Homozygous and frequent deletion of proximal 8p sequences in human prostate cancers: Identification of a potential tumor suppressor gene site

By using tissue microdissection and polymerase chain reaction (PCR) techniques, we examined 85 prostate tumors that were paired with normal tissues from the same patients for allelic loss at 26 highly polymorphic microsatellite sequences, 21 spanning 8p and 5 localized to 8q. Sixty-four tumors (75%) demonstrated loss of at least one 8p locus. Separate distal and proximal regions of deletion were observed as well as an intervening, staggered breakpoint. A novel region of homozygous deletion of sequences at the D8S87 locus was detected both by multiplex PCR and by fluorescence in situ hybridization within this breakpoint region. These data suggest that a tumor-suppressor gene mapping to proximal 8p is deleted frequently and is likely to be important for tumorigenesis in prostate tumors. Genes Chromosomes Cancer 23:255–262,1998. © 1998 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35128/1/8_ftp.pd

HMGIC (high mobility group protein isoform I-C)

Review on HMGIC (high mobility group protein isoform I-C), with data on DNA, on the protein encoded, and where the gene is implicated

Analysis of segmental residual growth after progressive bone lengthening in congenital lower limb deformity

SummaryIntroductionThe issue of prognosis in limb length discrepancy in children affected by congenital abnormality remains a subject of concern. Therapeutic strategy must take length prediction into account, to adapt equalization techniques and the timing of treatment. Initial prognosis, however, may need revising after completion of one or several surgical interventions on the pathologic limb. The aim of this study was to determine the different types of growth response that a bone segment can present after progressive lengthening in case of congenital limb length discrepancy.Materials and methodsA series of 114 bone lengthenings with external fixator, performed in 36 girls and 50 boys with congenital lower limb length discrepancy, was retrospectively analyzed. Bone segment growth rates were measured before lengthening, during the first year after frame removal and finally over long-term follow-up, calculating the ratios of radiological bone length to the number of months between two measurements. Mean follow-up was 4.54±0.2 years.ResultsChanges in short- and long-term growth rate distinguished five patterns of bone behavior after lengthening, ranging from growth acceleration to total inhibition.DiscussionThese five residual growth patterns depended on certain factors causing acceleration or, on the contrary, slowing down of growth: age at the lengthening operation, percentage lengthening, and minimal period between two lengthenings. These criteria help optimize conditions for resumed growth after progressive segmental lengthening, avoiding conditions liable to induce slowing down or inhibition, and providing a planning aid in multi-step lengthening programs.Level of evidenceLevel IV. Retrospective study

Low-grade extraskeletal osteosarcoma of the chest wall: case report and review of literature

<p>Abstract</p> <p>Background</p> <p>Low-grade extraskeletal osteosarcomas (ESOS) are extremely rare.</p> <p>Case presentation</p> <p>We present the first case of low-grade ESOS of the chest wall, which occurred in a 30-year-old man. Because of initial misdiagnosis and patient's refusal of surgery, the diagnosis was done after a 4-year history of a slowly growing mass in soft tissues, leading to a huge (30-cm diameter) calcified mass locally extended over the left chest wall. Final diagnosis was helped by molecular analysis of <it>MDM2 </it>and <it>CDK4 </it>oncogenes. Unfortunately, at this time, no surgical treatment was possible due to loco-regional extension, and despite chemotherapy, the patient died one year after diagnosis, five years after the first symptoms.</p> <p>Conclusion</p> <p>We describe the clinical, radiological and bio-pathological features of this unique case, and review the literature concerning low-grade ESOS. Our case highlights the diagnostic difficulties for such very rare tumours and the interest of molecular analysis in ambiguous cases.</p

SMARCB1/INI1 inactivation in renal medullary carcinoma

Aims: Renal medullary carcinoma (RMC), a rare and highly aggressive tumour which occurs in patients with sickle-cell disease, shares many clinicopathological features with collecting duct carcinoma (CDC). The molecular mechanisms underlying RMC and CDC are mainly unknown, and there is ongoing debate about their status as distinct entities. Loss of expression of SMARCB1/INI1, a chromatin remodelling regulator and repressor of cyclin D1 transcription, has been reported recently in RMC. The aim of our study was to investigate if such loss of expression is specific for RMC. SMARCB1/INI1 genetic alterations and cyclin D1 expression were also studied. Methods and results: Using immunochemistry, neoplastic cells showed complete loss of SMARCB1/INI1 expression in all six cases of RMC but in only one of 22 cases of CDC. In two RMC cases investigated, comparative genomic hybridization demonstrated complete loss of one SMARCB1/INI1 allele, with no other genomic imbalances, and no mutations were found on the remaining allele. Cyclin D1 was expressed in all RMCs, suggesting that SMARCB1/INI1 inactivation may result in increased cyclin D1 transcription. Conclusions: The specific SMARCB1/INI1 inactivation observed in RMCs suggests that RMC and CDC are different entities

MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified <it>MDM2 </it>gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy.</p> <p>Methods</p> <p>A panel of sarcoma cell lines with different <it>TP53 </it>and <it>MDM2 </it>status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined.</p> <p>Results</p> <p>Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type <it>TP53 </it>and amplified <it>MDM2</it>, or with Methotrexate in both <it>MDM2 </it>normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated <it>TP53</it>, but inhibited the effect of Methotrexate.</p> <p>Conclusion</p> <p>The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.</p

Running GAGs: myxoid matrix in tumor pathology revisited: What’s in it for the pathologist?

Ever since Virchow introduced the entity myxoma, abundant myxoid extracellular matrix (ECM) has been recognized in various reactive and neoplastic lesions. Nowadays, the term “myxoid” is commonly used in daily pathological practice. But what do today’s pathologists mean by it, and what does the myxoid ECM tell the pathologist? What is known about the exact composition and function of the myxoid ECM 150 years after Virchow? Here, we give an overview of the composition and constituents of the myxoid ECM as known so far and demonstrate the heterogeneity of the myxoid ECM among different tumors. We discuss the possible role of the predominant constituents of the myxoid ECM and attempt to relate them to differences in clinical behavior. Finally, we will speculate on the potential relevance of this knowledge in daily pathological practice

Le motif N-aminoamide pour la synthèse d'oligomères linéaires et cycliques ; étude de son impact conformationnel

This work describes the synthesis and the structural study of linear and cyclic mixed oligomers alternating N-aminoamide and amide bonds, named 1:1-[a/a-N-amino]mers. The first chapter is a bibliographic study on cyclization methods of peptides and pseudopeptides (backbone modified peptides) and their applications. It has been described that the incorporation of potential structural elements, like introduction of changes to peptide backbone, could be facilitating the cyclization of linear oligomers. With this in mind, the use of previous work in our laboratory, discussed in the second chapter, gives access to new phtaloylated 1:1-[a/a-N-amino]mers and also to the first protected cyclo-1:1-[a/a-N-amino]mers. The deprotection of phthalimid group of one of these cyclic compounds opens up new opportunities like functionalization of the deprotected nitrogen atom. The third chapter sums up the results of the structural analyses and principally highlights the original conformations adopted by these different oligomers and the influence of the N-aminoamide bond. The structures were established through a complete study using several spectroscopic techniques (NMR, IR, fluorescence, X-ray crystallography). For example, the X ray studies highlight the formation of nanotubes through an original self-assembling of deprotected cyclotetramers.Ce travail décrit la synthèse et l’étude structurale d’oligomères mixtes linéaires et cycliques, alternant des liens amides et N-aminoamides, nommés 1 :1-[a/a-N-amino]mères. Le premier chapitre est consacré à l’étude bibliographique des méthodes de cyclisation des peptides et pseudopeptides ainsi qu’à leurs nombreuses applications. Il a été décrit que l’incorporation d’éléments potentiellement structurants, comme l’introduction de modifications du squelette peptidique, pourrait faciliter la cyclisation des oligomères linéaires. Dans cette optique, l’exploitation de travaux antérieurs du laboratoire, exposée dans le deuxième chapitre, a donné accès à de nouveaux 1 :1-[a/a-N-amino]mères phtaloylés, puis aux premiers cyclo-1 :1-[a/a-N-amino]mères protégés. La déprotection du groupement phtalimide d’un de ces composés cycliques ouvre de nouvelles perspectives comme la fonctionnalisation de l’atome d’azote déprotégé. Le troisième chapitre résume les analyses structurales réalisées et met principalement en avant les conformations originales qu’adoptent ces différents oligomères ainsi que l’influence du lien N-aminoamide. Les structures ont été établies grâce à une approche complète associant plusieurs techniques spectroscopiques (RMN, IR, fluorescence et diffraction des rayons X). Par exemple, l’analyse par diffraction des rayons X a permis de mettre en évidence la formation de nanotubes due à un empilement original de cyclotétramères déprotégés