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Abnormal hyperphosphorylation of tau is believed to constitute a critical biochemical event in the process of neurofibrillary degeneration of Alzheimer's disease. We have developed a cellular model where apparently authentic PHF-like tau hyperphosphorylation is induced by okadaic acid. To gain deeper insight into the complex mechanisms of this pathological process we tested a variety of kinase inhibitors in this model. We found that K252a is differentiated from staurosporine by its inhibition of ERK2: both compounds are structurally related microbial metabolites generally believed to have only moderate kinase selectivity. However, since ERK2 inhibitors are exceedingly rare, we used this differential inhibitory property of K252a to demonstrate the involvement of ERK2 in PHF-type tau hyperphosphorylation. K252a was uniquely able to completely suppress the okadaic acid-induced tau hyperphosphorylation in SH-SY5Y cells and rat brain slices by way of including ERK2 in its inhibitory spectrum, and to conserve the normal binding of tau to tubulin. GSK3 inhibitors partially affected the normal state of tau phosphorylation in SH-SY5Y cells, but had no impact on okadaic acid-induced tau hyperhosphorylation. As K252a is the first molecule identified capable of preventing the spectrum of PHF-like tau hyperphosphorylation markers, it may represent a conceptual starting point for therapeutic development of suitable spectrum kinase inhibitors. [ABSTRACT FROM AUTHOR]

Glial tumours are a devastating, poorly understood condition carrying a gloomy prognosis for which clinicians sorely lack reliable predictive parameters facilitating a sound treatment strategy. Tp73, a p53 family member, expresses two main classes of isoforms--transactivatory activity (TA)p73 and DeltaTAp73--exhibiting tumour suppressor gene and oncogene properties, respectively. The authors examined their expression status in high- and low-grade adult gliomas. Isoform-specific real-time reverse transcription-polymerase chain reaction was used for the analysis of Tp73 isoform transcript expression in a series of 51 adult patients harbouring glial tumours, in order to compare tumour grades with each other, and with non-tumoural samples obtained from epileptic patients as well. Our data demonstrate increase of TAp73 and DeltaTAp73 transcript levels at onset and early stage of the disease. We also show that DeltaEx2-3 isoform expression in low-grade tumours anticipates clinical and imaging progression to higher grades, and correlates to the patients' survival. Expression levels of P1 promoter generated Tp73 isoforms--and particularly DeltaEx2-3--indeed allow for prediction of the clinical progression of low-grade gliomas in adults. Our data are the first such molecular biology report regarding low-grade tumours and as such should be of help for sound decision-making. [ABSTRACT FROM AUTHOR]

Abstract Since its molecular characterisation, Ostreid herpesvirus 1 (OsHV-1) has been regularly detected in Crassostrea gigas in France. Although its pathogenicity was demonstrated on larval stages, its involvement during mortality outbreaks at the juvenile stage was highly suspected but not evidenced. To investigate mortality outbreaks, the French National Network for Surveillance and Monitoring of Mollusc Health (REPAMO) carried out two surveys in juvenile C. gigas. The first survey lasted from 1998 to 2006 and was an epidemiological inquiry occurring when oyster farmers reported mortality outbreaks. The second survey, a longitudinal one, was set up in 1998 to complete the network observations on OsHV-1. Data analysis showed a specific pattern of mortality outbreaks associated with OsHV-1 detection. Ostreid herpesvirus 1 detection mainly appeared during the summer, suggesting the influence of the seawater temperature on its occurrence. It mostly presented a patchy distribution in the field in contrast to the nursery. Significant relationship between OsHV-1 detection and spat mortality was found, preferentially in sheltered and closed environments. The longitudinal survey confirmed most of the network observations. Although subsequent works particularly epidemiological surveys would be useful to confirm the causal link between the detection of OsHV-1 and the mortality outbreaks in juvenile C. gigas, the role of OsHV-1 in oyster mortality is progressing.

ATA-001-FKRP (NCT05224505) is an open-label multicenter study consisting of 2 parts: a dose-escalation and a pivotal randomized placebo-controlled phase. All patients had a confirmed diagnosis of LGMDR9 and presented with respiratory impairment defined as a forced vital capacity (FVC) below 80% of predicted values. Patients received a single intravenous administration of ATA-100. The primary endpoint of the dose escalation is the safety of ATA-100 over 48 weeks, with secondary endpoints including functional outcomes, biomarkers in muscle biopsy and changes in alpha-dystroglycan (aDG) glycosylation. Part 1 is exploring two ATA-100 dose levels (9.0E12 and 2.7E13 vector genomes [vg] per Kg of body weight). Part 2 will further explore the dose shown to be safe and efficacious in Part 1. Interim data from Part 1 are presented herein. By April 2024, enrolment of the first cohort of Part 1 was completed with 3 patients (aged 29, 41, and 42) who received ATA-100 at the dose of 9.0E12 vg/Kg, with a mean follow-up of 14 months (range 8-19). The first patient of cohort 2 was enrolled in January 2024. All patients were homozygote for the common FKRP mutation L276I. ATA-100 was overall well-tolerated. The first 2 patients of Cohort 1 showed transaminase increase at the end of the corticosteroid tapering period (around Month 3 after administration), well controlled with increase in immunosuppressant treatment. The patient in Cohort 2 experienced an earlier transaminase increase compared to Cohort 1 patients (one-month post administration). Preliminary functional outcome data and biomarker analysis in the 3-month muscle biopsies, including αDG glycosylation at baseline and follow-up, will be presented. In conclusion, no unexpected safety signals were reported with ATA-100 at 9E12 to 2.7E13 vg/Kg to date. In addition, preliminary data shows target engagement and early signals of functional and histological improvements. [ABSTRACT FROM AUTHOR]

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4 DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings., (© 2024. The Author(s).)

Volatile organic compounds are key components of the fruit metabolome that contribute to traits such as aroma and taste. Here we report on the diversity of 90 flavor-related fruit traits in date palms ( Phoenix dactylifera L.) including 80 volatile organic compounds, which collectively represent the fruit volatilome, as well as 6 organic acids, and 4 sugars in tree-ripened fruits. We characterize these traits in 148 date palms representing 135 varieties using headspace solid-phase microextraction gas chromatography. We discovered new volatile compounds unknown in date palm including 2-methoxy-4-vinylphenol, an attractant of the red palm weevil ( Rhynchophorus ferrugineus Olivier), a key pest that threatens the date palm crop. Associations between volatile composition and sugar and moisture content suggest that differences among fruits in these traits may be characterized by system-wide differences in fruit metabolism. Correlations between volatiles indicate medium chain and long chain fatty acid ester volatiles are regulated independently, possibly reflecting differences in the biochemistry of fatty acid precursors. Finally, we took advantage of date palm clones in our analysis to estimate broad-sense heritabilities of volatiles and demonstrate that at least some of volatile diversity has a genetic basis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Flowers, Hazzouri, Lemansour, Capote, Gros-Balthazard, Ferrand, Lebrun, Amiri and Purugganan.)

Seven date palm seeds ( Phoenix dactylifera L.), radiocarbon dated from the fourth century BCE to the second century CE, were recovered from archaeological sites in the Southern Levant and germinated to yield viable plants. We conducted whole-genome sequencing of these germinated ancient samples and used single-nucleotide polymorphism data to examine the genetics of these previously extinct Judean date palms. We find that the oldest seeds from the fourth to first century BCE are related to modern West Asian date varieties, but later material from the second century BCE to second century CE showed increasing genetic affinities to present-day North African date palms. Population genomic analysis reveals that by ∼2,400 to 2,000 y ago, the P. dactylifera gene pool in the Eastern Mediterranean already contained introgressed segments from the Cretan palm Phoenix theophrasti , a crucial genetic feature of the modern North African date palm populations. The P. theophrasti introgression fraction content is generally higher in the later samples, while introgression tracts are longer in these ancient germinated date palms compared to modern North African varieties. These results provide insights into crop evolution arising from an analysis of plants originating from ancient germinated seeds and demonstrate what can be accomplished with the application of a resurrection genomics approach., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

The genus Mammillaria occupies diverse habitats and exhibits diverse growth patterns and a large range of morphologies. Most of the species of this genus are used as ornamental plants and are subject to mass habitat loss. Due to these factors, they are being submitted to selective pressure that might affect conservational efforts and management plans. We obtained the 133 gene chloroplast genome as part of the project of sequencing the complete genome of pincushion cactus, including 88 protein-coding genes, 8 rRNA genes, and 37 tRNA genes. The phylogenetic tree indicates the pincushion cactus is a sister species of M. supertexta and M. huitzilopochtli ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Date palms (Phoenix dactylifera) are an important fruit crop of arid regions of the Middle East and North Africa. Despite its importance, few genomic resources exist for date palms, hampering evolutionary genomic studies of this perennial species. Here we report an improved long-read genome assembly for P. dactylifera that is 772.3 Mb in length, with contig N50 of 897.2 Kb, and use this to perform genome-wide association studies (GWAS) of the sex determining region and 21 fruit traits. We find a fruit color GWAS at the R2R3-MYB transcription factor VIRESCENS gene and identify functional alleles that include a retrotransposon insertion and start codon mutation. We also find a GWAS peak for sugar composition spanning deletion polymorphisms in multiple linked invertase genes. MYB transcription factors and invertase are implicated in fruit color and sugar composition in other crops, demonstrating the importance of parallel evolution in the evolutionary diversification of domesticated species.

Date palm ( Phoenix dactylifera L.) is a major fruit crop of arid regions that were domesticated ∼7,000 y ago in the Near or Middle East. This species is cultivated widely in the Middle East and North Africa, and previous population genetic studies have shown genetic differentiation between these regions. We investigated the evolutionary history of P. dactylifera and its wild relatives by resequencing the genomes of date palm varieties and five of its closest relatives. Our results indicate that the North African population has mixed ancestry with components from Middle Eastern P. dactylifera and Phoenix theophrasti , a wild relative endemic to the Eastern Mediterranean. Introgressive hybridization is supported by tests of admixture, reduced subdivision between North African date palm and P. theophrasti , sharing of haplotypes in introgressed regions, and a population model that incorporates gene flow between these populations. Analysis of ancestry proportions indicates that as much as 18% of the genome of North African varieties can be traced to P. theophrasti and a large percentage of loci in this population are segregating for single-nucleotide polymorphisms (SNPs) that are fixed in P. theophrasti and absent from date palm in the Middle East. We present a survey of Phoenix remains in the archaeobotanical record which supports a late arrival of date palm to North Africa. Our results suggest that hybridization with P. theophrasti was of central importance in the diversification history of the cultivated date palm., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

High throughput random mutagenesis is a powerful tool to identify which residues are important for the function of a protein, and gain insight into its structure-function relation. The human muscle nicotinic acetylcholine receptor was used to test whether this technique previously used for monomeric receptors can be applied to a pentameric ligand-gated ion channel. A mutant library for the α1 subunit of the channel was generated by error-prone PCR, and full length sequences of all 2816 mutants were retrieved using single molecule real time sequencing. Each α1 mutant was co-transfected with wildtype β1, δ, and ε subunits, and the channel function characterized by an ion flux assay. To test whether the strategy could map the structure-function relation of this receptor, we attempted to identify mutations that conferred resistance to competitive antagonists. Mutant hits were defined as receptors that responded to the nicotinic agonist epibatidine, but were not inhibited by either α-bungarotoxin or tubocurarine. Eight α1 subunit mutant hits were identified, six of which contained mutations at position Y233 or V275 in the transmembrane domain. Three single point mutations (Y233N, Y233H, and V275M) were studied further, and found to enhance the potencies of five channel agonists tested. This suggests that the mutations made the channel resistant to the antagonists, not by impairing antagonist binding, but rather by producing a gain-of-function phenotype, e.g. increased agonist sensitivity. Our data show that random high throughput mutagenesis is applicable to multimeric proteins to discover novel functional mutants, and outlines the benefits of using single molecule real time sequencing with regards to quality control of the mutant library as well as downstream mutant data interpretation., Competing Interests: All authors except L.G. Sivilotti are employed by the Novartis Institutes for BioMedical Research. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Somatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN., Methods: Genomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected., Results: In total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%±11% vs 34.9%±7%, log-rank p<0.05)., Conclusion: NBs harbouring regional amplification(s) without MNA are rare and seem to show atypical features in clinical presentation and genomic profile. Further high resolution genetic explorations are justified in this heterogeneous group, especially when considering these alterations as predictive markers for targeted therapy.

Neuroblastoma is a pediatric cancer of the peripheral nervous system in which structural chromosome aberrations are emblematic of aggressive tumors. In this study, we performed an in-depth analysis of somatic rearrangements in two neuroblastoma cell lines and two primary tumors using paired-end sequencing of mate-pair libraries and RNA-seq. The cell lines presented with typical genetic alterations of neuroblastoma and the two tumors belong to the group of neuroblastoma exhibiting a profile of chromothripsis. Inter and intra-chromosomal rearrangements were identified in the four samples, allowing in particular characterization of unbalanced translocations at high resolution. Using complementary experiments, we further characterized 51 rearrangements at the base pair resolution that revealed 59 DNA junctions. In a subset of cases, complex rearrangements were observed with templated insertion of fragments of nearby sequences. Although we did not identify known particular motifs in the local environment of the breakpoints, we documented frequent microhomologies at the junctions in both chromothripsis and non-chromothripsis associated breakpoints. RNA-seq experiments confirmed expression of several predicted chimeric genes and genes with disrupted exon structure including ALK, NBAS, FHIT, PTPRD and ODZ4. Our study therefore indicates that both non-homologous end joining-mediated repair and replicative processes may account for genomic rearrangements in neuroblastoma. RNA-seq analysis allows the identification of the subset of abnormal transcripts expressed from genomic rearrangements that may be involved in neuroblastoma oncogenesis.

Activating mutations of the ALK gene have been identified in sporadic and familial cases of neuroblastoma (NB), a cancer of the peripheral nervous system, and are thought to be the primary mechanism of oncogenic activation of this receptor in this pediatric neoplasm. To address the possibility that ALK activation may occur through genomic rearrangements as detected in other cancers, we first took advantage of high-resolution array-comparative genomic hybridization to search for ALK rearrangements in NB samples. Using complementary experiments by capture/paired-end sequencing and FISH experiments, various types of rearrangements were fully characterized, including partial gains or amplifications, in several NB cell lines and primary tumors. In the CLB-Bar cell line, we described a genomic rearrangement associated with an amplification of the ALK locus, leading to the expression of a 170 kDa protein lacking part of the extracellular domain encoded by exons 4 to 11, named ALK(Δ4-11). Analysis of genomic DNA from the tumor at diagnosis and relapse revealed that the ALK gene was amplified at diagnosis but that the rearranged ALK allele was observed at the relapse stage only, suggesting that it may be implicated in tumor aggressiveness. Consistently, oncogenic and tumorigenic properties of the ALK(Δ4-11) variant were shown after stable expression in NIH3T3 cells. Moreover, we documented an increased constitutive kinase activity of this variant, as well as an impaired maturation and retention into intracellular compartments. These results indicate that genomic rearrangements constitute an alternative mechanism to ALK point mutations resulting in receptor activation.

Neuroblastic tumours may occur in a predisposition context. Two main genes are involved: PHOX2B, observed in familial cases and frequently associated with other neurocristopathies (Ondine's and Hirschsprung's disease); and ALK, mostly in familial tumours. We have assessed the frequency of mutations of these two genes in patients with a presumable higher risk of predisposition. We sequenced both genes in 26 perinatal cases (prebirth and <1 month of age, among which 10 were multifocal), 16 multifocal postnatal (>1 month) cases, 3 pairs of affected relatives and 8 patients with multiple malignancies. The whole coding sequences of the two genes were analysed in tumour and/or constitutional DNAs. We found three ALK germline mutations, all in a context of multifocal tumours. Two mutations (T1151R and R1192P) were inherited and shared by several unaffected patients, thus illustrating an incomplete penetrance. Younger age at tumour onset did not seem to offer a relevant selection criterion for ALK analyses. Conversely, multifocal tumours might be the most to benefit from the genetic screening. Finally, no PHOX2B germline mutation was found in this series. In conclusion, ALK deleterious mutations are rare events in patients with a high probability of predisposition. Other predisposing genes remain to be discovered.

A simple, optical density-based assay for inhibitors of the mevalonate-dependent pathway for isoprenoid biosynthesis was developed. The assay uses pathway-sensitized Staphylococcus aureus strains and is fully compatible with high-density screening in a 1536-well format. S. aureus strains were constructed in which genes required for mevalonate-dependent isopentenyl pyrophosphate (IPP) synthesis were regulated by an isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible promoter. Inhibitors of the target enzymes displayed greater antibacterial potency in media containing low concentrations of IPTG, and therefore less induction of mevalonate pathway genes, than in media with high IPTG conditions. This differential growth phenotype was exploited to bias the cell-based screening hits toward specific inhibitors of mevalonate-dependent IPP biosynthesis. Screens were run against strains engineered for regulation of the enzymes HMG-CoA synthase (MvaS) and mevalonate kinase (mvaK1), mevalonate diphosphate decarboxylase (mvaD), and phosphomevalonate kinase (mvaK2). The latter three enzymes are regulated as an operon. These assays resulted in the discovery of potent antibacterial hits that were progressed to an active hit-to-lead program. The example presented here demonstrates that a cell sensitization strategy can be successfully applied to a 1.3-million compound high-throughput screen in a high-density 1536-well format.

Bonamia ostreae is an intracellular protistan parasite affecting flat oysters Ostrea edulis. It can be detected in juveniles but mortalities mainly affect oysters which are more than 2 years old. The parasite is usually observed inside haemocytes and sometimes free, notably in gill epithelia suggesting a parasite release through this organ. However, the infective form and ways of entry and release remain undetermined. Flat oysters incubate their larvae in their pallial cavity for 8-10 days before releasing them into the water column. Flat oysters in Bay of Quiberon in South Brittany (France) are known to be infected with B. ostreae since 1979 and is the most important area in France for O. edulis spat collection. Flat oysters incubating larvae were sampled in this area during summertime between 2007 and 2009. Both adults and larvae were preserved and assayed by PCR and in situ hybridisation (ISH). PCR tests revealed the presence of parasite DNA in some adults and larvae. Specific labelling could be detected by ISH in gills, digestive system, gonad and mantle in adults and in the epithelium surrounding the visceral cavity of some larvae. Our results demonstrate that larvae can be infected with B. ostreae. Larvae might thus contribute to the spread of the parasite during their planktonic life. In addition, their transfer for aquaculture purpose should be controlled especially when they are exported from infected zones., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Bonamia ostreae is an intracellular protozoan which is recognized as a cause of mortality in European populations of flat oysters (Ostrea edulis). Based on the recent characterization of actin genes of B. ostreae, specific primers were designed for real-time PCR using SYBR Green chemistry. Specificity was demonstrated by the unique melting temperature peak observed in positive samples and by the lack of amplification in samples of oysters infected by closely related parasites, including Bonamia exitiosa. A calibration curve using a cloned template was defined to estimate copy number. The assay had a 6 log- dynamic range, mean inter- and intra-assay variation coefficients of <1% and a minimum detection limit of 50 gene copies per reaction. Using infected oyster samples as templates, the assay was at least 10-fold more sensitive than conventional PCR. The quantitative assay was applied to test 132 oysters, and results were compared with the heart imprint method. There was a strong correlation between both techniques, and the results showed that the real-time PCR assay should be useful for studies of the ecology of B. ostreae and its host-parasite relationship.

Bonamiosis due to the intrahaemocytic protistan parasite Bonamia ostreae is a European endemic disease affecting the flat oyster Ostrea edulis. The parasite has been described in various ecosystems from estuaries to open sea, but no clear correlation has yet been demonstrated between disease development and environmental parameters. In this study, the effect of temperature and salinity on the survival of purified parasites maintained in vitro in seawater was investigated by flow cytometry. Purified parasites were incubated in various seawater media (artificial seawater, natural seawater, seabed borewater) at various temperatures (4, 15 and 25 degrees C) and subjected to a range of salinities from 5 to 45 g l(-1). Parasites were collected after 12, 24 and 48 h of incubation for flow cytometry analyses including estimation of parasite mortality and parasite viability through detection of non-specific esterase activities. Artificial seawater appeared unsuitable for parasite survival, and results for all media showed a significantly lower survival at 25 degrees C compared to 4 degrees C and 15 degrees C. Moreover, high salinities (> or = 35 g l(-1)) favoured parasite survival and detection of esterase activities. Flow cytometry appears to be a suitable technique to investigate survival and activities of unicellular parasites like B. ostreae under varied conditions. Although these results contribute to a better understanding of existing interactions between the parasite B. ostreae and its environment, validation through epidemiological surveys in the field is also needed.

Phenotypic chemogenomics studies require screening strategies that account for the complex nature of the experimental system. Unknown mechanism of action and high frequency of false positives and false negatives necessitate iterative experiments based on hypotheses formed on the basis of results from the previous step. Process-driven High Throughput Screening (HTS), aiming to "industrialize" lead finding and developed to maximize throughput, is rarely affording sufficient flexibility to design hypothesis-based experiments.In this contribution, we describe a High Throughput Cherry Picking (HTCP) system based on acoustic dispensing technology that was developed to support a new screening paradigm. We demonstrate the power of hypothesis-based screening in three chemogenomics studies that were recently conducted.

Scintillation proximity assays (SPAs) have become a powerful tool for high-throughput screening (HTS) because they can measure the activity and binding of very diverse classes of drug targets. By applying the basic principles of ligand-receptor binding and enzyme kinetics, it is possible to build a large variety of miniaturized, high-throughput assays and screen millions of compounds. SPAs are enabled by the diversity of radiolabeled molecules and affinity tags that are commercially available. These synthetic radiotracers allow for minimal disturbance of the natural binding interactions. This article will present a comprehensive review of the technique and provide detailed information on its applications related to HTS, highlighting the major uses and giving some suggestions for future research.

Case Report: A 13-year-old boy presented with a history of intracranial hypertension. Radiologic studies revealed triventricular hydrocephalus secondary to a space-occupying lesion in the pineal region. Endoscopic third ventriculostomy was performed to treat hydrocephalus, and the lesion was biopsied. Complete resection of the tumor was subsequently performed. After a period of uncertainty, the diagnosis of papillary tumor of the pineal region was established. Tumor bed radiotherapy at a dose of 50 Gy was associated. With a follow-up of 15 months, the postoperative course was satisfactory with return to school and no residual tumor on magnetic resonance imaging., Conclusion: Papillary tumors of the pineal region constitute a rare entity, with a difficult diagnosis, an uncertain prognosis, and a high risk of local recurrence; they must be treated by a combination of surgery and radiotherapy. The only identified prognostic factor is the complete or incomplete nature of surgical resection.

In high-throughput screening (HTS), compounds can be tested in self-deconvoluting matrices (SDMs) of 10 compounds per well. The SDM setup is based upon a systematic mixing of compound samples such that each compound appears twice in the screening assay, in two independent mixtures. In order to test the quality of the SDM approach, we compared it with a standard single-compound screening approach. In a CXCR3 scintillation proximity assay, we performed five multiple screening trials of 26,400 compounds at a 10 microM screening concentration to estimate false positive and false negative rates in the compound population. No potent hits (<6.2 microM IC50) were missed in any screening method. Forty-eight percent of all actives were found in every screening trial independent of compound handling method. The SDM strategy had an average of 25 false positives and 15 false negatives as compared with an average of 34 false positives and 15 false negatives with a more conventional single-compound screening approach. Most of the variability resulted from day-to-day variation around the hit cutoff criterion, rather than from any particular screening technique. In the two most extreme examples, a compound with a 7.5 microM IC50 was missed in one out of two mixture trials, and a compound with a 6.2 microM IC50 was missed in one out of three single-compound trials. In the CXCR3 assay presented herein, the SDM screening method had better predictive value than the single-compound screening approach.

Modern nuclear medicine tests can be of great help to today's surgical oncologists. The new techniques of positron emission tomography (PET) and single photon emission computed tomography (SPECT), and the availability of new radiopharmaceuticals for localization of tumors and assessment of organ function provide information vital to the management of oncology patients.

The insertion of the inflation needle during laparoscopic procedures carries the risk of severe vascular damage to the aorto-cava bifurcation. Interindividual anatomic variation is great as shown by magnetic resonance imaging, increasing the risk of vascular damage. Four simple technical precautions are recommended to prevent accidents: insertion at the lower umbilical margin, widen distance between the umbilicus and the greater vessels, a 45 degree insertion angle and strictly medial position.

Objectives: Evaluate the different quality of life parameters in treated breast cancer patients., Type of Study: Retrospective analysis from 1977 to 1987., Study Site: Bichat, Lariboisière and Tenon Hospitals., Patients: 239 operated patients, with or without irradiation following or before chemotherapy, with or without hormonotherapy. Patients were divided into 4 groups according to age. STUDY PARAMETERS: Essentially, gynaecologic consequences of treatments (flush, menstrual cycles, fertility, vaginal dryness, breast reconstruction), effect of tamoxifen on genital organs and osteopenia., Main Results: Tamoxifen acts as an oestrogen both on genital organs and bones., Conclusion: The impact of substitutive hormone therapy on quality of life should be evaluated in randomized studies.

Chemotherapy using cis dichlorodiamine platinum (CDDP) in doses of 30 and 60 mg/m2 was carried out in 6 patients who had adenocarcinoma of the ovary, that had not been treated before, 15 to 120 minutes before surgery was carried out. The results of doses of platin given on the blood levels are demonstrated. A slight and progressive increase in the plasma levels of CDDP with peaks between 0.6 and 1.95 of total platinum and 0.22 mcg/ml of free platin were found. The tissue levels in the region of the ovaries were found to be between 0.16 and 0.94 mcg/mg. There was a stepwise increase in the levels found in the pathological peritoneal cover of between 0.42 and 31.2 mcg/mg. This dropped as time went by; and then led to change in accordance with the intra-peritoneal concentrations. This study shows that it is possible when giving drugs intraperitoneally to avoid high plasma peaks and to obtain good levels of concentration of cisplatin in the peritoneum.

On the basis of six cases and a review of the literature, the authors identify the special features associated with the combination of von Recklinghausen's disease and pregnancy. Fertility is unaffected and pregnancy possible. Careful monitoring is required because of severe complications. In certain probably minor forms of the disease, the outcome of pregnancy is favourable with no complications.

This study concerns the effects of anti-oestrogens which from now on are an integral part of back-up treatment for cancer of the breast. Seven cases where fibroids led to the need for laparotomy occurred in menopausal women who had been treated with tamoxifen. This has led us to discuss the paradoxical effect of this molecule, which is said to be anti-oestrogenic. This ambivalence is confirmed by studying the literature. These cases raise two questions which we try to answer: 1. Is the action of tamoxifen really anti-oestrogenic? 2. What management should be carried out to lessen the likelihood of tamoxifen treatment leading to laparotomy?