RCAAP Repository

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.

The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials.

Retracing pathways of historical species introductions is fundamental to understanding the factors involved in the successful colonization and spread, centuries after a species’ establishment in an introduced range. Numerous plants have been introduced to regions outside their native ranges both intentionally and accidentally by European voyagers and early colonists making transoceanic journeys; however, records are scarce to document this. We use genotyping-by-sequencing and genotype-likelihood methods on the selfing, global weed, Plantago major, collected from 50 populations worldwide to investigate how patterns of genomic diversity are distributed among populations of this global weed. Although genomic differentiation among populations is found to be low, we identify six unique genotype groups showing very little sign of admixture and low degree of outcrossing among them. We show that genotype groups are latitudinally restricted, and that more than one successful genotype colonized and spread into the introduced ranges. With the exception of New Zealand, only one genotype group is present in the Southern Hemisphere. Three of the most prevalent genotypes present in the native Eurasian range gave rise to introduced populations in the Americas, Africa, Australia, and New Zealand, which could lend support to the hypothesis that P. major was unknowlingly dispersed by early European colonists. Dispersal of multiple successful genotypes is a likely reason for success. Genomic signatures and phylogeographic methods can provide new perspectives on the drivers behind the historic introductions and the successful colonization of introduced species, contributing to our understanding of the role of genomic variation for successful establishment of introduced taxa.

Até ao momento, vários estudos sugerem uma relação entre os níveis de ferro, a sua regulação, a patogénese e a gravidade da asma. No entanto, não foi possível estabelecer ainda, com significância, uma relação de causalidade entre a homeostasia do ferro e o seu papel na fisiopatologia da asma, podendo a alteração dos níveis de ferro ser uma consequência da inflamação crónica inerente à própria doença. O objetivo deste estudo foi avaliar a existência de uma correlação entre a asma grave e a anemia ferropénica. Foi efetuado um estudo clínico observacional retrospetivo, com base em dados de doentes com diagnóstico de asma grave seguidos no Serviço de Imunoalergologia do Centro Hospitalar Universitário Lisboa Norte até 2019, avaliando-se parâmetros laboratoriais, como hemograma e estudo do metabolismo do ferro. Foram igualmente recolhidos dados referentes a variáveis demográficas, tratamento com corticoterapia sistémica e resultados de questionários de avaliação do controlo da asma (ACT e CARAT). Dos 79 doentes com asma grave seguidos no Serviço de Imunoalergologia do Centro Hospitalar Universitário Lisboa Norte e com estudo do metabolismo do ferro, 2 doentes tinham ferropénia absoluta sem anemia (2,53%), 16 doentes tinham anemia (20,3%), dos quais apenas 7 tinham anemia ferropénica (8,9%). Segundo um estudo publicado em 2016, a prevalência de anemia em Portugal foi de 19,9%, sendo a prevalência de anemia ferropénica variável entre 5,8% e 18,4%, dependendo do valor de referência de ferritina utilizado. Concluindo, não foi possível estabelecer uma relação significativa de causalidade entre a asma grave e a anemia, sendo ela ferropénica ou de outra etiologia. Analisando os resultados deste estudo, pode ser colocada a hipótese do mau controlo da asma grave favorecer o desenvolvimento de anemia ou anemia ferropénica. Não foi possível, no entanto, inferir se a toma de corticosteroides sistémicos poderá favorecer o desenvolvimento de anemia ferropénica.

A leucoencefalopatia multifocal progressiva (LEMP) é uma doença desmielinizante do sistema nervoso central (SNC) caracterizada pela ativação do poliomavírus humano John Cunningham (JCV) em estados de imunossupressão severa, resultando numa apresentação heterogénea de sintomas neurológicos e cognitivos. Apesar de rara na população em geral, apresenta taxas de incidência consideráveis em grupos de risco, com elevada mortalidade e incapacidade progressiva. Apresenta-se o caso de dois doentes com LEMP que desenvolveram síndrome inflamatória de restituição imunológica (SIRI), tendo neste contexto realizado terapia antirretrovírica combinada (TARV) e corticoterapia. Estas medidas demonstram-se benéficas contenção do declínio neurológico e um resultado clínico favorável em termos de sobrevida e limitação funcional. Este trabalho reforça a importância do diagnóstico precoce e do follow-up de grupos de risco, levantando novas questões em relação à ação adjuvante da corticoterapia e ao papel da SIRI no desfecho clínico. Ao longo deste trabalho é efetuada uma revisão da literatura da LEMP e de JCV, procurando expor o enquadramento histórico e epidemiológico, a apresentação clínica, assim como, analisar as abordagens diagnósticas e terapêuticas.

A infeção por vírus da hepatite B tem uma grande prevalência a nível mundial, constituindo um importante problema de saúde pública. Em doentes com infeção crónica ou oculta, a reativação de vírus da hepatite B resultante do tratamento com fármacos imunossupressores e biológicos é uma causa de morbilidade e mortalidade. O objetivo principal desta dissertação é compreender os vários mecanismos associados à reativação de vírus da hepatite B e estratificar o risco consoante a classe farmacológica e a profilaxia. Para tal, procedeu-se a uma revisão da literatura científica publicada. Relativamente à reativação, devem considerar-se dois grupos de doentes, consoante os marcadores serológicos: antigénio HBs positivo ou antigénio HBs negativo e anticorpo anti-HBc positivo. Consoante a serologia e o tipo de terapêutica realizada, é possível determinar o risco de reativação, sendo este superior, se o antigénio HBs for positivo. O algoritmo de monitorização e profilaxia dependerá, tanto do tipo de doente, como do risco de reativação. Em todos os casos de risco elevado, deverá proceder-se à profilaxia antivírica com entecavir ou tenofovir. A profilaxia tem um papel preponderante, diminuindo a incidência da reativação e a severidade da hepatite. Numa situação de hepatite grave, torna-se necessário suspender a terapêutica imunossupressora. Com a emergência de novas terapêuticas biológicas e a ausência de relatos de reativação, é fundamental compreender os seus mecanismos de ação e a probabilidade de sua ocorrência, de modo a realizar-se uma profilaxia ou monitorização eficazes. Há que consciencializar as várias especialidades médicas acerca da reativação e das suas consequências e evitar a suspensão de terapêuticas que são essenciais para a situação médica do doente.

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CONTEXTUALIZAÇÃO: a pupila tem ganho importância na Oftalmologia desde a introdução da cirurgia refrativa e pseudofáquica. A sua avaliação pré-operatória é importante, uma vez que esta estrutura pode condicionar os resultados pós cirúrgicos. OBJETIVOS: fazer uma revisão da literatura acerca dos modelos esquemáticos do olho e o papel da pupila nestes, bem como das características da mesma e as dificuldades na sua medição. Será depois analisada e caracterizada a sua biometria (diâmetro e descentramento), a relação entre si e com o lado da órbita, diâmetro do limbus (WTW) e profundidade da câmara anterior (ACD) na população do Hospital da Luz Lisboa. Os resultados foram comparados com a literatura. RESULTADOS: o diâmetro pupilar (PD) médio foi de 4.109 ± 0.532mm, e a diferença entre olhos direitos e esquerdos foi significativa (p=0.005). ACD e WTW não estavam correlacionados com o PD (Pearson coefficient de 0.06 e 0.087). O descentramento pupilar horizontal (PCX) era de 0.259 ± 0.165mm, o vertical (PCY) de -0.010 ± 0.153mm, e o descentramento absoluto de 0.312 ± 0.144. O PCX e o descentramento absoluto correlacionavam-se com o PD (Pearson coefficient de 0.183 e de 0.174, respectivamente, e p<0.001). CONCLUSÃO: apesar de a pupila não ser contemplada na maioria dos modelos esquemáticos revistos, tem um papel significativo na qualidade de visão. Os resultados mostram valores genericamente similares à literatura, com algumas diferenças e limitações. Condições estandardizadas para pupilometria deviam ser propostas, e a possibilidade da existência de variabilidade inter-populacional dos parâmetros deveria ser testada.

Introduction: Assessment of SARS-CoV-2 seroprevalence may detect the real spread of the virus because antibody data can provide a long-lasting measure of infection. Existing serological studies in Portugal have tested new serology methods, albeit with small sample sizes and a lack the focus on geographical regions with a high rate of infection cases. The aim of this study was to estimate the serological prevalence of SARS-CoV-2 in Vila Nova de Gaia, the most populous municipality in the north of Portugal and one of those most affected during the first pandemic wave. Material and Methods: A cross-sectional observational study was conducted between June 23rd and July 17th, 2020. Included in the cohort were 18- to 74-year-old men and women living in the municipality of Vila Nova de Gaia, who were sampled through a nonprobabilistic quota-based approach. Cases with a previous RT-PCR diagnosis of COVID-19 were excluded. Sociodemographic and clinical information was collected using a self-administered, written questionnaire. Blood samples were collected for serological laboratory analysis to detect and quantify SARS-CoV-2 anti-IgG antibodies. Results: We tested 2754 participants. Our results show a SARS-CoV-2 seroprevalence of 3.03% (95% confidence interval: 2.37% – 3.87%). Being a smoker (odds ratio: 0.382, 95% confidence interval: 0.147 – 0.99) and having symptoms of COVID-19 (odds ratio: 2.480, 95% confidence interval: 1.360 – 4.522) were consistently associated with lower and higher odds of SARS-CoV-2 antibody presence, respectively, regardless of the analytic design. Moreover, without adjusting for any variables, having had contact with an infected person within the household was associated with increased odds of a positive test (odds ratio: 9.684, 95% confidence interval: 4.06 – 23.101); after adjusting, having self-reported chronic diseases (odds ratio: 0.448, 95% confidence interval: 0.213 – 0.941) was associated with decreased odds. Conclusion: This was the first study to estimate the serological prevalence of SARS-CoV-2 in one of the most populous municipalities in Portugal, representing the first step in the development of an epidemiological surveillance system in Portugal, which can help to improve the diagnosis of COVID-19.

O ácido hipocloroso (HOCl) é um oxidante forte produzido por neutrófilos e monócitos activados. Esta espécie reactiva de oxigénio (ROS) é gerada a partir da reacção do H2O2 com o Cl‒, catalisada pelo mieloperoxidase (MPO). Embora a formação de HOCl tenha como finalidade matar os microrganismos invasores dentro do fagossoma, pode ser libertado para fora da célula e levar à lesao dos tecidos, contribuindo para o processo inflamatório. O principal objectivo deste trabalho foi estudar as propriedades anti-inflamatórias de alguns flavonóides (quercetina, morina, apigenina e catequina), em relação à captação de HOCl, gerado por neutrófilos activados ex vivo, bem como os seus efeitos na activação do factor de transcrição NF-κB. Em relação à captação de HOCl, para cada flavonóide obtiveram-se diferentes valores de IC50, determinados através de diferentes métodos de competição: cloração da taurina e oxidação da sonda 3-aminofenilfluoresceína (APF), que foi seguida por espectrofluorimetria e citometria de fluxo. A quercetina e a morina apresentaram uma elevada actividade antioxidante com valores de IC50 semelhantes, uma vez que são compostos análogos e possuem as características estruturais que são determinantes para proteger as reacções de cloração/oxidação mediadas pelo HOCl. A apigenina, apesar de não possuir algumas dessas características estruturais, demonstrou possuir uma elevada capacidade antioxidante, devido à maior hidrofobicidade deste composto, quando comparado com a quercetina e a morina. Estudou-se, também, a capacidade dos flavonóides para induzir alterações na activação do NF-κB em células THP-1 activadas por LPS, usando duas abordagens diferentes. Quando as células foram transfectadas com um plasmídeo acoplado ao gene repórter da luciferase, que continha uma sequência kB de elevada afinidade para o NF-kB, e após activação com LPS, observou-se uma elevada activação do promotor do NF-kB. Na presença de alguns flavonóides (morina, apigenina, catequina e isorramnetina) observou-se uma diminuição na activação do promotor do NF-kB. Através da análise dos extractos celulares, por Western blot, também, se observou que a quercetina e a morina inibiam a activação do NF-kB. Esta resposta foi reflectida em termos da translocação do NF-κB para o núcleo e na inibição da degradação da proteína inibitória do NF-κB (IκB). Estes resultados sugerem que os flavonóides estudados podem exercer efeitos antiinflamatórios, através da captação de HOCl e, alguns deles, através da inibição do NF-kB.

Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.

Contemporary sculpture, as a form of public art, has been a protagonist in urban regeneration and requalification projects, playing an active role in the experience provided by cities to their inhabitants, since the latter half of the 20th century. The new relationship established between sculpture and urban space, together with the recognition of its particularities as important aspects that contaminate and inform artistic production, has been gradually shaping a new cultural and aesthetic context within which we fit sculpture parks. In this dissertation, we intend not only to frame the emergence of the first sculpture parks located in public space, but also to reflect on the main characteristics of these exhibitional structures and the challenges they pose for both programmers and curators, during the process of planning, implementation and maintenance; and for artists, throughout the sculpture design process. Along with a reflection on the key concepts that structure the investigation, we developed a critical analysis of three portuguese sculpture parks - the International Museum of Contemporary Sculpture of Santo Tirso, the International Sculpture Park of Carrazeda de Ansiães and the Contemporary Sculpture Park from Vila Nova da Barquinha –, revisiting the history of their creation and ruminating on the impact they have on the urban centers in which they are located. Consequently, six sculptures that are integrated within these parks were selected to be objects of a deeper analysis in order to clarify the way in which these works are born and projected within the places they are inserted - unraveling the dialogue established between them, on a physical and symbolic level - and determining to what extent they exist as participating entities in their daily life, promoting the construction of new narratives and interpretations about the city space.

Introduction: About one-third of patients with epilepsy have a refractory form which is associated with important economic and psychosocial burden. Most of these patients also suffer from comorbidities. One of the most frequent is cognitive impairment. Resective surgery or neuromodulation techniques may improve seizure control. Several factors have been proposed as potential predictors of the success of surgery regarding seizure frequency. We aimed to study preoperative cognitive performance as a predictor of the epilepsy surgery outcome. Methods: In this ambispective study we studied total intelligence quotients (IQ) measured before surgery with the Wechsler Adult Intelligence Scale (WAIS) as a potential predictor of Engel Class at 1 year after surgery. Then we included IQ in a multivariate model and tested its performance. Results: Preoperative IQ was a significant and independent predictor of the Engel Class at 1 year after surgery (OR 0.94; CI 0.90-0.98; p = 0.007). The multivariate model including the age at epilepsy onset, education level, sex, and the type of surgery (resective versus palliative surgery) showed an area under the ROC curve of 0.85. Conclusions: A low intelligence level may constitute a marker of worse prognosis after epilepsy surgery. However, other predictors should also be considered when evaluating surgical candidates.

The congeneric freshwater fish Squalius carolitertii and S. torgalensis inhabit different Iberian regions with distinct climates; Atlantic in the North and Mediterranean in the South, respectively. While northern regions present mild temperatures, fish in southern regions often experience harsh temperatures and droughts. Previous work with two hsp70 genes suggested that S. torgalensis is better adapted to harsher thermal conditions than S. carolitertii as a result of the different environmental conditions. We present a transcriptomic characterisation of these species' thermal stress responses. Through differential gene expression analysis of the recently available transcriptomes of these two endemic fish species, comprising 12 RNA-seq libraries from three tissues (skeletal muscle, liver and fins) of fish exposed to control (18 °C) and test (30 °C) conditions, we intend to lay the foundations for further studies on the effects of temperature given predicted climate changes. Results showed that S. carolitertii had more upregulated genes, many of which are involved in transcription regulation, whereas S. torgalensis had more downregulated genes, particularly those responsible for cell division and growth. However, both species displayed increased gene expression of many hsps genes, suggesting that they are able to deal with protein damage caused by heat, though with a greater response in S. torgalensis. Together, our results suggest that S. torgalensis may have an energy saving strategy during short periods of high temperatures, re-allocating resources from growth to stress response mechanisms. In contrast, S. carolitertii regulates its metabolism by increasing the expression of genes involved in transcription and promoting the stress response, probably to maintain homoeostasis. Additionally, we indicate a set of potential target genes for further studies that may be particularly suited to monitoring the responses of Cyprinidae to changing temperatures, particularly for species living in similar conditions in the Mediterranean Peninsulas.

Despite great efforts to enhance European epidemiological surveillance on carbapenemase-producing Enterobacteriaceae (CPE), information from several countries remains scarce. To address CPE epidemiology in Portugal, we have undertaken a retrospective cohort study of adults with CPE cultures identified in the microbiology laboratory of a tertiary hospital, in 2012. Sixty patients from 25 wards or intensive care units were identified. This is, to the best of our knowledge, the first report of clinical data on CPE in Portugal. It shows a hospital-wide CPE dissemination and alerts us to an evolving epidemiological situation not previously described.

There are multiple stages in the life cycle of Plasmodium that invade host cells. Molecular machinery involved is such host-pathogen interactions constitute excellent drug targets and/or vaccine candidates. A screen using a phage display library has previously demonstrated presence of enolase on the surface of the Plasmodium ookinete. Phage-displayed peptides that bound to the ookinete contained a conserved motif (PWWP) in their sequence. Here, direct binding of these peptides with recombinant Plasmodium falciparum enolase (rPfeno) was investigated. These peptides showed specific binding to rPfeno, but failed to bind to other enolases. Plasmodium spp enolases are distinct in having an insert of five amino acids ((104)EWGWS(108)) that is not found in host enolases. The possibility of this insert being the recognition motif for the PWWP containing peptides was examined, (i) by comparing the binding of the peptides with rPfeno and a deletion variant Δ-rPfeno lacking (104)EWGWS(108), (ii) by measuring the changes in proton chemical shifts of PWWP peptides on binding to different enolases and (iii) by inter-molecular docking experiment to locate the peptide binding site. Results from these studies showed that the pentapeptide insert of Pfeno indeed constitutes the binding site for the PWWP domain containing peptide ligands. Search for sequences homologous to phage displayed peptides among peritrophic matrix proteins resulted in identification of perlecan, laminin, peritrophin and spacran. The possibility of these PWWP domain-containing proteins in the peritrophic matrix of insect gut to interact with ookinete cell surface enolase and facilitate the invasion of mosquito midgut epithelium is discussed.

Global greenhouse gas (GHG) emissions have continued to grow persistently since 1750. The United Nations Framework Convention on Climate Change (UNFCCC) entered into force in 1994 to stabilize GHG emissions. Since then, the increasingly harmful impacts of global climate change and repeated scientific warnings about future risks have not been enough to change the emissions trend and enforce policy actions. This paper synthesizes the climate change challenges and the insofar insufficient mitigation responses via an integrated literature review. The fossil industry, mainstream economic thinking, national rather than international interests, and political strive for short-term interests present key barriers to climate mitigation. A continuation of such trends is reflected in the Dice model, leading to a 3.5 °C temperature increase by 2100. Despite receiving the Nobel Prize for integrating climate change into long-run macroeconomic analysis via the Dice model, increases in global mean temperatures overshooting the 1.5 °C to 2 °C Paris targets imply an intensified disruption in the human–climate system. Past and present policy delays and climate disruption pave the way for solar radiation management (SRM) geoengineering solutions with largely unknown and potentially dangerous side effects. This paper argues against SRM geoengineering and evaluates critical mitigation solutions leading to a decrease in global temperatures without overshooting the Paris targets. The essential drivers and barriers are discussed through a unified approach to tipping points in the human–climate system. The scientific literature presents many economically and technologically viable solutions and the policy and measures required to implement them. The present paper identifies the main barriers to integrating them in a globally cooperative way, presenting an efficient, long-term, and ethical policy approach to climate change.

Long-term global emission scenarios enable the analysis of future climate change, impacts, and response strategies by providing insight into possible future developments and linking these different climate research elements. Such scenarios play a crucial role in the climate change literature informing the Intergovernmental Panel on Climate Change’s (IPCC) Assessment Reports (ARs) and support policymakers. This article reviews the evolution of emission scenarios, since 1990, by focusing on scenario critiques and responses as published in the literature. We focus on the issues raised in the critiques and the possible impact on scenario development. The critique (280) focuses on four areas: 1) key scenario assumptions (40%), 2) the emissions range covered by the scenarios and missing scenarios (25%), 3) methodological issues (24%), and 4) the policy relevance and handling of uncertainty (11%). Scenario critiques have become increasingly influential since 2000. Some areas of critique have decreased or become less prominent (probability, development process, convergence assumptions, and economic metrics). Other areas have become more dominant over time (e.g., policy relevance & implications of scenarios, transparency, Negative Emissions Technologies (NETs) assumptions, missing scenarios). Several changes have been made in developing scenarios and their content that respond to the critique.

Replicative stress (RS) is a cell-intrinsic phenomenon enhanced by oncogenic transformation. Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. Taking this knowledge into account, one would predict CHK1 behaves strictly as a tumor suppressor. However, the reality seems far more complex. CHEK1 loss-of-function mutations have not been found in human tumors, and transgenic expression of Chek1 in mice promotes oncogene-induced transformation through RS inhibition. Moreover, CHK1 is overexpressed in various human cancers and CHK1 inhibitors have been developed as sensitizers to enhance the cytotoxicity of DNA damage-inducing chemotherapies. Here, we summarize the literature on the involvement of CHK1 in cancer progression, including our recent observation that CHK1 sustains T-cell acute lymphoblastic leukemia (T-ALL) cell viability. We also debate the importance of identifying patients that could benefit the most from treatment with CHK1 inhibitors, taking T-ALL as a model, and propose possible markers of therapeutic response.

Objective: Assistive devices based on keyboard access support communication and control tools for patients with Amyotrophic Lateral Sclerosis (ALS). The aim of this work was to explore movement activity in the use of keyboards and identify markers for upper limb (UL) dysfunction. Methods: We present a longitudinal study including 19 ALS patients, followed for 2-20 months. Typing activity was recorded with an accelerometer placed on the posterior part of patients' index finger. Participants performed the same 10-word typing task (2-6 assessments). Time and acceleration during keystroke were the main outcomes of this study. Patients were compared with 20 healthy subjects and 6 patients with other neuromuscular disorders. Results: During disease progression, mean time in holding down a key increased and was longer than in control subjects. Acceleration at key press and key release decreased with progression of UL dysfunction. Delay between tapping and pressing down each key increased with UL dysfunction. Conclusions: Delay in pressing and releasing keys are markers of UL dysfunction in ALS. The decrease in the acceleration of movements related to keystroke can contribute to monitor disease progression. Significance: Typing activity can be explored to access remotely and continuously to ALS progression by patients who use assistive communication devices.