal radial epiphysis of DEH. We are aware of only one case published previously with involvement of the distal radius in children. The surgical treatment of realignment osteotomy without complete removal of the lesion has enabled anatomical and functional improvement of the joint as well as a reduction in lesion size. LEVEL OF EVIDENCE: Level IV case report.

Genetic Diversity and Association Mapping for Agromorphological and Grain Quality Traits of a Structured Collection of Durum Wheat Landraces Including subsp. durum, turgidum and diccocon.

Association mapping was performed for 18 agromorphological and grain quality traits in a set of 183 Spanish landraces, including subspecies durum, turgidum and dicoccon, genotyped with 749 DArT (Diversity Array Technology) markers. Large genetic and phenotypic variability was detected, being the level of diversity among the chromosomes and genomes heterogeneous, and sometimes complementary, among subspecies. Overall, 356 were monomorphic in at least one subspecies, mainly in dicoccon, and some of them coincidental between subspecies, especially between turgidum and dicoccon. Several of those fixed markers were associated to plant responses to environmental stresses or linked to genes subjected to selection during tetraploid wheat domestication process. A total of 85 stable MTAs (marker-trait associations) have been identified for the agromorphological and quality parameters, some of them common among subspecies and others subspecies-specific. For all the traits, we have found MTAs explaining more than 10% of the phenotypic variation in any of the three subspecies. The number of MTAs on the B genome exceeded that on the A genome in subsp. durum, equalled in turgidum and was below in dicoccon. The validation of several adaptive and quality trait MTAs by combining the association mapping with an analysis of the signature of selection, identifying the putative gene function of the marker, or by coincidences with previous reports, showed that our approach was successful for the detection of MTAs and the high potential of the collection to identify marker-trait associations. Novel MTAs not previously reported, some of them subspecies specific, have been described and provide new information about the genetic control of complex traits.

Distribution and growth of Vibrio parahaemolyticus in southern Chilean clams (Venus antiqua) and blue mussels (Mytilus chilensis).

We evaluated the distribution and growth of Vibrio parahaemolyticus in the inland sea of southern Chile, where the world's largest foodborne gastroenteritis outbreak by the pandemic strain O3:K6 occurred in 2005. Intertidal samples of Mytilus chilensis and Venus antiqua were collected around port towns between 41°28'S and 43°07'S, during April to May 2011 and January to March 2012. We used most probable number real-time polymerase chain reaction (MPN-PCR) for enumeration of the tlh, tdh, and trh genes in freshly harvested bivalves and after a controlled postharvest temperature abuse. Pathogenic markers (tdh+ or trh+) were not detected. Total V. parahaemolyticus (tlh+) in freshly harvested samples reached up to 0.38 and 3.66 log MPN/g in 2011 and 2012, respectively, with values close to or above 3 log MPN/g only near Puerto Montt (41°28'S, 72°55'W). Enrichments by temperature abuse (>2 log MPN/g) occurred mainly in the same zone, regardless of the year, suggesting that both natural or anthropogenic exposure to high temperatures were more critical. Lower salinity and higher sea surface temperature in Reloncaví Sound and Reloncaví Estuary were consistent with our observations and allowed confirmation of the existence of a high-risk zone near Puerto Montt. Based on the results, a strategy focused on risk management inside this defined hazard zone is recommended.

Factores pronósticos en la leucemia linfocítica crónica / Prognostic factors in chronic lymphocytic leukemia

La leucemia linfocítica crónica (LLC) es una hemopatía maligna heterogénea, en parte por las características genéticas de sus células. Si bien los sistemas de Binet y Rai continúan siendo los índices más utilizados para establecer el pronóstico, no predicen el curso individual en estadios iniciales. En este sentido, los nuevos factores pronósticos bioquímicos, la generalización del uso de las técnicas de hibridación in situ fluorescente (FISH), la determinación del estado mutacional del gen VH y la expresión de CD38 y ZAP-70, entre otros, han producido un gran avance en el estudio de los factores pronósticos. Las alteraciones citogenéticas estudiadas mediante FISH identifican grupos con pronóstico favorable (13q- y citogenética normal) y desfavorable (11q- y 17p-) y el estudio de las mutaciones somáticas de VH ponen de manifiesto que los pacientes con patrón no mutado presentan características clínico citogenéticas y pronósticas desfavorables, con una buena correlación con la expresión de ZAP-70 y una mayor tendencia a citogenéticas de mal pronóstico. Aun así, la importancia clínica de estas alteraciones presenta algunas controversias y quedan por definir aspectos pronósticos de algunas alteraciones citogenéticas menos frecuentes. En los últimos años, el estudio de nuevos marcadores moleculares así como la secuenciación del genoma de la LLC y los avances en la bioinformática y robótica han producido una revolución en el estudio de esta enfermedad...