Preferential methylation of Wnt inhibitory factor-1 in acute promyelocytic leukemia: an independent poor prognostic factor.
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Adaptor Proteins, Signal Transducing↗
Biomedical subjects
A Pang
Publications and source records attributed to A Pang.
Aberrant promoter methylation of the retinoic acid receptor alpha gene in acute promyelocytic leukemia.
The retinoic acid receptor alpha (RARA) gene is disrupted by PML/RARA fusion in acute promyelocytic leukemia (APL). The P2 promoter of RARA, controlling the RARalpha2 isoform, contains an RA-responsive element and may be targeted in APL. To test whether aberrant methylation of P2 was involved, 47 APL at diagnosis, 16 APL at first relapse, 50 acute myeloid leukemia (AML) and 22 acute lymphoblastic leukemia (ALL) were tested by methylation-specific polymerase chain reaction. RARA P2 methylation was highly associated with APL (APL: 25/63 vs AML/ALL: 2/75, P<0.0001). P2 methylation occurred at similar frequencies in APL at diagnosis and relapse, suggesting it was an initiating leukemogenic event. In the APL line NB4, RARalpha2 was not expressed, with the untranslocated RARA shown to be P2 methylated. 5-Azacytadine treatment of NB4 led to progressive P2 demethylation and re-expression of RARalpha2, confirming that RARA methylation collaborated with PML/RARA in totally suppressing RARalpha. In APL, RARA P2 methylation was unrelated to gender, age, presenting leukocyte counts and additional cytogenetic aberrations. For APL patients receiving all-trans retinoic acid for induction, P2 methylation did not affect the complete remission rates and survivals. RARA is the first myeloid-specific transcription factor shown to be dysregulated by both translocation and aberrant methylation.
Acute Disease↗
Nonhematologic malignancies after allogeneic hematopoietic stem cell transplantation: incidence and molecular monitoring.
Survivors of allogeneic hematopoietic stem cell transplantation (HSCT) are at a life-long increased risk of secondary nonhematologic malignancies. In 615 adult Chinese allogeneic HSCT patients, nine developed nonhematologic malignancies. The 5-year cumulative incidence was 6.1%, 4.5 times the background cancer incidence. Early-onset (within first 6 months) and late-onset (>3 years) subtypes were observed. Secondary cancers included hepatocellular carcinoma, oral and esophageal squamous cell tumors and lung adenocarcinoma in a female nonsmoker. The spectrum reflected local cancer epidemiology, which was different from Western populations. The pathogenesis might be related to acceleration of pre-existing cancers (early-onset type), or prolonged immunosuppression (late-onset type). DNA chimerism studies showed that all tumors were recipient-derived. In the plasma, DNA in all cases was apparently donor-derived, although aberrantly methylated p15 was detectable in a patient with a p15-methylated secondary cancer, implying that minute quantities of tumor (and therefore recipient) derived DNA might be present.
Adult↗
Clinicopathologic significance of genetic alterations in hepatocellular carcinoma.
Hepatocarcinogenesis may involve multiple mutations with distinctive pathogenetic and clinicopathologic significance. To test this hypothesis, 68 cases of hepatocellular carcinoma (HCC) were studied prospectively for genetic-clinicopathologic correlation. Ten pathologic characteristics were evaluated. TP53 (alias p53) gene mutation was studied by a polymerase chain reaction (PCR)-single-strand conformation polymorphism-sequencing; CDKN2B (alias p15) and CDKN2A (alias p16) gene methylation by methylation-specific PCR; and genetic imbalances by comparative genomic hybridization (CGH). TP53 gene mutations occurred in 25% of cases, more than half being codon 249 G to T transversion. Methylation of CDKN2A was frequent (61.7%); of CDKN2B, rare (5.9%). The CGH analysis showed a median of nine aberrations per case, with amplifications more frequent than deletions. Isochromosomes might be involved in about 25% of cases. Amplifications of 1q and 8q were most frequent. Clinicopathologic correlations showed that CDKN2A methylation was significantly associated with tumors arising in cirrhotic livers; amplifications of 17q was significant in multiple parameters of tumor invasiveness (size, venous invasion, poor cellular differentiation, microsatellite formation); other amplifications (1q, 6p, 10p, and 20p) were also significant in tumor invasion; and deletions (at 1p, 11q, 4q, and 14q) were significant in tumor growth. Consistent patterns of genetic alterations were defined in HCC, which might represent distinctive pathways in hepatocarcinogenesis.
Adolescent↗
Treatment of postrenal transplantation lymphoproliferative disease manifesting as plasmacytoma with nonmyeloablative hematopoietic stem cell transplantation from the same kidney donor.
Posttransplantation lymphoproliferative disease (PTLD) presenting as an Epstein-Barr-virus (EBV)-related nasal plasmacytoma developed in a renal-allograft recipient 13 years after transplantation. Systemic dissemination occurred despite immunosuppression withdrawal, surgery, irradiation, and chemotherapy. A nonmyeloablative hematopoietic-stem-cell-transplantation (HSCT) with peripheral blood HSC from the kidney donor was performed. With the onset of graft-versus-host disease, resolution of the systemic disease was demonstrated clinically and molecularly by serial quantification of plasma EBV-DNA. Isolated relapse occurred in the central nervous system (CNS), a known tumour sanctuary site, ultimately leading to death. Nonmyeloablative HSCT might be considered a cellular therapy for PTLD, but possible CNS relapse must be effectively tackled.
Aged↗
Acute lymphoblastic leukemia in a patient with fragile X syndrome: cytogenetic and molecular features.
Malignancies in patients with fragile X syndrome are rarely reported. A 42-year-old man with fragile X syndrome presented with precursor B-cell acute lymphoblastic leukemia (ALL). Cytogenetic analysis showed a stemline 46, XY,t(9;22)(q34;qll) and a sideline 46,XY, t(8;14)(q24;qll), t(9;22)(q34;qll). Molecular analysis of the FMR1 gene showed a neoplastic leukemic clone possessing a full expansion of the CGG repeat, with associated aberrant methylation of the promoter CpG islands. However, analysis during morphologic remission showed that the promoter CpG island was apparently unmethylated in the regenerating normal hematopoietic cells. During subsequent relapses, the FMRI CGG repeat was unstable, with the appearance of multiple leukemic subclones possessing different repeat expansions. Our case suggested that deregulation of the FMR1 gene might have contributed to leukemogenesis in our case.
Adult↗
Deletion 6q as a recurrent chromosomal aberration in T-cell large granular lymphocyte leukemia.
T-cell large granular lymphocyte (T-LGL) leukemia is an uncommon disease, with limited information on karyotypic aberrations. No consistent chromosomal changes have thus far been described. We report two cases of T-LGL leukemia who presented with severe anemia. The LGL were CD3+, CD4-, CD8+, CD56-, and CD161-, with variable expression of CD94, CD158a, and CD158b, and had clonal T-cell receptor gene rearrangement. A deletion of the long arm of chromosome 6 was the sole aberration in both cases. This is the first report of a recurrent chromosomal aberration in T-LGL leukemia.
Antigens, CD↗
Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study.
Arsenic trioxide (As2O3) effectively induces remissions in relapsed acute promyelocytic leukaemia (APL), but the safety of its long-term administration is unknown. The anthracycline idarubicin is highly active alone or in combination chemotherapy for the treatment of APL. To minimize arsenic exposure and based on the high sensitivity of APL cells to anthracyclines, we conducted a prospective study to evaluate induction with As2O3 followed by consolidation with idarubicin in the treatment of APL in relapse. Eight patients were treated with As2O3 at a daily dose of 10 mg until remission, followed by three monthly courses of idarubicin, at 6 mg/m(2)/day for 5 days in the first course and 6 mg/m(2)/day for 2 days in the subsequent two courses. All patients achieved morphological but not molecular remission after As2O3 treatment. During As2O3 therapy, an increase in white cell count peaking at a median of 17 days occurred in all the cases. Serial flow cytometric analysis of apoptosis, with mitochondrial APO2.7 antigen expression and the sub-G1 cell fraction on DNA histogram as markers, showed induction of apoptosis of APL cells in vivo. With both qualitative and real-time quantitative polymerase chain reaction, all patients were shown to attain molecular remission after subsequent idarubicin treatment. With a median follow up of 13 months, seven of eight patients have remained in complete clinical remission, with six patients in molecular remission as well. One patient who was in third remission became PCR-positive after being transiently negative. One patient died from an intracranial extramedullary relapse after achieving marrow molecular remission. We conclude that As2O3 induction followed by idarubicin consolidation is an effective therapy for APL in relapse. This regimen avoids the possible long-term toxicities of As2O3 and mutagenicity of combination chemotherapy, a strategy that might be suitable for this potentially curable leukaemia.
Adult↗
Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines.
c-Src tyrosine kinase activity is elevated in several types of human cancer, and this has been attributed to elevated c-Src expression levels, increased c-Src specific activity, and activating mutations in c-Src. We have found a number of human breast cancer cell lines with elevated c-Src specific activity that also possess elevated phosphatase activity directed against the carboxyl-terminal negative regulatory domain of Src family kinases. To identify this phosphatase, cell extracts from MDA-MB-435S cells were chromatographed and the fractions were assayed for phosphatase activity. Four peaks of phosphatase activity directed against the nonspecific substrate poly(Glu/Tyr) were detected. One peak also dephosphorylated a peptide modeled against the c-Src carboxyl-terminal negative regulatory domain and intact human c-Src. Immunoblotting and immunodepletion experiments identified the phosphatase as protein-tyrosine phosphatase 1B (PTP1B). Examination of several human breast cancer cell lines with increased c-Src activity showed elevated levels of PTP1B protein relative to normal control breast cells. In vitro c-Src reactivation experiments confirmed the ability of PTP1B to dephosphorylate and activate c-Src. In vivo overexpression of PTP1B in 293 cells caused a 2-fold increase of endogenous c-Src kinase activity. Our findings indicate that PTP1B is the primary protein-tyrosine phosphatase capable of dephosphorylating c-Src in several human breast cancer cell lines and suggests a regulatory role for PTP1B in the control of c-Src kinase activity.
Breast Neoplasms↗
Characterization of an overexpressed spindle protein during a baculovirus infection.
The nucleopolyhedrovirus CfDEFNPV contains a gene encoding a viral protein, which accumulates as bipyramidal inclusion bodies (spindles) in the cytoplasm of infected cells. The spindles appear as early as 24 h postinfection, approximately 1 day earlier than viral occlusion bodies (OBs). Purification and characterization of the spindle protein was complicated by the fact that the OBs copurified with the spindles. We therefore modified CfDEFNPV by replacing the polyhedrin gene (plh) with a cassette containing the green fluorescent protein (GFP) gene. The recombinant virus did not produce OBs; however, the synthesis and morphogenesis of the spindles were not altered. When analyzed by SDS-PAGE, the spindles produced a 50-kDa protein, which was termed spindlin. Tunicamycin inhibition and endoglycosidase studies showed that spindlin was glycosylated. The N-terminus of spindlin was sequenced and its gene (gp50) was located on the viral genome. The gene was cloned and sequenced. Homologs of gp50 were found in several baculoviruses as well as in entomopoxviruses (EPV). In the latter virus, the homologous gene is that of fusolin, which also encodes a protein that forms spindle-shaped inclusion bodies in the cytoplasm of infected cells. Immunoblot analysis indicated that spindlin and fusolin were not serologically related, even though they share conserved polypeptide domains. Sequence analysis showed that gp50 of CfDEFNPV contains two late promoter motifs (TTAAG) in its 5' flanking region. Both were used, but the proximal motif (-14 to -18 nt relative to the ATG) was the primary sequence from which most of the mRNA was initiated. When gp50 was cloned in a heterologous baculovirus expression system, spindlin was synthesized, although the spindles were irregular in shape. This suggested that the spindle structure may be species-specific or it may require more than one gene product for its morphogenesis.
Amino Acid Sequence↗
Memory and organizational strategies in chronic and acute schizophrenic patients.
The memory profile of acute and chronic schizophrenic patients was examined according to the information processing model, with which encoding, retention and retrieval processes of these patients were compared. The effects of an external organizational strategy on their verbal learning and memory were also examined. Twenty chronic and 20 acute schizophrenic patients were tested with a list learning task consisting of a random (i.e., words presented randomly) and a blocked (i.e., words presented in clusters) word-list. The schizophrenic patients, as compared with age- and education-matched normal control subjects, demonstrated impaired learning, and the duration of their illness was not a significant factor in the severity of their learning impairment. However, the acute and chronic schizophrenic patients seem able to retain most of the newly acquired materials, regardless of the presentation format, after 30 min. In addition, the learning and subjective organizational strategy of the chronic patients, but not that of the acute patients, improved significantly by the blocked presentation. However, semantic organization could facilitate both the chronic and acute schizophrenic patients to retain more newly learned items.
Acute Disease↗
ProFeel: low cost visual-haptic perceptualization of protein structure-structure alignments.
We describe ProFeel, an application for exploring molecular data from protein structure-structure alignments using a force-feedback joystick. Protein structure analysis is a useful application for multimodal information perceptualization because researchers in this area typically use several independent measures in assessment. A system that allows the user to simultaneously evaluate different criteria would therefore be quite useful. Four variables are assigned three different haptic effects each to allow the user to discern twelve separate data values. The haptic representation is coupled with a traditional molecular graphics visual display.
Computer Graphics↗
A breakdown of event schemas in patients with schizophrenia: an examination of their script for dining at restaurants
Event schemas, the conceptualization of past experience, in schizophrenic patients were examined based upon script theory. Forty schizophrenic patients and 40 age- and education-matched normal control subjects participated in this study. This experiment consisted of three tasks. In the recall task, subjects recalled a typical scenario of going to a formal restaurant. In the frequency judgment task, subjects determined whether the given events happen frequently, occasionally or rarely in a restaurant. In the sequencing task, the subjects put the randomly presented events in the correct order. The responses of the schizophrenic patients in the recall task, when compared with those of the normal control subjects, had significantly fewer concepts and a greater proportion of highest-frequency concepts. In addition, the sequence of their responses was less accurate than that of normal individuals. This abnormality is unlikely due primarily to a retrieval deficit (i.e. generating fewer concepts in the recall task) given that their performances on the frequency judgment and sequencing tasks, tasks that require less retrieval effort, were consistent with those of the recall task. These results suggest that event schemas in schizophrenic patients contain little detailed information and are incoherent in organization.
Journal Article↗
Activation of Src in human breast tumor cell lines: elevated levels of phosphotyrosine phosphatase activity that preferentially recognizes the Src carboxy terminal negative regulatory tyrosine 530.
Elevated levels of Src kinase activity have been reported in a number of human cancers, including colon and breast cancer. We have analysed four human breast tumor cell lines that exhibit high levels of Src kinase activity, and have determined that these cell lines also exhibit a high level of a phosphotyrosine phosphatase activity that recognizes the Src carboxy-terminal P-Tyr530 negative regulatory site. Total Src kinase activity in these cell lines is elevated as much as 30-fold over activity in normal control cells and specific activity is elevated as much as 5.6-fold. When the breast tumor cells were grown in the presence of the tyrosine phosphatase inhibitor vanadate, Src kinase activity was reduced in all four breast tumor cell lines, suggesting that Src was being activated by a phosphatase which could recognize the Tyr530 negative regulatory site. In fractionated cell extracts from the breast tumor cells, we found elevated levels of a membrane associated tyrosine phosphatase activity that preferentially dephosphorylated a Src family carboxy-terminal phosphopeptide containing the regulatory tyrosine 530 site. Src was hypophosphorylated in vivo at tyrosine 530 in at least two of the tumor cell lines, further suggesting that Src was being activated by a phosphatase in these cells. In preliminary immunoprecipitation and antibody depletion experiments, we were unable to correlate the major portion of this phosphatase activity with several known phosphatases.
Breast Neoplasms↗
Protalign: a 3-dimensional protein alignment assessment tool.
Protein fold recognition (sometimes called threading) is the prediction of a protein's 3-dimensional shape based on its similarity to a protein of known structure. Fold predictions are low resolution; that is, no effort is made to rotate the protein's component amino acid side chains into their correct spatial orientations. The goal is simply to recognize the protein family member that most closely resembles the target sequence of unknown structure and to create a sensible alignment of the target to the known structure (i.e., a structure-sequence alignment). To facilitate this type of structure prediction, we have designed a low resolution molecular graphics tool. ProtAlign introduces the ability to interact with and edit alignments directly in the 3-dimensional structure as well as in the usual 2-dimensional layout. It also contains several functions and features to help the user assess areas within the alignment. ProtAlign implements an open pipe architecture to allow other programs to access its molecular graphics capabilities. In addition, it is capable of "driving" other programs. Because amino acid side chain orientation is not relevant in fold recognition, we represent amino acid residues as abstract shapes or glyphs much like Lego (tm) blocks and we borrow techniques from comparative flow visualization using streamlines to provide clean depictions of the entire protein model. By creating a low resolution representation of protein structure, we are able to at least double the amount of information on the screen. At the same time, we create a view that is not as busy as the corresponding representations using traditional high resolution visualization methods which show detailed atomic structure. This eliminates distracting and possibly misleading visual clutter resulting from the mapping of protein alignment information onto a high resolution display of the known structure. This molecular graphics program is implemented in Open GL to facilitate porting to other platforms.
Amino Acid Sequence↗
PROMUSE: a system for multi-media data presentation of protein structural alignments.
We present and evaluate PROMUSE: an integrated visualization/sonification system for analyzing pairwise protein structural alignments (superpositions of two protein structures in three-dimensional space). We also explore how the use of sound can enhance the perception and recognition of specific aspects of the local environment at given positions in the represented molecular structure. Sonification presents several opportunities to researchers. For those with visual impairment, data sonification can be a useful alternative to visualization. Sonification can further serve to improve understanding of information in several ways. One use for data sonification is in tasks such as background monitoring, in which case sounds can be used to indicate thresholding events. With PROMUSE, data represented visually may be enhanced or disambiguated by adding sound to the presentation. This aspect of data representation is particularly important for showing features that are difficult to represent visually, due to occlusion or other factors. Another feature of our system is that by representing some variables through sound and others visually, the amount of information that may be represented simultaneously is extended. Our tool aims to augment the power of data visualization rather than replace it. To maximize the utility of our sonifications to represent data, we employed musical voices and melodic components with unique characteristics. We also used sound effects such as panning a voice to the left or right speaker and changing its volume to maximize the individuality of the sonification elements. By making the sonification parameters distinct, we allow the user to focus on those portions of the sonification necessary to resolve possible ambiguities in the visual display. Sonifications of low level data such as raw protein or DNA sequences tend to sound random, and not very musical. We chose instead to sonify an analysis of data features, and thereby present a higher level view of the data. We also used brief melodic phrases rather than single notes in order to generate sounds that were more pleasing and musically idiomatic. To validate the utility of our system, we present the results of an experiment in which PROMUSE was used to test the use of sound as an aid for clarifying visual information. We also compare the overall effectiveness of visual versus aural information delivery.
Computer Graphics↗
Low frequency of rearrangements of the homeobox gene HOXA9/t(7;11) in adult acute myeloid leukemia.
Translocation (7;11)(p15;p15) is uncommon in acute myeloid leukemia (AML) and may have a predilection to occur in Asian patients. It results in a reciprocal fusion of the homeobox gene HOXA9 and the nucleoporin gene NUP98. To ascertain the molecular features and the clinicopathological and prognostic significance of t(7;11)(p15;p15), 208 adult Chinese patients with AML were screened by Southern blot analysis with an HOXA9 cDNA probe and reverse transcription-polymerase chain reaction for NUP98/HOXA9. Three cases were found to have rearrangement of the HOXA9 gene. Two cases were found to have an NUP98/HOXA9 fusion transcript, with a breakpoint at NUP98 different from that previously described. The remaining case had no rearrangement of NUP98, nor was NUP98/HOXA9 detected. All positive cases had refractory AML with poor treatment outcome. In conclusion, t(7;11)/HOXA9 rearrangement was a rare event (3/208, 1.5%) in AML, even in a population where it was considered to be more prevalent. Two breakpoints in NUP98 may occur, and this is of importance in the design of primers to amplify t(7;11).
Adolescent↗
Comparison of the response of midgut epithelial cells and cell lines from lepidopteran larvae to CryIA toxins from Bacillus thuringiensis.
The cytotoxic responses of midgut epithelial cells (MEC) from spruce budworm (SBW), gypsy moth (GM) and silkworm (SW) larvae were compared with the cytotoxic response of lepidopteran cell lines (SF-9, SE-1a, and CF-1) to CryIA toxins from Bacillus thuringiensis. The MEC from SBW, SW and GM had binding proteins for CryIA(a,b,c) toxins, whereas the lepidopteran cell lines had binding proteins for CryIA(c). Single MEC exposed to CryIA(a,b,c) toxins in a qualitative lawn assay were equally susceptible to the toxins with a threshold response at about 1ng. The cell lines were not susceptible to CryIA(a,b) toxins in the dose range tested, but had threshold responses for CryIA(c) of 3.4ng for SF-9, 50.2ng for SE-1a and 5.9ng for CF-1. In the quantitative Live/Dead assay, MEC were equally susceptible to CryIA(a,b,c) toxins with a threshold effect at about 1ng and a maximum effect at about 10ng. CF-1 was most sensitive to CryIA(c) with a threshold effect at 0.39ng and a maximal effect at about 1ng. In contrast, a 25-50 times greater dose of CryIA(a) or CryIA(b) was required to elicit a similar response as CryIA(c) for CF-1. SF-9 and SE-1a were most susceptible to CryIA(c) with a threshold effect observed at about 0.5ng and maximal effects at about 2ng. SF-9 cells have a threshold and maximum response to CryIA(a,b) of about 10ng and 20ng, respectively. SE-1a cells have a threshold and maximal response to CryIA(a,b) of 5ng and 10ng, respectively. Intact midgut epithelium exposed to CryIA(a,b,c) toxins had a threshold dose of 2ng for CryIA(b), 10-30ng for CryIA(a) and 2-30ng for CryIA(c). This study has shown that MEC are affected by a broader spectrum of toxins compared to the lepidopteran larvae and insect cell lines.
Journal Article↗