Blind Super Resolution of Real-Life Video Sequences.

Super resolution (SR) for real-life video sequences is a challenging problem due to complex nature of the motion fields. In this paper, a novel blind SR method is proposed to improve the spatial resolution of video sequences, while the overall point spread function of the imaging system, motion fields, and noise statistics are unknown. To estimate the blur(s), first, a nonuniform interpolation SR method is utilized to upsample the frames, and then, the blur(s) is(are) estimated through a multi-scale process. The blur estimation process is initially performed on a few emphasized edges and gradually on more edges as the iterations continue. Also for faster convergence, the blur is estimated in the filter domain rather than the pixel domain. The high-resolution frames are estimated using a cost function that has the fidelity and regularization terms of type Huber-Markov random field to preserve edges and fine details. The fidelity term is adaptively weighted at each iteration using a masking operation to suppress artifacts due to inaccurate motions. Very promising results are obtained for real-life videos containing detailed structures, complex motions, fast-moving objects, deformable regions, or severe brightness changes. The proposed method outperforms the state of the art in all performed experiments through both subjective and objective evaluations. The results are available online at http://lyle.smu.edu/~rajand/Video_SR/.

Molecular pathogenesis of secondary acute promyelocytic leukemia.

Balanced chromosomal translocations that generate chimeric oncoproteins are considered to be initiating lesions in the pathogenesis of acute myeloid leukemia. The most frequent is the t(15;17)(q22;q21), which fuses the PML and RARA genes, giving rise to acute promyelocytic leukemia (APL). An increasing proportion of APL cases are therapy-related (t-APL), which develop following exposure to radiotherapy and/or chemotherapeutic agents that target DNA topoisomerase II (topoII), particularly mitoxantrone and epirubicin. To gain insights into molecular mechanisms underlying the formation of the t(15;17) we mapped the translocation breakpoints in a series of t-APLs, which revealed significant clustering according to the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast cancer or multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp "hotspot" region in PML intron 6, which was confirmed to be a preferential site of topoII-mediated DNA cleavage induced by mitoxantrone. Chromosome 15 breakpoints falling outside the "hotspot", and the corresponding RARA breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the PML and RARA loci are susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL.

Maternal hemoglobin concentration during pregnancy and risk of infant leukaemia: a children's oncology group study.

In contrast to the positive association found in three studies between maternal anaemia during pregnancy and childhood leukaemia, no such association was found in infant leukaemia (odds ratio 0.85, 95% confidence interval 0.53-1.37).

Multidimensional, mapping-based complex wavelet transforms.

Although the discrete wavelet transform (DWT) is a powerful tool for signal and image processing, it has three serious disadvantages: shift sensitivity, poor directionality, and lack of phase information. To overcome these disadvantages, we introduce multidimensional, mapping-based, complex wavelet transforms that consist of a mapping onto a complex function space followed by a DWT of the complex mapping. Unlike other popular transforms that also mitigate DWT shortcomings, the decoupled implementation of our transforms has two important advantages. First, the controllable redundancy of the mapping stage offers a balance between degree of shift sensitivity and transform redundancy. This allows us to create a directional, nonredundant, complex wavelet transform with potential benefits for image coding systems. To the best of our knowledge, no other complex wavelet transform is simultaneously directional and nonredundant. The second advantage of our approach is the flexibility to use any DWT in the transform implementation. As an example, we exploit this flexibility to create the complex double-density DWT: a shift-insensitive, directional, complex wavelet transform with a low redundancy of (3M - 1)/(2M - 1) in M dimensions. No other transform achieves all these properties at a lower redundancy, to the best of our knowledge. By exploiting the advantages of our multidimensional, mapping-based complex wavelet transforms in seismic signal-processing applications, we have demonstrated state-of-the-art results.

Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation.

We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.

Simultaneous determination of etoposide and its catechol metabolite in the plasma of pediatric patients by liquid chromatography/tandem mass spectrometry.

The anticancer drug etoposide is associated with leukemias with MLL gene translocations and other translocations as a treatment complication. The genotype of cytochrome P450 3A4 (CYP3A4), which converts etoposide to its catechol metabolite, influences the risk. In order to perform pharmacokinetic studies aimed at further elucidation of the translocation mechanism, we have developed and validated a liquid chromatography/electrospray/tandem mass spectrometry assay for the simultaneous analysis of etoposide and its catechol metabolite in human plasma. The etoposide analog teniposide was used as the internal standard. Liquid chromatography was performed on a YMC ODS-AQ column. Simultaneous determination of etoposide and its catechol metabolite was achieved using a small volume of plasma, so that the method is suitable for pediatric patients. The limits of detection were 200 ng ml(-1) etoposide and 10 ng ml(-1) catechol metabolite in human plasma and 25 ng ml(-1) etoposide and 2.5 ng ml(-1) catechol metabolite in protein-free plasma, respectively. Acceptable precision and accuracy were obtained for concentrations in the calibration curve ranges 0.2--100 microg ml(-1) etoposide and 10--5000 ng ml(-1) catechol metabolite in human plasma. Acceptable precision and accuracy for protein-free human plasma in the range 25--15 000 ng ml(-1) etoposide and 2.5--1500 ng ml(-1) etoposide catechol were also achieved. This method was selective and sensitive enough for the simultaneous quantitation of etoposide and its catechol as a total and protein-free fraction in small plasma volumes from pediatric cancer patients receiving etoposide chemotherapy. A pharmacokinetic model has been developed for future studies in large populations.

Leukemias related to treatment with DNA topoisomerase II inhibitors.

The epipodophyllotoxins etoposide and teniposide and other DNA topoisomerase II inhibitors including anthracyclines and dactinomycin are highly efficacious anticancer drugs. All are associated with a distinct form of leukemia characterized by chromosomal translocations as a treatment complication. Most of the translocations disrupt a breakpoint cluster region (bcr) of the MLL gene at chromosome band 11q23. Other characteristic translocations also may occur. The normal function of the nuclear enzyme DNA topoisomerase II is to catalyze changes in DNA topology between relaxed and supercoiled states by transiently cleaving and re-ligating both strands of the double helix. Anticancer drugs that are DNA topoisomerase II inhibitors are cytotoxic because they form complexes with DNA and DNA topoisomerase II. The complexes decrease the re-ligation rate, disrupt the cleavage-re-ligation equilibrium, and have a net effect of increasing cleavage. The increased cleavage damages the DNA and leads to chromosomal breakage. Cells with irreparable DNA damage die by apoptosis. The association of DNA topoisomerase II inhibitors with leukemia suggests that the drug-induced, DNA topoisomerase II-mediated chromosomal breakage may be relevant to translocations in addition to this anti-neoplastic, cytotoxic action. Epidemiological studies, genomic translocation breakpoint cloning and in vitro DNA topoisomerase II cleavage assays together lead to a model for treatment-related leukemia in which DNA topoisomerase II causes chromosomal breakage and translocations form when the breakage is repaired.

Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints.

Chromosomal breakage resulting from stabilization of DNA topoisomerase II covalent complexes by epipodophyllotoxins may play a role in the genesis of leukemia-associated MLL gene translocations. We investigated whether etoposide catechol and quinone metabolites can damage the MLL breakpoint cluster region in a DNA topoisomerase II-dependent manner like the parent drug and the nature of the damage. Cleavage of two DNA substrates containing the normal homologues of five MLL intron 6 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha, ATP, and either etoposide, etoposide catechol, or etoposide quinone. Many of the same cleavage sites were induced by etoposide and by its metabolites, but several unique sites were induced by the metabolites. There was a preference for G(-1) among the unique sites, which differs from the parent drug. Cleavage at most sites was greater and more heat-stable in the presence of the metabolites compared to etoposide. The MLL translocation breakpoints contained within the substrates were near strong and/or stable cleavage sites. The metabolites induced more cleavage than etoposide at the same sites within a 40 bp double-stranded oligonucleotide containing two of the translocation breakpoints, confirming the results at a subset of the sites. Cleavage assays using the same oligonucleotide substrate in which guanines at several positions were replaced with N7-deaza guanines indicated that the N7 position of guanine is important in metabolite-induced cleavage, possibly suggesting N7-guanine alkylation by etoposide quinone. Not only etoposide, but also its metabolites, enhance DNA topoisomerase II cleavage near MLL translocation breakpoints in in vitro assays. It is possible that etoposide metabolites may be relevant to translocations.

t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene.

The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5' ends and random hexamers at the 3' ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLL exon 7 or exon 8 with the GMPS (GUANOSINE 5'-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene of MLL on chromosome 3q and the first gene of this type in leukemia-associated translocations. (Blood. 2000;96:4360-4362)

Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations.

Chromosomal aberrations are frequently associated with therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) and are thought to result from exposure to genotoxic drugs, including alkylating agents and DNA topoisomerase II poisons. The NUP98 gene on chromosome band 11p15 is involved in several different chromosomal aberrations that have been associated with t-MDS/AML. We have cloned the translocation breakpoints from two cases of t-MDS harboring a t(11;20)(p15;q11). Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocations between NUP98 and TOP1. There were no known recombinogenic sequences identified at or near the breakpoints. However, four bp microduplications present at the translocation crossover points suggested that these translocations may have been initiated by 4 bp staggered double-stranded DNA breaks, which are known to be associated with the action of topoisomerase II. Given the history of patient exposure to topoisomerase II poisons, and the fact that these drugs stabilize staggered breaks with a 4 bp overhang, it seems possible that drug-induced topoisomerase II cleavage and subunit exchange was involved in these translocations. These results suggest that NUP98 is a recurrent target for therapy-related malignancies induced by multiagent chemotherapy, and suggest a role for DNA topoisomerase II poisons in the generation of these translocations. Published 2000 Wiley-Liss, Inc.

Panhandle PCR for cDNA: a rapid method for isolation of MLL fusion transcripts involving unknown partner genes.

Identifying translocations of the MLL gene at chromosome band 11q23 is important for the characterization and treatment of leukemia. However, cytogenetic analysis does not always find the translocations and the many partner genes of MLL make molecular detection difficult. We developed cDNA panhandle PCR to identify der(11) transcripts regardless of the partner gene. By reverse transcribing first-strand cDNAs with oligonucleotides containing coding sequence from the 5' MLL breakpoint cluster region at the 5' ends and random hexamers at the 3' ends, known MLL sequence was attached to the unknown partner sequence. This enabled the formation of stem-loop templates with the fusion point of the chimeric transcript in the loop and the use of MLL primers in two-sided PCR. The assay was validated by detection of the known fusion transcript and the transcript from the normal MLL allele in the cell line MV4-11. cDNA panhandle PCR then was used to identify the fusion transcripts in two cases of treatment-related acute myeloid leukemia where the karyotypes were normal and the partner genes unknown. cDNA panhandle PCR revealed a fusion of MLL with AF-10 in one case and a fusion of MLL with ELL in the other. Alternatively spliced transcripts and exon scrambling were detectable by the method. Leukemias with normal karyotypes may contain cryptic translocations of MLL with a variety of partner genes. cDNA panhandle PCR is useful for identifying MLL translocations and determining unknown partner sequences in the fusion transcripts.

Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors.

Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.

Glutathione S-transferase genotypes in children who develop treatment-related acute myeloid malignancies.

Epipodophyllotoxin-associated secondary myeloid leukemia is a devastating complication of acute lymphoblastic leukemia (ALL) therapy. The risk factors for treatment-related myeloid leukemia remain incompletely defined. Genetic deficiencies in glutathione S-transferase (GST) activities have been linked to higher frequencies of a number of human malignancies. Our objective was to determine whether the null genotype for GSTM1, GSTT1, or both, was more frequent in children with ALL who developed treatment-related myeloid malignancies as compared to those who did not. A PCR technique was used to assay for the null genotype for GSTM1 and GSTT1 in 302 children with ALL, 57 of whom also subsequently developed treatment-related acute myeloid leukemia or myelodysplastic syndrome. Among children with ALL who did not develop treatment-related myeloid malignancies, the frequencies of GSTM1 and GSTT1 wild-type, GSTM1 null-GSTT1 wild-type, GSTM1 wild-type-GSTT1 null, and GSTM1 and GSTT1 null genotypes were 40%, 42%, 9% and 9%, respectively. The corresponding frequencies for patients who developed acute myeloid malignancies were 42%, 32%, 11% and 16%, respectively (P = 0.26). A statistically significant increase in the frequency of the GST null genotype was observed in male patients who developed myeloid malignancies as compared to male ALL control patients (P = 0.036), but was not observed in female patients (P = 0.51). Moreover, a logistic regression analysis of possible predictors for myeloid malignancies, controlling for gender and race, did not reveal an association of GSTM1 or GSTT1 null genotypes (P = 0.62 and 0.11, respectively) with treatment-related malignancies. Our data suggest that GSTM1 and GSTT1 null genotypes may not predispose to epipodophyllotoxin-associated myeloid malignancies.

The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion.

The NUP98 gene is involved in 3 distinct chromosomal rearrangements, t(7;11)(p15;p15), t(2;11)(q31;p15), and inv(11)(p15q22); all of these NUP98 rearrangements have been identified in the malignant cells of patients with therapy-related acute myelogenous leukemia or myelodysplastic syndrome (t-AML/MDS). Here we report the cloning and characterization of a t(11;20)(p15;q11) translocation from patients with t-MDS. The breakpoint on chromosome 11p15 targets the NUP98 gene and results in the separation of the N-terminal FXFG repeats from the RNA-binding domain located in the C-terminus. The breakpoint on chromosome 20q11 occurs within the gene encoding human DNA topoisomerase I (TOP1). As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I is produced. These results indicate that NUP98 is a recurrent target in therapy-related malignancies, and that TOP1 is a previously unrecognized target for chromosomal translocations.

Leukemia in infants.

Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants have in common a high incidence of translocations of the MLL gene at chromosome band 11q23. Similar translocations occur in leukemias associated with chemotherapies that target DNA topoisomerase II. MLL has numerous different partner genes. The role of the many MLL fusion proteins in leukemogenesis is not yet understood. The t(4;11) translocation, the most common translocation in infant ALL, adversely affects the outcome. Additional genetic changes, especially Ikaros alterations, are found in infant ALL. Other forms of myeloid leukemia in infants present as myelodysplastic and myeloproliferative syndromes, which may be associated with constitutional disorders. This review will consider all leukemia in infants, but will focus on leukemias with MLL gene translocations.

High incidence of secondary brain tumours after radiotherapy and antimetabolites.

BACKGROUND: Brain tumours rarely occur in survivors of childhood acute lymphoblastic leukaemia after cranial radiotherapy. An unusually high frequency of brain tumours seen among children enrolled in one of our leukaemia treatment protocols, Total Therapy Study XII, prompted us to identify the potential causes of this complication. METHODS: We assessed clinical, biological, and pharmacokinetic features in all 52 children who received prophylactic cranial radiotherapy. We compared the cumulative incidence of brain tumours between subgroups, and with that of 421 children who received radiotherapy in previous studies. FINDINGS: The incidence of brain tumours among irradiated children (six of 52, 12.8% [SE 5.0]) was high compared with patients in the same study who did not receive radiotherapy (none of 101; p=0.0008) and with other protocols that included cranial radiotherapy (p<0.0001). Of the six children, four had erythrocyte concentrations of thioguanine nucleotide metabolites higher than the 70th percentile for the entire cohort, and three had a genetic defect in thiopurine catabolism. The 8-year cumulative incidence of brain tumour among children with defective versus wild-type thiopurine methyltransferase phenotype was 42.9% (SE 20.6) versus 8.3% (4.7; p=0.0077). This protocol differed from previous protocols, in that more intensive systemic antimetabolite therapy was given before and during radiotherapy. INTERPRETATION: These data support the elimination of prophylactic radiotherapy for acute lymphoblastic leukaemia except in patients at high risk of central-nervous-system relapse. Underlying genetic characteristics and treatment variables may be associated with an increased risk of radiation-associated brain tumours.

Duplicated regions of AF-4 intron 4 at t(4;11) translocation breakpoints.

BACKGROUND: AF-4 is a common partner gene of MLL. AF-4 breakpoints occur in introns, but most AF-4 introns are uncharacterized. METHODS AND RESULTS: We cloned AF-4 intron 4 and examined the frequency of breakpoints in this intron. The 5.8-kb intron is rich in repeat sequences and was the site of translocation in 3 of 17 leukemias with t(4;11). We cloned the der (11) and der (4) breakpoints and isolated the fusion transcripts in the cell line MV4-11 and in a de novo acute lymphoblastic leukemia (ALL). Both translocations joined MLL intron 6 and AF-4 intron 4. In MV4-11, 249 bases from AF-4 were present in both derivative chromosomes, indicating duplication. In the de novo ALL, duplication of 446 bases from MLL and AF-4 occurred. Reciprocal fusion transcripts were expressed. CONCLUSIONS: Intronic sequence of AF-4 is useful for molecular diagnosis of t(4;11). Duplicated intronic regions suggest staggered chromosomal breakage.