Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin.

To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage-response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL.

Novel BRD4-NUT fusion isoforms increase the pathogenic complexity in NUT midline carcinoma.

Nuclear protein in testis (NUT)-midline carcinoma (NMC) is a rare, aggressive disease typically presenting with a single t(15;19) translocation that results in the generation of a bromodomain-containing protein 4 (BRD4)-NUT fusion. PER-624 is a cell line generated from an NMC patient with an unusually complex karyotype that gave no initial indication of the involvement of the NUT locus. Analysis of PER-624 next-generation transcriptome sequencing (RNA-Seq) using the algorithm FusionFinder identified a novel transcript in which Exon 15 of BRD4 was fused to Exon 2 of NUT, therefore differing from all published NMC fusion transcripts. The three additional exons contained in the PER-624 fusion encode a series of polyproline repeats, with one predicted to form a helix. In the NMC cell line PER-403, we identified the 'standard' NMC fusion and two novel isoforms. Knockdown by small interfering RNA in either cell line resulted in decreased proliferation, increased cell size and expression of cytokeratins consistent with epithelial differentiation. These data demonstrate that the novel BRD4-NUT fusion in PER-624 encodes a functional protein that is central to the oncogenic mechanism in these cells. Genomic PCR indicated that in both PER-624 and PER-403, the translocation fuses an intron of BRD4 to a region upstream of the NUT coding sequence. Thus, the generation of BRD4-NUT fusion transcripts through post-translocation RNA-splicing appears to be a common feature of these carcinomas that has not previously been appreciated, with the mechanism facilitating the expression of alternative isoforms of the fusion. Finally, ectopic expression of wild-type NUT, a protein normally restricted to the testis, could be demonstrated in PER-403, indicating additional pathways for aberrant cell signaling in NMC. This study contributes to our understanding of the genetic diversity of NMC, an important step towards finding therapeutic targets for a disease that is refractory to current treatments.

Electrophysiological correlates of phonological processing: a cross-linguistic study.

It is well known that speech perception is deeply affected by the phoneme categories of the native language. Recent studies have found that phonotactics, i.e., constraints on the cooccurrence of phonemes within words, also have a considerable impact on speech perception routines. For example, Japanese does not allow (nonnasal) coda consonants. When presented with stimuli that violate this constraint, as in / ebzo/, Japanese adults report that they hear a /u/ between consonants, i.e., /ebuzo/. We examine this phenomenon using event-related potentials (ERPs) on French and Japanese participants in order to study how and when the phonotactic properties of the native language affect speech perception routines. Trials using four similar precursor stimuli were presented followed by a test stimulus that was either identical or different depending on the presence or absence of an epenthetic vowel /u/ between two consonants (e.g., "ebuzo ebuzo ebuzo- ebzo"). Behavioral results confirm that Japanese, unlike French participants, are not able to discriminate between identical and deviant trials. In ERPs, three mismatch responses were recorded in French participants. These responses were either absent or significantly weaker for Japanese. In particular, a component similar in latency and topography to the mismatch negativity (MMN) was recorded for French, but not for Japanese participants. Our results suggest that the impact of phonotactics takes place early in speech processing and support models of speech perception, which postulate that the input signal is directly parsed into the native language phonological format. We speculate that such a fast computation of a phonological representation should facilitate lexical access, especially in degraded conditions.

Involvement of Sp1 and microsatellite repressor sequences in the transcriptional control of the human CD30 gene.

CD30, as a member of the tumor necrosis factor (TNF) receptor family, is expressed on the surface of activated lymphoid cells. CD30 overexpression is a characteristic of lymphoproliferative diseases such as Hodgkin's/non-Hodgkin's lymphomas, embryonal carcinoma, and a number of Th2-associated diseases. The CD30 gene has been mapped to a region of the murine genome that is involved in susceptibility to systemic lupus erythematosus. Functionally, CD30 may play a role in the deletion of autoreactive T cells. We were interested in determining the molecular nature of CD30 overexpression. Sequence comparison has revealed significant identity between the TATA-less human and murine CD30 promoters; they share a number of common consensus binding motifs. Transfection assays identified three regions of transcriptional importance; the region between position -1.2 kb and -336 bp, containing a CCAT microsatellite sequence, a conserved Sp1 site at positions -43 to -38, and a downstream promoter element (DPE) at positions +24 to +29. EMSA and DNase I footprinting showed specific DNA-protein interactions of the CD30 promoter with the Sp1 site and the CCAT repeat region. The DPE element was shown to be essential for start site selection. We conclude that the conserved Sp1 site at -43 to -38 is associated with maximum reporter gene activity, the DPE element is required for start site selection, and the CCAT tetranucleotide repeats act to repress transcription. We also have shown that the microsatellite is multiallelic, when we screened a random healthy population. Further studies are required to determine whether microsatellite instability in the repressor predisposes susceptible individuals to CD30 overexpression.

[Idiopathic peri-cerebral enlargement in infants: simple anatomical variant or hemorrhagic risk factor?]. / Epanchement péricérébral idiopathique du nourrisson: simple variante anatomique ou facteur de risque hémorragique?

BACKGROUND: Idiopathic subarachnoid space enlargement (ISSE) is usually regarded as a benign lesion. CASE REPORTS: Two infants, 6 and 8 months old respectively, were hospitalized for neurological disorders revealing subdural hematoma. The first one was drowsy after an apparent life threatening event. The CT scan showed a recent subdural hematoma with ISSE. The outcome was spontaneously uneventful. The second patient presented a febrile hemiconvulsion preceding a status epilepticus. The diagnosis of empyema complicating subdural hematoma with ISSE was done on MRI. Recovery occurred after a 3 week course of parenteral antibiotics and 1 year of antiepileptic treatment. In these two cases, there was no history of head injury and the retrospective study of cranial perimeter growth curves showed acceleration before the acute event. CONCLUSION: The reputation of benignity is not usurped regarding the ISSE. Nevertheless, it must be recognized as a factor furthering emergence of subdural hematoma, even in absence of injury context.

[Closure of a hypogastric urinary fistula after replacement enterocystoplasty with a flap of the rectus abdominis muscle]. / Fermeture d'une fistule urinaire hypogastrique après entérocystoplastie de remplacement par lambeau musculaire de grand droit.

Urinary fistulization to the skin is a rare complication of cystoprostatectomy with replacement enterocystoplasty. In two cases, fistulization did not respond to continuous drainage of the urine and was treated with a muscle flap using the abdominus rectus. This method offers rapid parietal repair giving a reliable rapid cicatrization since the interpositioned flap is well vascularized in an area of poor tissue quality.

[TULIP: transurethral ultrasound-guided laser-induced prostatectomy. One-year clinical results]. / TULIP: transurethral ultrasound-guided laser-induced prostatectomy. Résultats cliniques à un an.

The TULIP (transurethral ultrasound-guided laser-induced prostatectomy) system combines a real-time ultrasound transducer and a Nd:YAG laser delivery system with a 1.064 microns wavelength within a 22 F urethral probe. The goal is to produce a coagulation necrosis of the prostatic parenchyma, with a subsequent elimination of tissue in the urine. 29 patients have been included in this study, and 13 have a minimal one year follow-up. No complication occurred. 2 patients underwent a transurethral resection of the prostate secondary to the TULIP treatment. All patients complained of irritative urinary symptoms (frequency, burning on urination...) in the days or weeks following the treatment, and suprapubic catheterization tube had to be left in place for a mean duration of 13.8 days. Inclusion/exclusion criteria and evaluation modalities have been the same as in the American national study published elsewhere. At one year, our success rate for at least one criteria has been 84.6%, but only 2 (15%) out of 13 patients have been successful both in symptom score and flow rate.

[TULIP: transurethral ultrasound-guided laser-induced prostatectomy. Clinical results after on year]. / TULIP: transurethral ultrasound-guided laser-induced prostatectomy. Résultats cliniques à un an.

The TULIP (Transurethral Ultrasound-guided Laser-Induced Prostatectomy) system combines a real-time ultrasound transducer and a Nd:YAG laser delivery system with a 1.064 micron wavelength within a 22 F urethral probe. The goal is to produce a coagulation necrosis of the prostatic parenchyma, with a subsequent elimination of tissue in the urine. 29 patients have been included in this study, and 13 have a minimal one year follow-up. No complication occurred. 2 patients underwent a transurethral resection of the prostate secondary to the TULIP treatment. All patients complained of irritative urinary symptoms (frequency, burning on urination...) in the days or weeks following the treatment, and suprapubic catheterization tube had to be left in place for a mean duration of 13.8 days. Inclusion/exclusion criteria and evaluation modalities have been the same as in the American national study published elsewhere. At one year, our success rate for at least one criteria has been 84.6%, but only 2 (15%) out of 13 patients have been successful both in symptom score and flow rate.