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In a first study, we identified signatures of 3 mRNAs (semaphorin 3D [SEMA3D], cytokeratin 16 [KRT16] and UL16 binding protein 2 [ULBP2]) associated to response to a cisplatin-vinorelbin chemotherapy and to survival of advanced non-small cell lung cancers (NSCLC).The aim of this study was to develop immunohistochemistry tests for KRT16, ULBP2 and SEMA3D and to test proteins expression for prediction of response and survival in biopsies of the same patients.We were not able to reproduce by the protein expression study the signature predicting response to chemotherapy in advanced NSCLC.We highlight the difficulties of translational research in thoracic oncology emphasizing the complexity in obtaining adequate tissue samples and the difficulties in conduction and transposing in routine practice high throughput technique for transcriptomic analyses.

The recent literature included interesting reports on the pathogenic mechanisms of hereditary neuropathies. The axonal traffic and its abnormalities in some forms of Charcot-Marie-Tooth (CMT) disease were particularly reviewed by Bucci et al. Many genes related to CMT disease code for proteins that are involved directly or not in intracellular traffic. KIF1B controls vesicle motility on microtubules. MTMR2, MTMR13 and FIG4 regulate the metabolism of phosphoinositide at the level of endosomes. The HSPs are involved in the proteasomal degradation. GDAP1 and MFN2 regulate the mitochondrial fission and fusion respectively and the mitochondial transport within the axon. Pareyson et al. reported a review on peripheral neuropathies in mitochondrial disorders. They used the term of "mitochondrial CMT" for the forms of CMT with abnormal mitochondrial dynamic or structure. Among the new entities, we can draw the attention to a proximal form of hereditary motor and sensory neuropathy with autosomal dominant inheritance, which is characterized by motor deficit with cramps and fasciculations predominating in proximal muscles. Distal sensory deficit can be present. The gene TFG on chromosome 3 has been recently identified to be responsible for this form. Another rare form of axonal autosomal recessive neuropathy due to HNT1 gene mutation is characterized by the presence of hands myotonia that appears later than neuropathy but constitute an interesting clinical hallmark to orientate the diagnosis of this form. In terms of differential diagnosis, CMT4J due to FIG4 mutation can present with a rapidly progressive and asymmetric weakness that resembles CIDP. Bouhy et al. made an interesting review on the therapeutic trials, animal models and the future therapeutic strategies to be developed in CMT disease.

Antigen carbohydrate CA125 is a tumor marker used in the monitoring of epithelial ovarian cancers. It is a transmembranaire glycoprotein with a high molecular weight. It is a mucin with a carbohydrate content estimated to be 24-28%. CA125 is encoded by the gene MUC16 which is rich of tandem repeats. Different hypothesis were suggested concerning the mechanism of secretion of CA125 that could be soluble or attached to the cellular surface. This last form of CA125 has many molecular interactions such as with mesothelin and galectin. These interactions play a key role in the stimulation and the dissemination of ovarian cancer via the tumor marker CA125.

Malignant pleural mesothelioma (MPM) is a serious issue worldwide because of its increasing incidence and poor prognosis despite real recent improvements in the disease management. Most of the patients are diagnosed late in the course of the disease when radical treatment is no more an option. Therefore an earlier diagnosis of MPM is needed to significantly increase the survival of patients. Some soluble markers, including soluble mesothelin and osteopontin, have been previously proposed for MPM diagnosis but none has been validated yet. Soluble mesothelin, assessed in blood and in pleural effusion, seems to be the most promising candidate. However, even if it has a good diagnostic and prognostic value, it is quite specific for the epithelioid subtype, the most frequent one of mesothelioma, thus limiting its usefulness in practice. Despite sometimes a good sensitivity, other potential markers as osteopontin are of little interest for MPM diagnosis because of a low specificity. In conclusion, the present data do not justify the use of biology for MPM diagnosis in routine yet but rather suggest a need for a continuing evaluation of soluble mesothelin in clinical studies and the search for other potential tumor markers.

The increasing number of malignant pleural mesothelioma (MPM) is a serious public health problem. The prognosis of this tumor is poor and most of the patients are diagnosed late in the disease's course when curative treatment is no more an option. It is therefore necessary to diagnose earlier MPM in these patients in order to obtain a potential significant improvement in survival. Some serum markers have been previously proposed for MPM diagnosis but none had sufficient sensitivity and specificity for being use in routine. Recently, soluble mesothelin and osteopontin have been proposed as diagnostic markers for mesothelioma. The authors reviewed recent data concerning the utility of these two molecules in the diagnosis and the treatment of MPM. Mesothelin seems to be a specific marker for the epithelioid subtype of mesothelioma. Despite a good sensitivity, osteopontin has a low specificity for mesothelioma diagnosis. However, there is not enough data yet to propose guidelines on the use of these markers in a day to day practice.

Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene (C282Y mutation). The p.Cys282Tyr mutation of the HFE gene leads to an abnormal reduction in hepatic expression of hepcidin, a protein that appears to control the release of iron from enterocytes and macrophages towards plasma. Abnormally low hepcidin levels promote an increase in the bioavailability of plasma iron, characterized by elevated transferrin saturation and the appearance of non transferrin bound iron. This nontransferrin-bound iron is avidly taken up by the liver, heart, and pancreas, the principal target organs for systemic iron overload. The variable penetrance of this disease is related to environmental and genetic factors. Among the genetic factors, mutations of some newly identified genes may aggravate the phenotype of iron overload associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene; these new genes include those of hemojuvelin (HJV), transferrin receptor 2 (TfR2), and hepcidin (HAMP).

The poor prognosis of pancreatic cancer has remained unchanged for many years, with a 5-year survival of less than 5 %. Current methods for diagnosing pancreatic cancer are inadequate at identifying small tumors that can be resected by surgery. Characterization of gene expression patterns in pancreatic cancer provided a list of genes that are specifically overexpressed in cancer cells. These genes are putative novel markers for the diagnosis and the prognosis of pancreatic cancer and for the development of targeted therapies. Gene expression analysis should lead to the discovery of molecular markers for early detection of pancreatic cancer that could benefit patients at high risk of developing pancreatic cancer.

Because the GnRH receptor plays a paramount role within the reproductive axis, the understanding of the molecular apparatus that governs the tissue-specific expression and regulation of this gene must lead to a better knowledge of the physiology and the physiopathology of the gonadotrope function. To elucidate these mechanisms, we have used two complementary in vivo and in vitro approaches. Firstly, we have isolated the pituitary promoter of the rat GnRH receptor gene and investigated its activity using transient transfection into two gonadotrope-derived cell lines, the alphaT3-1 and the LbetaT2 cell lines. We have thus defined a primary set of transcription factors involved in the tissue-specific expression of the GnRH receptor gene. These include the steroidogenic factor-1 (SF-1) which plays a decisive role while functionally interacting with proteins related to the GATA and LIM homeodomain families of transcription factors. In addition, we highlighted the critical implication of SF-1 and its functional interaction with a CREB-related factor in the stimulatory action of PACAP (Pituitary Adenylate Cyclase Activating Polypeptide) on promoter activity. These results have led us to analyze the activity of this promoter by transgenesis in the mouse using human placental alkaline phosphatase as a reporter gene. In agreement with the in vitro data, the pituitary promoter was found to confer gonadotrope-specific activity in the pituitary. It was also able to direct transgene expression in several areas of the central nervous system known to express the endogenous GnRH receptor, in particular in the hippocampo-septal complex. Some of these tissue do not express SF-1, suggesting that, in vivo, its role would not be as decisive as suggested by the in vitro experiments. Surprisingly, during pituitary ontogenesis, the transgene is expressed as early as E 13.5 whereas SF-1 is not yet present in the pituitary. Thus, in vivo, SF-1 would not be necessary for the activation of the GnRH receptor gene during the early developmental stages in the pituitary. These results are consistent with data obtained following general or pituitary-specific knockout of the gene encoding SF-1, suggesting that the GnRH receptor is expressed despite the absence of this factor. Identifying the factors responsible for the activation of the GnRH receptor gene at these early developmental stages should make it possible to refine the role of SF-1, not only in gene regulation but more generally, in the physiology and the physiopathology of the gonadotrope function.