Mutation Patterns of 16 Genes in Primary and Secondary Acute Myeloid Leukemia (AML) with Normal Cytogenetics

Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML.     

Weather effect on widely distributed seabirds through migration flyways: a case study with the Northern Gannet Morus bassanus in the Bay of Biscay

Capsule: Northern Gannet Morus bassanus counts obtained from a coastal monitoring network in northern Spain were highly determined by wind conditions.

Aims: To determine how external factors including weather conditions affect seabird counts in a land-based seabird monitoring project (Red de observación de Aves y Mamíferos marinos, RAM project; Seabird & Marine Mammal Observation Network).

Methods: Seabird counts were obtained from four study capes situated in the southeastern part of the Bay of Biscay in northern Spain. Counts were conducted on a monthly-basis for a period of 3 hours starting at dawn on each sampling day. Data used here were compiled over a 10-year period (2006–15).

Results: Northern Gannet numbers were chiefly influenced by meteorological conditions at a local spatial scale. Northwesterly winds were found to positively influence gannet abundance, whereas high relative humidity caused a decrease in abundance. Moreover, gannets were more abundant during the non-breeding period as compared to breeding period.

Conclusion: We recommend considering the effect of the wind and relative humidity on land-based seabird counts in the Bay of Biscay when handling data from the RAM protocol in order to avoid biases and misinterpretation of data. Since seabirds approach the coast during harsh weather conditions, the RAM protocol should be improved in order to better account for the distance at which the birds are seen.     

Food availability as a potential source of bias in the egg production method for copepods

The measurement of copepod adult female fecundity as an estimateof adult growth (production) rates has been an approach widelyused in both laboratory and field studies. Here we demonstratethat the basic assumption of this approach, i.e. that estimatedegg production during the incubation reflects the ‘insitu’ conditions, is not always legitimate and that itis temperature dependent. The enhancement of metabolic ratesinduced by high temperatures induces a more accented bias ofthe method. We also provide guidelines on how to conduct theincubations in order to obtain more reliable estimates.     

Sea-level dynamics and palaeoecological factors affecting trace fossil distribution in Eocene turbiditic deposits (Gorrondatxe section,N Spain)

Ichnological analysis of the upper Ypresian–lower Lutetian interval at the Gorrondatxe section (W Pyrenees, N Spain), reveals a relationship between sea-level dynamics and the eco-sedimentary factors influencing trace fossil assemblages. The 600 m thick section of deep-sea turbiditic deposits contains 41 ichnospecies belonging to 28 ichnogenera, which are typical of the Nereites ichnofacies, and mostly of the Paleodictyon ichnosubfacies, suggesting deposition in a basin plain to fan-fringe setting. The trace fossil diversity and abundance fluctuate, irrespective of turbidite frequency. These ichnological features are strongly affected by trophic level changes related partly to sea-level dynamics according to the sequence stratigraphic interpretations for the studied section. Temperature, oxygenation and substrate changes are also considered as relevant factors. Increased ichnodiversity, particularly among graphoglyptids, coincides with moderate oligotrophy and stable ecological conditions. Eutrophisation, lowered oxygenation and drop of temperature, typical of low sea level, can reduce ichnodiversity.     

Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human Stroke

Background

The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans.

Methodology/Principal Findings

Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes.

Conclusions/Significance

In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.     

Comparative population structure, abundance and vertical distribution of six copepod species in the North Atlantic: Evidence for intraguild predation?

The abundance, vertical distribution and stage composition of the copepods Euchaeta norvegica, Metridia lucens and Pleuromamma robusta and the abundance and vertical distribution of Acartia sp., Oithona spp. and Oncaea sp. were analysed for a period of 4.5 years (1971-1974), based on data previously collected at weather station India in the North Atlantic (59°N, 19°W). The results were compared with previously published results on Calanus finmarchicus during the same study. The factor analysis showed two well-differentiated groups. The cohort development and abundance of C. finmarchicus, E. norvegica and Oncaea were related to successive phytoplankton blooms. On the contrary, the cohort development and abundance of M. lucens, P. robusta, Acartia spp. and Oithona spp. were not related to phytoplankton concentration and showed negative relationships with Calanus abundance. We suggest that C. finmarchicus, which largely dominates the biomass at station India, could play a key role in the structuring of the community: as prey for the carnivorous E. norvegica, vectoring the spring bloom to deep waters through faecal pellet consumption by the coprophagous Oncaea spp., and through intraguild predation on the early stages of other omnivorous copepods such as Acartia, Oithona, M. lucens and P. robusta.     

Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. Although it is well known that CML cells are genetically unstable, the mechanisms accounting for this genomic instability are still poorly understood. Because the Fanconi anemia (FA) pathway is believed to control several mechanisms of DNA repair, we investigated whether this pathway was disrupted in CML cells. Our data show that CML cells have a defective capacity to generate FANCD2 nuclear foci, either in dividing cells or after DNA damage. Similarly, human cord blood CD34(+) cells transduced with BCR/ABL retroviral vectors showed impaired FANCD2 foci formation, whereas FANCD2 monoubiquitination in these cells was unaffected. Soon after the transduction of CD34(+) cells with BCR/ABL retroviral vectors a high proportion of cells with supernumerary centrosomes was observed. Similarly, BCR/ABL induced a high proportion of chromosomal abnormalities, while mediated a cell survival advantage after exposure to DNA cross-linking agents. Significantly, both the impaired formation of FANCD2 nuclear foci, and also the predisposition of BCR/ABL cells to develop centrosomal and chromosomal aberrations were reverted by the ectopic expression of BRCA1. Taken together, our data show for the first time a disruption of the FA/BRCA pathway in BCR/ABL cells, suggesting that this defective pathway should play an important role in the genomic instability of CML by the co-occurrence of centrosomal amplification and DNA repair deficiencies.     

Microglial immune response is impaired against the neurotropic fungus Lomentospora prolificans

Lomentospora (Scedosporium) prolificans is an opportunistic pathogen capable of causing invasive infections in immunocompromised patients. The fungus is able to disseminate via the bloodstream finally arriving at the central nervous system producing neurological symptoms and, in many cases, patient death. In this context, microglial cells, which are the resident immune cells in the central nervous system, may play an important role in these infections. However, this aspect of anti‐L. prolificans immunity has been poorly researched to date. Thus, the interactions and activity of microglial cells against L. prolificans were analysed, and the results show that there was a remarkable impairment in their performance regarding phagocytosis, the development of oxidative burst, and in the production of pro‐inflammatory cytokines, compared with macrophages. Interestingly, L. prolificans displays great growth also when challenged with immune cells, even when inside them. We also proved that microglial phagocytosis of the fungus is highly dependent on mannose receptor and especially on dectin‐1. Taken together, these data provide evidence for an impaired microglial response against L. prolificans and contribute to understanding the pathobiology of its neurotropism.