In vitro hydroquinone-induced instauration of histone bivalent mark on human retroelements (LINE-1) in HL60 cells.

Benzene is extensively used in industry despite its leukemogenic activity, representing a significant occupational hazard. We investigated if long-term treatment with low-doses hydroquinone (HQ), a benzene metabolite, might be sufficient to alter in vitro the epigenetic signature underlining LINE-1 sequences, a poorly explored step in health risks associated with benzene exposure. In HL-60 cell line, exploring the epigenetic events occurring in chromatin, we found the transient instauration of the distinctive signature combining the repressive H3Lys27 tri-methylation mark and the activating H3Lys4 tri-methylation mark (H3K27me3/H3K4me3), indicating a tendency toward a poised chromatin conformation.

Long-term storage and safe retrieval of human papillomavirus DNA using FTA elute cards.

Biobanking or collection and storage of specimens for future research purposes have become an essential tool in many fields of biomedical research and aims to provide a better understanding of disease mechanisms as well as the identification of disease-specific biomarkers that can navigate in complex diseases. In this study, we assessed the use of Flinders Technology Associates (FTA) cards as a long-term storage device for cervical specimens with suspected human papillomavirus (HPV) infections. HPV detection and genotyping results in liquid-based transport media were compared to HPV results from FTA cards.

[Reply to « Why is it difficult to implement biomedical policy? The ase of the Cancéropôles, the French cancer organizations », by Audrey Vézian, Med Sci (Paris) 2014 Aug-Sep; 30 (8-9) : 803-7].

The authors, all in charge of the administration of one of the 7 French Cancéropôles, reply to the article authored by Audrey Vézian, and -provide an alternative and more supportive view of the initiatives -sponsored by these regional cancer research networks.

Apoptotic HPV positive cancer cells exhibit transforming properties.

Previous studies have shown that DNA can be transferred from dying engineered cells to neighboring cells through the phagocytosis of apoptotic bodies, which leads to cellular transformation. Here, we provide evidence of an uptake of apoptotic-derived cervical cancer cells by human mesenchymal cells. Interestingly, HeLa (HPV 18+) or Ca Ski (HPV16+) cells, harboring integrated high-risk HPV DNA but not C-33 A cells (HPV-), were able to transform the recipient cells.

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression.

Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression.

In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1α target genes and decreases tumor angiogenesis.

Topoisomerase I is a privileged target for widely used anticancer agents such as irinotecan. Although these drugs are classically considered to be DNA-damaging agents, increasing evidence suggests that they might also influence the tumor environment. This study evaluates in vivo cellular and molecular modifications induced by irinotecan, a topoisomerase I-directed agent, in patient-derived colon tumors subcutaneously implanted in athymic nude mice.

Histologic characteristics of non-microsatellite-instable colon adenomas correlate with distinct molecular patterns.

Colon carcinogenesis encompasses the stepwise accumulation of genomic aberrations correlated with the transition of aberrant crypt-adenoma-carcinoma. Recent data have revealed that, in addition to the microsatellite-instable phenotype, the chromosome instability pathway, representing four fifth of the colon carcinoma, could be involved in heterogeneous molecular alterations. Our project was aimed at determining the existence of distinct molecular subtypes in 159 non-microsatellite-instable colon polyps and their correlation with histology and dysplasia, using allelotyping, MGMT promoter gene methylation status, and K-RAS mutation analyses.

Interleukin-10 gene down-expression in circulating mononuclear cells during infusion of drotrecogin-α activated: a pilot study.

Introduction: The purpose of this study was to investigate the gene expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in circulating mononuclear cells harvested from septic shock patients on drotrecogin-α activated (DAA) in order to determine whether this treatment has any effect on the inflammation phase.

Methods: We conducted a prospective cohort study in two intensive care departments. Blood samples were collected at inclusion (T1) and 36 hours later (T2) to measure plasma cytokines and the changes in intracellular TNF-α, IL-10 and IFN-γ mRNA expressions using the real-time quantitative polymerase chain reaction (RT-qPCR).

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping.

Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity.

Marked activity of irinotecan and rapamycin combination toward colon cancer cells in vivo and in vitro is mediated through cooperative modulation of the mammalian target of rapamycin/hypoxia-inducible factor-1alpha axis.

Purpose: Despite recent progress, colon cancer is often resistant to combination chemotherapy, highlighting the need for development of novel therapeutic approaches. An attractive target is hypoxia-inducible factor-1alpha (HIF-1alpha), a key transcription factor with a pivotal role in tumor cell metabolism. One potential class of therapeutic agents targeting HIF-1alpha are mammalian target of rapamycin inhibitors such as rapamycin.

EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system. The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma with EGFR exon 19 deletion, associated with sensitivity to EGFR-TKI.

Diminution of Circulating CD4+CD25 high T cells in naïve Crohn's disease.

Crohn's disease is considered to be caused either by an excess of T-cell effector functions and/or by a defective regulatory T-cell compartment. The aim of this study was to assess in Crohn's disease the frequency of circulating CD4(+)CD25(high) T cells that possess regulatory T-cell functions and CD4(+)CD25(low) T cells that contain activated T cells. Flow cytometry of peripheral blood was used to assess CD4(+)CD25(high) and CD4(+)CD25(low) T-cell frequencies in a cohort of 66 patients with Crohn's disease in comparison to 19 patients with ulcerative colitis and 31 healthy individuals enrolled as controls.

Expression, purification, crystallization and preliminary crystallographic study of the SRA domain of the human UHRF1 protein.

Human UHRF1 belongs to the unique mammalian family of proteins which contain a SET- and RING finger-associated (SRA) domain. This 180-residue domain has been reported to play key roles in the functions of the protein. It allows UHRF1 to bind methylated DNA, histone deacetylase 1 and DNA methyltransferase 1, suggesting a bridge between DNA methylation and the histone code.

The PHD domain of Np95 (mUHRF1) is involved in large-scale reorganization of pericentromeric heterochromatin.

Heterochromatic chromosomal regions undergo large-scale reorganization and progressively aggregate, forming chromocenters. These are dynamic structures that rapidly adapt to various stimuli that influence gene expression patterns, cell cycle progression, and differentiation. Np95-ICBP90 (m- and h-UHRF1) is a histone-binding protein expressed only in proliferating cells.

MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naïve cohort.

Introduction: Recent clinical success of epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) have raised hopes that targeting other deregulated growth factor signaling, such as the hepatocyte growth factor/MET pathway, will lead to new therapeutic options for NSCLC. Furthermore, NSCLC present secondary EGFR-TKIs resistance related to exons 20 and 19 EGFR mutations or more recently to MET amplification. The aim of this study was to determine MET copy number related to EGFR copy number and K-Ras mutations in a targeted TKI naive NSCLC cohort.

[Translational research and Cancer Plan].

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it.

Involvement of MET/TWIST/APC combination or the potential role of ossification factors in pediatric high-grade osteosarcoma oncogenesis.

Dysregulated cell growth or differentiation due to misexpression of developmental critical factors seems to be a decisive event in oncogenesis. As osteosarcomas are histologically defined by malignant osteoblasts producing an osteoid component, we prospected in pediatric osteosarcomas treated with OS94 protocol the genomic status of several genes implied in ossification processes. In 91 osteosarcoma cases, we focused on the analysis of the fibroblast growth factor receptors (FGFRs) TWIST, APC, and MET by allelotyping, real-time quantitative polymerase chain reaction, gene sequencing, and protein polymorphism study.

Nonrandom variations in human cancer ESTs indicate that mRNA heterogeneity increases during carcinogenesis.

Virtually all cancer biological attributes are heterogeneous. Because of this, it is currently difficult to reconcile results of cancer transcriptome and proteome experiments. It is also established that cancer somatic mutations arise at rates higher than suspected, but yet are insufficient to explain all cancer cell heterogeneity.

KIT gene in pediatric osteosarcomas: could it be a new therapeutic target?

In our previous study, a frequent rearrangement at 4q12 has been identified by allelotyping in our large and homogeneous population of pediatric osteosarcomas and it was significantly linked to c-kit protein overexpression. To confirm and understand the involvement of KIT in this tumor, the next step of the study was designed to detect the potential mutations of KIT gene by sequencing the frequently mutated exons 6, 8, 10, 11, 13, 17 and 21 and, in case of unmutated samples, to confirm the genomic amplifications of the wild-type receptor by real-time quantitative PCR (QPCR). A new microsatellite and QPCR targeting PDGFRA was also added to check the accuracy of the 4q11-12 locus.

Influence of drotrecogin alpha (activated) infusion on the variation of Bax/Bcl-2 and Bax/Bcl-xl ratios in circulating mononuclear cells: a cohort study in septic shock patients.

Objective: Drotrecogin alpha (activated) (DAA), or recombinant human activated protein C, is a new treatment in sepsis-induced multiple organ failure, leading to significant reduction in the mortality rate, thanks to its anticoagulant properties. It has been suggested that DAA has anti-inflammatory and antiapoptotic effects in sepsis animal models. This study investigates the potential actions of DAA on circulating mononuclear cells apoptosis in human septic shock.

Allelotyping analyses of synchronous primary and metastasis CIN colon cancers identified different subtypes.

In colorectal cancer, the molecular alterations that lead to metastasis are not clearly established, probably because of their high genetic complexity. To identify combinations of genetic changes involved in tumor progression and metastasis, we focused on chromosome instable (CIN) colon cancers. We compared by allelotyping of 33 microsatellites, the genomic alterations of 38 primary colon tumors with the synchronously resected matched liver metastases (CLM).

[Value of urinary microsatellite analysis in the diagnosis of renal cancer].

Objective: To detect the presence of tumour DNA in urine of patients with renal cancer based on microsatellite analysis.

Material And Method: Blinded, comparative, experimental study conducted between July 1996 and December 2003. Preoperative urine and blood samples were collected from 69 patients with renal cancer (pT1 to pT4).

Primary tumour genetic alterations and intra-tumoral heterogeneity are maintained in xenografts of human colon cancers showing chromosome instability.

Evaluation of the role of clonal heterogeneity in colon tumour sensitivity/resistance to drugs and/or in conferring metastatic potential requires an adequate experimental model in which the tumour cells maintain the initial genetic alterations and intra-tumoral heterogeneity through maintenance of the genetic clones present in the initial tumour. Therefore, we xenografted subcutaneously into nude mice seven human colonic tumours (from stages B1 to D) that showed chromosome instability and transplanted them sequentially for up to 14 passages. Maintenance after xenografting of the genetic alterations present in the initial tumours was scored by allelotype studies targeting 45 loci localized on 18 chromosomes.

Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas.

The identification of genes as markers for chromosome aberrations in specific tumors might facilitate oncogenesis mechanism comprehension, cancer detection, prediction of clinical outcomes, and response to therapy. Previous physiologic and oncologic data identified the TWIST gene as a marker for mesodermal derivative and bone tissue differentiation, but its contribution to bone malignancies has not been investigated. In the present study, search for genomic alterations in high-grade pediatric osteosarcomas was focused on the 7p21 region, and more specifically on the TWIST gene.