A Novel BCR-ABL1 Mutation in a Patient with Philadelphia Chromosome-Positive B-Cell Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) represents the most common genetic subtype of adult ALL (20%-30%) and accounts for approximately 50% of all cases in the elderly. It has been considered the subgroup of ALL with the worst outcome. The introduction of tyrosine kinase inhibitors (TKIs) allows complete hematologic remission virtually in all patients, with improved disease-free survival and overall survival. Nevertheless, the emergence of resistant mutations in BCR-ABL1 may require different TKI strategies to overcome the patient's resistance and disease relapse. Here, we report a Ph+B-ALL case with persistent minimal residual disease (MRD) after treatment with dasatinib. The patient expressed the P190BCR-ABL1 isoform and a novel BCR-ABL1 mutation, p.Y440C. The latter is in the C-terminal lobe of the kinase domain, which likely induces deviations in the protein structure and activity and destabilizes its inactive conformation. The treatment was substituted by bosutinib, which binds to the active conformation of the protein, prior to allogeneic bone marrow transplant to overcome the lack of a complete response to dasatinib. These findings strengthen the importance of BCR-ABL1 mutational screening in Ph+ patients, particularly for those who do not achieve complete molecular remission.info:eu-repo/semantics/publishedVersio

Within-Person Variation in Personality and Psychological Well-Being

Personality is one of the most broad and complex areas in psychology. This has led to many researchers attempting to reduce this complexity by focusing solely on how habitual personality differs between each individual (inter-individual differences). This is important to study, but it has been focused on so heavily that research into how each individual personality varies within the person (intra-individual differences) has been neglected in comparison. Recent research has started to examine intra-individual variation in personality more thoroughly. One research aim of this programme was to establish the nature of several different types of within person variability including inter-item variation (variation within the test responses for a personality trait), and cross-contextual variation in personality (variation according to context), to see whether these types of variability are associated with psychological outcomes. Three research questions were examined to this end: 1) What is the extent of meaningful variability in personality trait test responding? 2) What are the predictors of intra-individual variability in personality? 3) What is the relative importance of the person and situational factors in personality variability? The first question was developed to try and determine whether the individual can display meaningful inter-item variation in ratings of specific behaviours within personality trait measures. Trait questionnaires are usually only analysed at the between subject level, and within subject variation in inter-item ratings have not been extensively examined in relation to meaningful psychological outcomes. The second and third questions were developed to look into the nature of cross-contextual personality, and establish whether within person personality differences are influenced more strongly by the person or situation. The studies conducted towards answering these questions demonstrated a person-based capacity to display intra-individual variability. A second aim of the research programme was to see whether the capacity to display these types of variability can be utilised in behaviour change. The fourth research question was developed to try and understand how a person can display intra-individual variability, yet still be resistant to changing negative habits: 4) How do the different aspects in personality variability help explain why some people are resistant to change, especially with regard to behaviours that are bad for them? This question was answered by theoretically discussing the findings from the three previous studies which proposed that positive or problematic behaviour could be interpreted with a simple path to understand the process of behavioural action: The individual receives feedback from a behaviour response which either validates or invalidates their action in the situation context (does or does not receive a desired outcome). Reinforcement of the behaviour happens if it is validated by positive feedback. Alternately reconstruction of the situation happens if the behaviour is invalidated. This allows for two types of intra-individual variability. One is flexibility in behaviour responses to different situations under the individual’s control. The other is change according to the situation, where the behaviour is invalidated and an alternative is attempted. A problematic behaviour may have benefit in stopping something invalidating, but if repeated it may become a habit needed for psychological functioning. As part of the second research aim a behaviour change strategy was developed and piloted to try and bring the individual closer to their construct of the ideal self. Instructions were provided for the individual to experiment with that differed from their disposition. The programmes had varied degrees of success depending on the participant. The implications for personality research and behaviour change are discussed

Riddling : Chimera’s dilemma

We wish to acknowledge the support: Sao Paulo Research Foundation (FAPESP) under Grants 2011/19296-1, 2015/05186-0, 2015/07311-7, 2015/50122-0, and 2017/20920-8, Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq), and Coordena¸cao de Aperfei¸coamento de Pessoal de Nıvel Superior (CAPES).Peer reviewedPublisher PD

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies

Acessível em: www.ncbi.nlm.nih.gov/pmc/articles/PMC4423738/Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition

Acesso a Tratamento Endovascular para Acidente Vascular Cerebral Isquémico em Portugal

Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Discussion: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.info:eu-repo/semantics/publishedVersio

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies

Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue – GLA p.(Arg118Cys) –, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands’ close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease, since the allelic frequency in stroke patients was 0.0087 (p=0.0185 vs the general population). The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for “rare” conditio