The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88

The oncogenic nucleoporin CAN/Nup214 is essential in vertebrate cells. Its depletion results in defective nuclear protein import, inhibition of messenger RNA export and cell cycle arrest. We recently found that CAN associates with proteins of 88 and 112 kDa, which we have now cloned and characterized. The 88 kDa protein is a novel nuclear pore complex (NPC) component, which we have named Nup88. Depletion of CAN from the NPC results in concomitant loss of Nup88, indicating that the localization of Nup88 to the NPC is dependent on CAN binding. The 112 kDa protein is the human homologue of yeast CRM1, a protein known to be required for maintenance of correct chromosome structure. This human CRM1 (hCRM1) localized to the NPC as well as to the nucleoplasm. Nuclear overexpression of the FG-repeat region of CAN, containing its hCRM1-interaction domain, resulted in depletion of hCRM1 from the NPC. In CAN-/- mouse embryos lacking CAN, hCRM1 remained in the nuclear envelope, suggesting that this protein can also bind to other repeat-containing nucleoporins. Lastly, hCRM1 shares a domain of significant homology with importin-beta, a cytoplasmic transport factor that interacts with nucleoporin repeat regions. We propose that hCRM1 is a soluble nuclear transport factor that interacts with the NPC.     

A PMLRARalpha transgene initiates murine acute promyelocytic leukemia

The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.     

An efficient method of FIR filtering based on impulse responserounding

A new method of implementing efficient FIR filters is presented. It involves approximation of an equiripple FIR by a rounding operation and application of the derived impulse response by a simple recursive equation. The technique is extremely efficient for lowpass, highpass, bandpass, and bandstop filters with sharp transitions and low edge frequencies     

Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.     

The Transmogrifier-2: a 1 million gate rapid-prototyping system

This paper describes the Transmogrifier-2 (TM-2), a second-generation multifield programmable gate array (FPGA) rapid-prototyping system. The largest version of the system will comprise 16 boards that each contain two Altera 10K50 FPGA's, four I-Cube interconnect chips, and up to 8 Mbytes of memory. The inter-FPGA routing architecture of the TM-2 uses a novel interconnect structure, a nonuniform partial crossbar, that provides a constant delay between any two FPGA's in the system. The TM-2 architecture is modular and scalable, meaning that systems of various sizes can be constructed from copies of the same board, while maintaining routability and the constant delay feature. Other features include a system-level programmable clock that allows single-cycle access to off-chip memory, and programmable clock waveforms with edge resolution of 10 ns. The first Transmogrifier-2 boards have been manufactured and are functional. They have recently been used successfully in some simple graphics acceleration applications     

Method for preventing delay ambiguity

A detection error mechanism termed delay ambiguity is identified as one of the main causes of the irreducible bit error rate observed for data detection over fast fading communication channels. A periodic sequence of phase rotations applied to the phase shift keyed (PSK) transmit data symbols is proposed to prevent this type of detection error     

The L5178Y/tk+/- mouse lymphoma specific gene and chromosomal mutation assay a phase III report of the U.S. Environmental Protection Agency Gene-Tox Program

The L5178Y/tk+/- (-)3.7.2C mouse lymphoma assay (MLA) which detects mutations affecting the heterozygous thymidine kinase (tk) locus is capable of responding to chemicals acting as clastogens as well as point mutagens. Improvements in the assay to enhance detection of this spectrum of genetic events are summarized, and criteria for evaluating the data are defined. Using these criteria, the Phase III Work Group reviewed and evaluated literature containing MLA results published from 1976 through 1993. The data base included 602 chemicals of which 343 were evaluated as positive, 44 negative, 18 equivocal, 54 apparently inappropriate for evaluation in this test system with the published protocols, and 142 that were inadequately tested, and thus a definitive call could not be made. The overall performance of the assay is summarized by chemical class, and the outcome of testing 260 chemicals in the MLA is compared with Gene-Tox and National Toxicology Program evaluations of rodent carcinogenesis bioassay results for the same chemicals. Based on the Work Group's evaluation of published MLA data for chemicals that were considered adequately tested, it is concluded that for most chemicals the L5178Y/tk+/- mouse lymphoma assay is eminently well suited for genotoxicity testing and for predicting the potential for carcinogenicity.     

Multicenter study on the clinical value of fetal pulse oximetry. I. Methodologic evaluation. The French Study Group on Fetal Pulse Oximetry

OBJECTIVE: Our purpose was to evaluate the feasibility of intrapartum fetal pulse oximetry, the distribution of fetal oxygen saturation values, and the relationship with the neonatal outcome in a population with an abnormal fetal heart rate. STUDY DESIGN: A prospective multicenter observational study was performed from June 1994 to November 1995. Fetal oxygen saturation was continuously recorded with use of a Nellcor N-400 fetal pulse oximeter in case of an abnormal fetal heart rate during labor. Simultaneous readings of fetal oxygen saturation and fetal blood analysis were obtained at inclusion and before birth. Feasibility, adverse effects, distribution of fetal oxygen saturation values, and relationship with neonatal outcome were assessed. RESULTS: One hundred seventy-four patients were included. From 172 attempted sensor placements, the procedure was impossible in three cases and fetal oxygen saturation values were obtained in 164 cases (95.3%). Physicians considered sensor placement an easier task than an attempt at fetal blood analysis (easy in 87.5% vs 78.9% for fetal blood analysis, p = 0.03). The mean reliable signal time (+/- SD) was 64.7% +/- 32% during the first stage. There were no serious adverse effects in the study population. The mean fetal oxygen saturation during the first stage of labor was 42.2% +/- 8.0% (10th to 90th percentile range 30% to 53%). Fetal oxygen saturation was significantly correlated with scalp pH (r = 0.29, p = 0.01) but not with neonatal umbilical artery pH or gas values. There was a significant association between low fetal oxygen saturation (< 30%) and poor neonatal condition. CONCLUSION: The feasibility of fetal pulse oximetry is satisfactory in clinical practice. It is easy to use and provides a fair rate of recorded values, even in a population with suspicion of fetal distress. A low fetal oxygen saturation is significantly associated with an abnormal neonatal outcome.     

Large cell neuroendocrine carcinoma of the thymus

AIM: We highlight the occurrence of an unusual neuroendocrine tumour, a large cell neuroendocrine carcinoma, arising from the thymus. CASE DETAILS: A 68-year-old man with a history of cigarette smoking had a large mediastinal tumour arising from the thymus removed. Two years later the tumour recurred; it was debulked surgically but the patient died 2 months later: Histological examination of both tumour specimens revealed a tumour with an endocrine pattern, composed of large pleomorphic cells with large nuclei and prominent nucleoli. The mitotic count ranged from 19 to 26 per 10 high-power fields and large tracks of coagulative tumour necrosis were present. The tumour cells were strongly positive for neuron-specific enolase (NSE), chromogranin, CAM5.2 and AE1/3, with cytoplasmic dot-like accentuation for the latter three markers. The tumour fulfilled the criteria for a diagnosis of large cell neuroendocrine carcinoma. CONCLUSIONS: Large cell neuroendocrine carcinoma should be distinguished from atypical carcinoid and small cell carcinoma. It is a distinctive neuroendocrine malignancy with a prognosis between that of atypical carcinoid and small cell carcinoma, and needs to be treated aggressively.