In this work we present XMuSer, a multi-relational framework suitable to explore temporal patterns available in multi-relational databases. XMuSer’s main idea consists of exploiting frequent sequence ...mining, using an efficient and direct method to learn temporal patterns in the form of sequences. Grounded on a coding methodology and on the efficiency of sequential miners, we find the most interesting sequential patterns available and then map these findings into a new table, which encodes the multi-relational timed data using sequential patterns. In the last step of our framework, we use an ILP algorithm to learn a theory on the enlarged relational database that consists on the original multi-relational database and the new sequence relation.
We evaluate our framework by addressing three classification problems. Moreover, we map each one of three different types of sequential patterns: frequent sequences, closed sequences or maximal sequences.
Structural activity prediction is one of the most important tasks in chemoinformatics. The goal is to predict a property of interest given structural data on a set of small compounds or drugs. ...Ideally, systems that address this task should not just be accurate, but they should also be able to identify an interpretable discriminative structure which describes the most discriminant structural elements with respect to some target.
The application of ILP in an interactive software for discriminative mining of chemical fragments is presented in this paper. In particular, it is described the coupling of an ILP system with a molecular visualisation software that allows a chemist to graphically control the search for interesting patterns in chemical fragments. Furthermore, we show how structural information, such as rings, functional groups such as carboxyls, amines, methyls, and esters, are integrated and exploited in the search.
The discharge of industrial and domestic wastewater is one of the main causes of contamination of water bodies by heavy metals. Among these heavy metals, nickel (Ni) is one of the most used in ...industrial processes, such as the production of alloys, stainless steel and automotive batteries, as well as electroplating activities, causing high concentrations in the effluents of these industries. Several techniques, such as chemical precipitation and filtration, have been studied in order to promote the removal of these heavy metals from wastewater. However, these techniques are often financially and technically costly. Under this context, adsorption using activated carbons (ACs) appears as an alternative, which is characterized by being an effective and economically viable technique. Citrus fruits, such as tangerine, are of great importance in the Portuguese economic context. In 2017, just over 374.4 thousand tons were produced, with 10% of this volume corresponding to tangerine. This research aimed, therefore, to produce ACs from tangerine peels and use them in the adsorption of nickel from aqueous medium. The ACs were produced in two stages: activation and carbonization. Upon activation, the hydrothermal carbonization process (HTC) was used considering FeCl3 as activating agent under three concentrations (0.5, 1.0 and 2.5 M). Afterwards, the prepared materials were carbonized in a tubular oven at 800 ºC for 4 h. The samples were named as follows: TW-C (pyrolyzed peels without HTC), TW-Fe-0.5-C / TW-Fe-1.0-C / TW-Fe-2.5-C (HTC and pyrolyzed peels) and TW-Fe-2.5 (peels with HTC without pyrolysis). The physico-chemical properties of the ACs, such as elemental analysis, ash content, acidity and basicity, were determined to correlate with their performance. The kinetic and isotherm adsorption of Ni(II) onto the ACs was assessed at the following operating conditions: 2.5 g L-1 of AC, 25 ºC and pH 6 and modelled by the kinetic models of pseudo-first order, pseudo-second order and Elovich, as well as the adsorption isotherms of Langmuir, Freundlich and the General Isotherm Equation (GIE) of Tóth. The materials TW-C showed the best adsorption results and removed 99% of Ni(II) at pH 9. The kinetic models that best described the adsorption process were pseudo-second order (TW-Fe-2.5-C) and Elovich (TW-C). The GIE of Tóth showed the best fit, however, its parameters did not show statistical significance at the 5% confidence level, being rejected. The Freundlich model was able to represent the experimental data with certain precision (R² reached 0.9557 and 0.9785 for TW-C and TW-Fe-2.5-C, respectively) and statistical significance according to the t-test and F-test.
Abstract 121
The genetic landscape of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in children above 10 years and adolescents remains poorly defined. Specifically, more than half of these ...patients have none of the cytogenetic abnormalities that define oncogenic subtypes and underlie risk stratification. To uncover new genetic abnormalities in these unassigned cases, we studied 85 BCP-ALL from patients aged 10 to 17 diagnosed at St-Louis hospital (Paris, France), for which the main classifying genetic lesions were assessed (i.e. high hyperdiploidy, t(12;21)/ETV6-RUNX1, t(1;19)/TCF3-PBX1, t(9;22)/BCR-ABL1, iAMP21, MLL translocations, low hypodiploidy, and near haploidy). Fifty of these BCP-ALL presented no classifying genetic lesions. Paired leukemic and remission samples could be analysed by high density array-CGH (Agilent 1M arrays) in 17 of these unassigned cases. We focused on acquired, focal, and recurrent copy-number abnormalities. A mono-allelic intragenic deletion of the ETS-related Gene (ERG) was found in 3 cases. ERG belongs to the ETS family of transcription factors and is implicated in chromosomal translocations associated with several cancer types including acute myeloid leukemia. The possibility of a cryptic unbalanced translocation was ruled out in the 3 cases by FISH analysis. The deletions encompassed exons 3 to 7, or 3 to 9, and the breakpoints were tightly clustered. Based on the breakpoint sequences we designed a PCR assay that allowed us to screen ERG intragenic deletions in the whole cohort. ERG deletion was identified in 9 additional cases, none of them having any of the known classifying genetic lesions, bringing up to 25% (12 out of 50) the frequency of ERG deletion in unassigned BCP-ALL of children older than 10. These results suggested that ERG deletion characterized a novel oncogenic subtype of BCP-ALL. Of note, these results were consistent with independent data of Harvey et al. (2010) that reported ERG deletions in a distinct gene-expression cluster.
To confirm and extend these findings in the whole population of paediatric BCP-ALL, we used our breakpoint-specific PCR assay to screen ERG deletions in an independent cohort of 822 unselected patients aged 1 to 17, enrolled in the EORTC 58951 trial. ERG deletion was identified in 31/822 (3.7%) patients. Again, none of them had another known classifying genetic lesion, confirming that ERG deletion characterizes a distinct oncogenic subtype. Patients with ERG deletion were significantly older compared to other patients (median 7.0 vs 4.0, p=0.002), but they had similar white blood counts at diagnosis. They had a favourable outcome, with a 8-year event free survival (EFS) of 82.4% and overall survival (OS) of 96.0%, which is similar to EFS of 83.4% and OS of 91.6% obtained for patients having no very high risk initial features (i.e. no t(9;22)/BCR-ABL1, MLL rearrangement or haploidy/low hypodiploidy).
IKZF1 deletion is a cooperative genetic lesion that has been recently shown to be associated with a poor outcome in BCP-ALL. Remarkably, the incidence of IKZF1 deletions in patients with ERG deletion was significantly higher than in other BCR-ABL1-negative patients, especially when considering the IKZF1 intragenic deletion Δ4-7 (10/31, 32.3% vs 34/744, 4.6%, P<0.001), and this regardless of age. Surprisingly, IKZF1 deletion had no impact on the prognosis of ERG deleted patients. Indeed, patients combining ERG and IKZF1 Δ4-7 deletions had a better outcome than other BCR-ABL1-negative patients with IKZF1 deletions (8-year EFS 83.3% vs 53.0%, hazard ratio (HR) 0.19, 95% CI 0.02–1.41; p=0.069).
Altogether, we have identified a novel oncogenic subtype of BCP-ALL characterized by ERG deletion. This subtype is frequently associated with IKZF1 deletions, suggesting a preferred oncogenic cooperation. Importantly, despite having older age and frequent IKZF1 deletions, which are factors usually predictive of a poor prognosis, patients with ERG deletion have a favourable outcome. Therefore, this genetic abnormality may be systematically assessed as part of the diagnostic work-up of BCP-ALL and taken into account when considering treatment stratification.
No relevant conflicts of interest to declare.
Abstract 2477
MLL gene rearrangements are found in more than 70% of the cases of infant leukemia, both acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), but are less frequent in ...leukemia from older children. MLL translocations are also found in approximately 10% of adult AML and in a small proportion of patients with therapy-related leukemia. Independently of their association with other high-risk features at presentation, MLL rearrangements are in most cases predictive of poor clinical outcome. In this study, we report the clinical characterization and frequency and type of MLL rearrangements present in a consecutive series of 45 patients that were diagnosed with acute leukemia in the Portuguese Oncology Institute, Porto, Portugal, over the last 13 years (1998–2011).
Conventional cytogenetic, fluorescence in situ hybridization (FISH), and molecular genetic studies (RT-PCR and LDI-PCR) were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. Additionally, a detailed patient clinical characterization was also performed and statistical analysis using the Kaplan-Meier method as used to evaluate patient survival.
In 43 patients (96% of the cases) we could identify the fusion partner, the most common being the MLLT3, AFF1, MLLT1, MLLT10, ELL, and MLLT4 genes, accounting for 88% of all cases. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloblastic leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype and treatment protocol. However, patients that received a bone marrow transplant had a better survival than patients that received chemotherapy alone. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults.
The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant.
No relevant conflicts of interest to declare.
Abstract 133▪▪This icon denotes a clinically relevant abstract
T-cell acute lymphoblastic leukemia (ALL) accounts for 15% of ALL cases in children and has been associated with a higher risk for ...central nervous system (CNS) relapse and a worse prognosis. In EORTC trials 58831 and 2, standard risk (SR) patients (pts) were not irradiated but received intermediate dose methotrexate (MTX) courses; for medium and high risk pts, high dose (HD) MTX was added to the treatment regimen and the administration of cranial radiotherapy (RT) was randomised. The omission of RT didn't result in an increase of CNS or systemic relapse and consequently, CNS-directed chemotherapy was substituted for RT in all following trials. The long-term outcome of T-ALL pts in the subsequent phase III trials (58881 and 58951) are presented here.
The BFM backbone for ALL treatment was applied to all EORTC-CLG trials since 1983. As CNS treatment in study 58881, SR pts received 4 HD MTX courses (5 g/m2) in interval therapy and 10 IT MTX injections during the intensive treatment phases. Pts with CNS-3 status at diagnosis received 2 additional IT injections during induction, 2 during consolidation and 6 HD MTX courses + IT during maintenance. T-ALL pts with poor prephase response (PPR) at day 8 or who didn’t achieve complete remission (CR) after induction were included in the very high risk (VHR) group. VHR CNS-directed chemotherapy included 10 IT MTX injections, 6 IT triple and 10 HD MTX courses during intensive treatment phases, followed by 4 IT MTX injections during maintenance (the latter for CNS-3 pts only). In the 58951 trial, all T-ALL pts had an intensified induction. The CNS-directed therapy of all average risk T-ALL pts was intensified to 11 HD MTX courses, 1 IT with MTX and 15 triple IT. MRD ≥ 1% at the end of induction was added as VHR criterium. All non-transplanted VHR pts received 1 IT MTX injection, 19 IT triple and 9 HD MTX courses. Several randomized questions were addressed in both trials of which most relevant for T-ALL pts: in study 58881 the comparison E.coli asparaginase (ASP) Medac versus (vs) “other ASP” (= Erwinia ASP or E.coli ASP Bayer); in trial 58951 1) the comparison dexamethasone (DEX 6 mg/m2/d) vs prednisolone (PRED 60 mg/m2/d) in induction and 2) conventional vs prolonged E.coli ASP for non-VHR pts.
303 and 296 T-ALL pts were included in trials 58881 and 58951 resp, representing 14.5% and 15.2% of all pts. Outcome results and type of events for the entire 58881 and 58951 cohorts and according to several subgroups are presented in the table. The 8-year isolated and overall CNS relapse incidences were 6.8% and 10.9% in study 58881, 5.3% and 8.5% in study 58951. The 8-year EFS, DFS and OS improved remarkably in study 58951. In the latter trial, outcome improvement was particularly seen in pts with initial WBC<100x10E9/L and in the good prephase responders (GPR) which had a significant better outcome than those with PPR. 58881 pts assigned to the “other ASP” arm had an inferior outcome. Concerning the DEX/PRED comparison in the 58951 T-ALL cohort, no advantage was seen for EFS (hazard ratio (HR) (99%CI): 1.26 (0.70;2.27)) or OS. There even was a trend towards worse EFS for pts with initial WBC>100x10E9/L and for pts with PPR treated in the DEX arm (HR (99%CI): 1.52 (0.63;3.64) and 1.47 (0.64;3.35)). Prolonged ASP treatment did not improve outcome of the whole T-ALL 58951 cohort.
Prophylactic and therapeutic RT can safely be omitted from frontline treatment of children with T-ALL. Adequate ASP therapy, intensified induction treatment and CNS directed therapy can result in a significant improvement of the outcome of at least 2/3rd of T-ALL pts, particularly those with initial WBC<100x10E9/L and GPR.5888158951Other ASPE.coli ASP MedacAllPREDDEXAllAll EFSN=94N=209N=303N=151N=145N=2968-yr %52.1%71.6%65.1%76.7%71.3%74.0%WBC<100N=53N=110N=163N=101N=87N=1888-yr %58.4%71.8%66.9%79.7%77.8%78.8%WBC>=100N=41N=99N=140N=50N=58N=1088-yr %43.9%71.2%63.0%70.5%61.6%65.6%GPRN=59N=126N=185N=101N=91N=1928-yr %57.6%76.8%70.3%81.6%80.7%81.2%PPRN=35N=82N=117N=48N=54N=1028-yr %42.9%64.6%57.5%67.6%55.6%61.4%All CRsN=89N=204N=293N=145N=141N=286DFS55.0%73.3%67.3%78.2%73.3%75.8%Isolated CNS relapse11.1%5.4%6.8%5.5%5.0%5.3%CNS relapse16.9%8.4%10.9%9.8%7.1%8.5%Non-CNS relapse20.3%14.4%16.5%10.5%15.3%12.9%Death in CR7.9%3.9%5.3%1.5%4.3%2.9%OSN=94N=209N=303N=151N=145N=2968-yr %59.6%77.7%71.9%84.1%74.2%78.2%
No relevant conflicts of interest to declare.
Abstract 134
Asparaginase (ASP) is an essential component in combination chemotherapy for childhood ALL and NHL, as indicated by several randomized trials. However, the optimal number of ASP ...administrations is still unknown. We conducted a randomized phase III trial comparing conventional E.coli ASP regimen (short-ASP, 12 doses) with prolonged E.coli ASP therapy (long-ASP, 24 doses).
The European Organization for Research and Treatment of Cancer Children’s Leukemia Group (EORTC-CLG) phase III 58951 trial was open to de novo ALL or NHL patients (pts) < 18 y. This BFM-based study addressed 2 main randomized questions. The first evaluated the value of dexamethasone (DEX, 6mg/m2/d) vs prednisolone (PRED, 60mg/m2/d) in induction for all pts. In the second question all non-very high risk (VHR) pts were randomized for either short- or long-ASP. All patients had to receive 8×10000 U/m2 in induction. In the short-ASP arm pts had to receive 4×10000 U/m2 in late intensification; pts in the long-ASP arm had to receive 8×5000 U/m2E.coli ASP injections in consolidation and 8 (4×10000 U/m2 + 4×5000U/m2) in late intensification. Patients with grade ≥2 allergy to E.coli ASP had to be switched to equivalent doses of Erwinia or PEG ASP. Central randomization was stratified by the 1st randomized arm, risk group (VLR, AR1, AR2) and center. The primary endpoint of the study was disease-free survival (DFS), secondary endpoints were overall survival (OS) and toxicity. Intention-to-treat analysis was performed.
Between December 1998 and August 2008, 2038 patients were randomized for the 1st question and 1552 pts, ALL (n=1481) and NHL (n=71), were randomly assigned to receive long-ASP (n=775) or short-ASP (n=777). At a median follow-up of 7 years there were 97 vs 112 events in the long- vs short-ASP group (see table). The 8-year DFS rate was 87.0% in the long-ASP and 84.2% in short-ASP group (hazard ratio (HR) = 0.87, 95% CI 0.66–1.14, 2-sided logrank p=0.30). The 8-year OS rate was comparable in both treatment arms: 92.6% in the long-ASP group and 91.3% in the short-ASP group (HR = 0.89, 95% CI 0.61–1.29, 2-sided log rank p=0.53). Similar treatment differences were observed in each risk group, in randomized arm (PRED vs DEX), and B- and T-lineage ALL pts.
The incidence of grade 3–4 infection was higher in the long- vs short-ASP group during consolidation (25.2% vs 14.5%) and late intensification (22.6% vs 15.9%). This difference was more pronounced in pts who were randomly assigned to DEX (see table). In the long- vs short-ASP group grade 2–4 allergy to ASP was 22.5% vs 0.3% in consolidation and 10.3% vs 21.5% in late intensification. During the whole treatment period, the incidence of grade 2–4 allergy was 30.5% in the long-ASP arm and 21.7% in the short-ASP arm. In the long- vs short-ASP arm approximately 67% vs 95% pts received at least the total number of E.coli or equivalent ASP administrations as planned according to the treatment arm.
At long follow-up (median= 7 yrs) prolonged E.coli asparaginase therapy in consolidation and late intensification for VLR and AR pts did not improve significantly the outcome. Intensive ASP treatment did increase infection rate in consolidation and late intensification and resulted in more grade 2–4 allergic reactions. In the future, we aim to improve outcome rates by the use of PEG ASP and monitoring of asparaginase activity and antibody formation.EndpointLong-ASP (N=775)Short-ASP (N=777)DFS8-yr % (SE%)87.0% (1.3%)84.2% (1.4%)DFS status, NCCR678665Events97112NoCR02Relapse87103CNS relapse1011Non-CNS7792Death CR107OS8-yr % (SE%)92.6% (1.0%)91.3% (1.2%)Grade 3-4 InfectionConsolidation25.2%14.5%DEX/PRED27.3%/23.1%11.6%/17.3%Late intensification22.6%15.9%DEX/PRED23.9%/21.4%13.9%/18%Grade 2-4 allergy22.5%0.3%Consolidation10.3%21.5%Late intensification30.5%21.7Total23.0%0.5%Switch ASP10.8%24.8%ConsolidationLate intensification
No relevant conflicts of interest to declare.
O presente artigo tem o objetivo de investigar a evolução da atividade empreendedora no Brasil, com base nos relatórios do Global Intrapreneurship Monitor (GEM), no período de 2000 a 2013. A revisão ...da literatura está fundamentada na relação entre o crescimento econômico com a atividade empreendedora, bem como nas características empreendedoras orientadas pelo GEM. Para tanto, foram utilizados dados secundários dos relatórios do GEM entre o período compreendido de 2000 a 2013. Os resultados da pesquisa apontam que as principais características da atividade empreendedora no Brasil são: (a) altas e constantes taxas de empreendedorismo em relação aos outros países pesquisados; (b) o governo brasileiro, ao mesmo tempo em que apoia atividade com políticas públicas, dificulta o empreendedorismo com entraves tributários; (c) as mulheres cada vez mais se apresentaram como praticantes da atividade empreendedora; e (d) apesar de apresentar altas taxas de empreendedorismo, a atividade no Brasil se caracteriza por ter baixo índice de inovação. Ainda, é possível concluir que o crescimento econômico influencia positivamente a prática empreendedora, aumentando o poder de compra das pessoas, facilitando o acesso a financiamentos e gerando novas empresas. Porém, também se pode concluir que a desaceleração da economia ocasiona altas taxas de desemprego, fazendo com que as pessoas busquem alternativas de renda, como abrir o próprio negócio. Assim, uma economia frágil também influencia a atividade empreendedora. Como contribuição teórica, este artigo destaca a relação não exaustiva entre crescimento econômico e atividade empreendedora, que se caracteriza por ser positiva em alguns casos e negativa em outros, bem como apresenta um panorama abrangente destacando pontos importantes da atividade empreendedora brasileira nos últimos 14 anos. Como contribuição metodológica, o artigo utiliza-se de pesquisa documental em dados secundários de um projeto já conceituado e pouco utilizado em pesquisas acadêmicas, o GEM. Como contribuição gerencial, o artigo é um direcionador para políticas públicas.
Yeast overexpressing SOD1, the gene for Cu,Zn-superoxide dismutase (Cu,Zn-Sod), was used to determine how Sod1p overexpression influences the chronological lifespan the survival of non-dividing ...stationary (G0) phase cells over time, the replicative lifespan (the number of buds produced by actively dividing yeast cells) and stress resistance. Increasing the level of active Cu,Zn-Sod in yeast was found to require either growth in the presence of high copper, or the simultaneous overexpression of both SOD1 and CCS1 (the latter being the gene that encodes the chaperone dedicated to Cu(2+)-loading of Sod1p in vivo). Dual SOD1 + CCS1 overexpression elevated the levels of Cu,Zn-Sod activity six- to eight-fold in vegetative cultures. It also increased the optimized survival of stationary cells up to two-fold, showing this chronological lifespan is ultimately limited by oxidative stress. In contrast, several detrimental effects resulted when the SOD1 gene was overexpressed in the absence of either high copper or a simultaneous overexpression of CCS1. Both the chronological and the replicative lifespans were shortened; the cells displayed an abnormally high level of endogenous oxidative stress, resulting in a high rate of spontaneous mutation. Such harmful effects were all reversed through the overexpression of CCS1. It is apparent therefore that they relate to the incomplete Cu(2+)-loading of the overexpressed Sod1p, most probably accumulation of a Cu(2+)-deficient Sod1p to appreciable levels in vivo. The same events may generate the detrimental effects that are frequently, though not universally, observed when Cu,Zn-Sod overexpression is attempted in metazoans.
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