High expression of DNA repair pathways is associated with metastasis in melanoma patients.

We have identified a gene-profile signature for human primary malignant melanoma associated with metastasis to distant sites and poor prognosis. We analyse the differential gene expression by looking at whole biological pathways rather than individual genes. Among the most significant pathways associated with progression to metastasis, we found the DNA replication (P=10(-14)) and the DNA repair pathways (P=10(-16)).

A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib.

Non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g.

Robust interlaboratory reproducibility of a gene expression signature measurement consistent with the needs of a new generation of diagnostic tools.

Background: The increasing use of DNA microarrays in biomedical research, toxicogenomics, pharmaceutical development, and diagnostics has focused attention on the reproducibility and reliability of microarray measurements. While the reproducibility of microarray gene expression measurements has been the subject of several recent reports, there is still a need for systematic investigation into what factors most contribute to variability of measured expression levels observed among different laboratories and different experimenters.

Results: We report the results of an interlaboratory comparison of gene expression array measurements on the same microarray platform, in which the RNA amplification and labeling, hybridization and wash, and slide scanning were each individually varied.

Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.

Various T cell adhesion molecules and their cognate receptors on target cells promote T cell receptor (TCR)-mediated cell killing. In this report, we demonstrate that the interaction of epithelial cell marker E-cadherin with integrin alpha(E)(CD103)beta(7), often expressed by tumor-infiltrating lymphocytes (TILs), plays a major role in effective tumor cell lysis. Indeed, we found that although tumor-specific CD103(+) TIL-derived cytotoxic T lymphocyte (CTL) clones are able to kill E-cadherin(+)/intercellular adhesion molecule 1(-) autologous tumor cells, CD103(-) peripheral blood lymphocyte (PBL)-derived counterparts are inefficient.

p210(BCR-ABL) reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription.

The BCR-ABL oncoprotein exhibits deregulated protein tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph)-positive human leukemias. Here, we report that ectopic expression of p210(BCR-ABL) in the megakaryoblastic Mo7e cell line and in primary human CD34(+) progenitors trigger erythroid differentiation at the expense of megakaryocyte (MK) differentiation. Clonal culture of purified CD41(+)CD42(-) cells, a population highly enriched in MK progenitors, combined with the conditional expression of p210(BCR-ABL) tyrosine kinase activity by imatinib identified a true lineage reprogramming.

Digestive tumor bank protocol: from surgical specimens to genomic studies of digestive cancers.

Cancer is a complex polygenic and multifactorial disease, resulting from successive dynamic changes in the genome of somatic cells and from the accumulation of molecular alterations in both tumour cells and host cells. For the majority of cancers, including many malignancies of the gastrointestinal tract, our current means of diagnosis and treatment of the tumors are grossly insufficient. In recent years the development of several gene expression profiling methods such as comparative genomic hybridization (CGH), differential display, serial analysis of gene expression (SAGE) and DNA arrays, together with the sequencing of the human genome, has provided an opportunity to monitor and investigate the complete cascade of molecular events leading to tumor development and progression.

Microarray-based identification of tenascin C and tenascin XB, genes possibly involved in tumorigenesis associated with neurofibromatosis type 1.

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical manifestations. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors, which are resistant to conventional therapies.

Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach.

Polyploidization is a part of the normal developmental process leading to platelet production during megakaryocyte (MK) differentiation. Ploidization is mainly involved in cell enlargement, but it is not clear whether gene expression is modified during MK ploidization. In this study, human MKs were grown from CD34(+) cells in the presence of thrombopoietin and sorted according to their ploidy level.

The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes.

We recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB). Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis. Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes.

Expression and possible role of hPTTG1/securin in cutaneous malignant melanoma.

Human pituitary tumour-transforming gene 1 or hPTTG1 is a proto-oncogene that codes for securin, a protein involved in sister chromatid separation. Based on previous microarray data, we studied the expression of hPTTG1/securin in melanocytic lesions. In contrast to nevi and radial growth phase melanomas, securin was expressed by scattered cells in the vertical growth phase, suggesting a role in tumour progression.

Apoptosis regulation in tetraploid cancer cells.

Tetraploidy can result in cancer-associated aneuploidy. As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis. Knockout of Bax or overexpression of Bcl-2 facilitated the survival of tetraploid cells at least as efficiently as the p53 or p21 knockout.

Gene expression profiling of primary cutaneous melanoma and clinical outcome.

Background: Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma.

Methods: Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray.

Follicular thyroid tumors with the PAX8-PPARgamma1 rearrangement display characteristic genetic alterations.

Follicular thyroid carcinomas (FTC) arise through oncogenic pathways distinct from those involved in the papillary histotype. Recently, a t(2;3)(q13;p25) rearrangement, which juxtaposes the thyroid transcription factor PAX8 to the peroxisome proliferator-activated receptor (PPAR) gamma1, was described in FTCs. In this report, we describe gene expression in 11 normal tissues, 4 adenomas, and 8 FTCs, with or without the PAX8-PPARgamma1 translocation, using custom 60-mer oligonucleotide microarrays.

AIF deficiency compromises oxidative phosphorylation.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex.

Epstein-Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells.

Epstein-Barr virus (EBV) latently infects and immortalizes B lymphocytes and causes lymphoproliferative malignancies. We show here that the EBV nuclear antigen EBNA2 induces expression of the 2 chains of the interleukin-18 receptor (IL-18R) in Burkitt lymphoma (BL) cell lines and in nontransformed B cells. Activation of IL-18R expression by EBNA2 is independent of its interaction with the transcriptional repressor RBPJ kappa.

Irofulven cytotoxicity depends on transcription-coupled nucleotide excision repair and is correlated with XPG expression in solid tumor cells.

Background: Irofulven is a novel alkylating agent with promising clinical activity, particularly toward ovarian and hormone-refractory prostate cancers. To facilitate additional clinical development, we have aimed to identify biological markers associated with sensitivity to the compound.

Methods: Fibroblasts derived from patients with xeroderma pigmentosum or Cockayne's syndrome along with a panel of 20 human cancer cell lines (eight different tumor types) were examined to establish the importance of nucleotide excision repair proteins in the sensitivity to irofulven.

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation.

[Beta-lactam resistance in aquatic Enterobacter cloacae strains using phenotypic and genotypic criteria].

Bacterial resistance by producing of beta-lactamases represents an increasing problem of infections chemotherapy. beta-lactam hydrolyzing activities are detected in virtually all bacteria, from witch Enterobacter cloacae produce chromosomal beta-lactamases included in inducible class AmpC beta-lactamases. The purpose of this preliminary study was to investigate the antibiotic susceptibility of 7 inducible beta-lactamase-producing Enterobacter cloacae strains isolated from aquatic sources (river and polluted waters).

[Clonal analysis of some multiple antibiotic resistant E. coli strains isolated from river and polluted waters].

Several multiple antibiotic resistant E. coli strains isolated from river and polluted waters were compared for their genetic relatedness. Antibiotic susceptibility testing was performed for gentamycin, kanamycin, ampicillin, tetracycline, chloramphenicol, ceftazidime and cefotaxime, as described by Kirby-Bauer disk diffusion method following NCCLS recommendations.

[Correlation between multiple antibiotic resistance and heavy-metal tolerance among some E.coli strains isolated from polluted waters].

Self-transmissible plasmids conferring multiple antibiotic resistance are wide-spread in coliforms populations. In soil and water, multiple antibiotic resistance is clearly associated with resistance/tolerance to heavy-metals (Hg2+, Cu2+, Pb2+, Zn2+, Ca2+). For different genera the genes for heavy-metals resistance are often plasmid encoded.

[Distribution and diversity of conjugative plasmids among some multiple antibiotic resistant E.coli strains isolated from river waters].

In natural bacterial communities the microbial structure and functions are subjected to dynamic environmental and genetic adaptation. Plasmid-mediated horizontal genes transfer has a major impact on the adaptability of bacteria, exemplified by the interspecific and intergeneric transfer of antibioresistance genes in a variety of aquatic media. The high incidence of resistant bacteria has been documented for fresh waters, marine waters and chronically polluted waters.

[Study of antibiotic influence on adherence capacity of gram positive and gram negative bacteria to the cellular substrate].

Bacterial adherence to the cellular substrate (skin and mucosa) represents a precondition of infectious pathology. It was demonstrated that bacteria which adhere and form biofilms on catheters and other inert materials used in medicine are resistant to the therapeutic antibiotic concentrations being protected by the biofilm mathrix and generating severe and hard to treat infections. There are only few studies on the influence of antibiotics on the bacterial adhesins synthesis and bacterial adherence to the cellular substrate.

[ Study of exo-enzymatic profile and cytotoxic effect of bacterial culture supernatants in different growth phase].

Bacterial quorum-sensing represents an ubiquitary regulating system in which the pheromones (small molecules with different chemical structures, i.e. homoserin-lactones, octapeptides, aminoacids) act as extracellular mediators of signaling and intercellular communication.

[Factors influencing the capacity of cellular substrate adherence of vibrio cholerae O1 and non O1 strains].

Bacterial adherence to eukariotic cells represents an important step of tissue colonization and is mediated by specific molecules called adhesins. Bacterial adherence to cellular substrate is a very complex process consisting in specific interactions between the surface of host cell and bacterial cell surface respectively. Adherence to cellular substrate confers selective advantages to bacterial cells, as: rapid growth rate by shorter lag period and protection against antibodies and lysozime.