Online and offline heuristics for inferring hierarchies of repetitions in sequences

Hierarchical dictionary-based compression schemes form a grammar for a text by replacing each repeated string with a production rule. While such schemes usually operate online, making a replacement as soon as repetition is detected, offline operation permits greater freedom in choosing the order of replacement. In this paper, we compare the online method with three offline heuristics for selecting the next substring to replace: longest string first, most common string first, and the string that minimized the size of the grammar locally. Surprisingly, two of the offline techniques, like the online method, run in time linear in the size of the input. We evaluate each technique on artificial and natural sequences. In general, the locally-most-compressive heuristic performs best, followed by most frequent, the online technique, and, lagging by some distance, the longest-first technique

NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches

Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies

Patterns of care and survival for adolescents and young adults with acute leukaemia – a population-based study

We report a population-based study of patterns of care and survival for people with acute leukaemia diagnosed at age 15–29 years during 1984–94 in regions of England and Wales covered by specialist leukaemia registries. There were 879 patients: 417 with acute lymphoblastic leukaemia (ALL) and 462 with acute myeloid leukaemia (AML). For ALL, actuarial survival rates were 43% at 5 years after diagnosis and 37% at 10 years. Survival improved significantly between 1984–88 and 1989–94 for those aged 15–19 at diagnosis. Patients entered in national clinical trials and those not entered had similar survival rates. Survival rates were similar at teaching and non-teaching hospitals and at hospitals treating different numbers of study patients per year. For AML, survival rates were 42% at 5 years after diagnosis and 39% at 10 years. Survival improved significantly between 1984–88 and 1989–94. Patients entered in the Medical Research Council AML10 trial had a higher survival rate than those who were in the earlier AML9 trial. Survival did not vary with category of hospital. We conclude that survival has improved for adolescents and young adults with acute leukaemia but that there is at present no evidence that centralized treatment results in a survival benefit for patients in this age group. © 1999 Cancer Research Campaig

Pharmacokinetic Modeling of an Induction Regimen for In Vivo Combined Testing of Novel Drugs against Pediatric Acute Lymphoblastic Leukemia Xenografts

Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL), or for re-induction post relapse, use a combination of vincristine (VCR), a glucocorticoid, and l-asparaginase (ASP) with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX) and ASP (VXL) against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL

A second course of treatment for childhood acute lymphoblastic leukaemia: long-term follow-up is needed to assess results.

We report the results of long-term follow-up of 94 children who completed treatment for acute lymphoblastic leukaemia (ALL) between 1974 and 1986 and subsequently experienced a bone marrow relapse before 1992. 91 children received further induction, intensification and CNS directed therapy; 19 proceeded to BMT or ABMT and the remainder were treated on one of three protocols which increased in intensity. The duration of second remission improved significantly with increasing intensity of treatment and bone marrow transplantation was followed by fewer relapses than chemotherapy. Analysis of factors influencing the duration of second remission showed that only length of first remission was of additional significance; the median duration of second remission being only 19 months in children with a first remission of less than 4 years and 62 months in those with longer first remissions. 29 children electively stopped chemotherapy a second time but only 11 of these remain still in second remission with recurrences occurring for up to 7 years from the the time first relapse. Only three of the 24 long-term survivors had no significant late effects of treatment; these were most marked in children who had received a second course of radiotherapy. We conclude that very long follow-up is necessary to determine whether patients may be successfully re-treated following late bone marrow relapse and that all such treatment is associated with a high incidence of late effects

Long survival in childhood lymphoblastic leukaemia.

Long term follow-up of 378 children with acute lymphoblastic leukaemia (ALL) treated at a single centre showed that at six years from diagnosis 202 (53%) were alive, of whom 140 (37%) remained in first remission. Only three children had a first relapse after six years. Children who survived six years despite a single extramedullary relapse in the testis or CNS were likely to remain in second remission but patients with previous marrow or with multiple relapses continued at risk for up to ten years from diagnosis. Presenting factors influencing event-free survival were: leucocyte count, age and sex. After allowing for these factors morphological (FAB) subtype and liver enlargement retained their prognostic significance. Immunological type of ALL was not of independent prognostic significance, except for the small number of patients with B-ALL. Most factors lost their significance after 2-4 years. It is concluded that patients alive 6 years from diagnosis without relapse or even with a single extramedullary relapse of ALL, have a high chance of prolonged survival and cure