Uveal vs. cutaneous melanoma. Origins and causes of the differences

Melanoma is a malignant tumour derived from melanocytes (dendritic cells originated from the neural crest and capable to produce melanin synthesis) that could be established on the skin or less frequently on the uvea. The cellular origin from both kind of melanoma seems to be the same but the melanocytes migrates to the epithelia for cutaneous melanoma, while for uveal melanoma, they migrate to mesodermic tissues. Despite the common origin, both melanomas show extreme differences in their metastatic potential, clinical response to treatments, immune response and genetic alterations. We will describe some of those differences in this review (AU)

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Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays.

To identify genomic abnormalities characteristic of pancreatic ductal adenocarcinoma (PDAC) in vivo, a panel of 27 microdissected PDAC specimens were analysed using high-density microarrays representing approximately 116 000 single nucleotide polymorphism (SNP) loci. We detected frequent gains of 1q, 2, 3, 5, 7p, 8q, 11, 14q and 17q (> or =78% of cases), and losses of 1p, 3p, 6, 9p, 13q, 14q, 17p and 18q (> or =44%). Although the results were comparable with those from array CGH, regions of those genetic changes were defined more accurately by SNP arrays. Integrating the Ensembl public data, we have generated 'gene' copy number indices that facilitate the search for novel candidates involved in pancreatic carcinogenesis. Copy numbers in a subset of the genes were validated using quantitative real-time PCR. The SKAP2/SCAP2 gene (7p15.2), which belongs to the src family kinases, was most frequently (63%) amplified in our sample set and its recurrent overexpression (67%) was confirmed by reverse transcription-PCR. Furthermore, fluorescence in situ hybridization and in situ RNA hybridization analyses for this gene have demonstrated a significant correlation between DNA copy number and mRNA expression level in an independent sample set (P<0.001). These findings indicate that the dysregulation of SKAP2/SCAP2, which is mostly caused by its increased gene copy number, is likely to be associated with the development of PDAC.

Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation.

Pancreatic ductal adenocarcinoma (PDAC) is characterised pathologically by a marked desmoplastic stromal reaction that significantly reduces the sensitivity and specificity of cytogenetic analysis. To identify genetic alterations that reflect the characteristics of the tumour in vivo, we screened a total of 23 microdissected PDAC tissue samples using array-based comparative genomic hybridisation (array CGH) with 1 Mb resolution. Highly stringent statistical analysis enabled us to define the regions of nonrandom genomic changes. We detected a total of 41 contiguous regions (>3.0 Mb) of copy number changes, such as a genetic gain at 7p22.2-p15.1 (26.0 Mb) and losses at 17p13.3-p11.2 (13.6 Mb), 18q21.2-q22.1 (12.0 Mb), 18q22.3-q23 (7.1 Mb) and 18q12.3-q21.2 (6.9 Mb). To validate our array CGH results, fluorescence in situ hybridisation was performed using four probes from those regions, showing that these genetic alterations were observed in 37-68% of a separate sample set of 19 PDAC cases. In particular, deletion of the SEC11L3 gene (18q21.32) was detected at a very high frequency (13 out of 19 cases; 68%) and in situ RNA hybridisation for this gene demonstrated a significant correlation between deletion and expression levels. It was further confirmed by reverse transcription-PCR that SEC11L3 mRNA was downregulated in 16 out of 16 PDAC tissues (100%). In conclusion, the combination of tissue microdissection and array CGH provided a valid data set that represents in vivo genetic changes in PDAC. Our results raise the possibility that the SEC11L3 gene may play a role as a tumour suppressor in this disease.

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the beta4 integrin and the PI3k pathway.

Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the alpha(6)beta(4) integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

Integrated watershed management in Quebec (Canada): a participatory approach centred on local solidarity.

The Quebec Water Policy was launched in November 2002 in support of reform of the water governance. One of the government commitments is to gradually implement watershed-based management for 33 major watercourses located primarily in the St. Lawrence plain. At the local and regional levels, watershed organizations are responsible for implementing integrated management, from a sustainable-development perspective, by preparing a master plan for water (MPW), which will include watercourses, lakes, wetlands and aquifers. These watershed organizations rely on public consultation, as well as local and regional expertise, on the responsibilities for water of the municipalities and regional county municipalities of the territory, as well as those of the ministries and other government agencies. They are also required to observe national priorities regarding protection, restoration, and development of water resources and to comply with relevant guidelines, directives, standards, regulations, and legislation. The role of watershed organizations is to act as planning and consultation tables. Government representatives are present, on the initial process, as the facilitator and for scientific and technical support. They do not have, at this moment, any voting or decisional rights. After two years, integrated water management mobilized water stakeholders on watersheds and they are on their way to initiating their first MPW.

Identification and cloning of an 85-kDa protein homologous to RING3 that is upregulated in proliferating endothelial cells.

A central event in angiogenesis is proliferation of blood vessels, which plays a major role in the progression of a number of inflammatory and neoplastic diseases. It is responsible for the switch of endothelial cells from an antiangiogenic to an angiogenic phenotype. To identify novel activated/proliferating-related proteins in human endothelial cells, a subtractive immunization approach was used to elicit a host antibody response against human dermal microvascular endothelial cells (HDMECs) stimulated with a potent angiogenic cytokine such as VPF/VEGF165. In this study, a new mAb, LY9, which is highly specific to VPF/VEGF165-activated HDMECs, was isolated. Stimulation of HDMECs by VPF/VEGF165 or basic fibroblast growth factor (bFGF) resulted in a dose-dependent and time-dependent increase in the binding of LY9. On Western-blot analysis, LY9 identified an 85-kDa protein (p85) in the lysates of several endothelial cells derived from microvascular or large vessel sources, the expression of which is dramatically increased by VPF/VEGF165. The mAb also identified p85 in primary cell cultures of human foreskin keratinocytes but failed to recognize human fibroblasts (MRC5) and a number of different human tumor cell lines, including MG63 osteosarcoma and MCF7 breast carcinoma cells. Immunological screening of a human keratinocyte lambdagt11 cDNA expression library with LY9 identified a partial cDNA clone of 750 bp. DNA sequencing of this clone and predicted amino acids showed more than 93% homology to RING3 kinase, a member of a newly described family of bromodomain-containing proteins that transactivates in the nucleus the promoters of a number of the E2F family of transcription factors. This molecule may represent a new signaling target activated by VPF/VEGF165 and bFGF that allows endothelial cells to enter the proliferative phase of the angiogenic process.

A new Mr 55,000 surface protein implicated in melanoma progression: association with a metastatic phenotype.

Emergence of the invasive phenotype is a key event in the progression of human melanoma from benign proliferative lesions to malignant lesions. Recently we successfully selected in vivo from a poorly metastatic M4Beu. human melanoma cell line two variants (7GP and T1P26) that generate a higher frequency of spontaneous metastases to the lungs into immune-suppressed neonatal rats. Both cell lines showed no significant differences in the integrin profile of the subunits analyzed except for beta3, which was reduced to a background level in metastatic variants. To investigate how these variant sublines of human melanomas manage to sustain growth in the absence of alpha(v)beta3, a subtractive immunization approach was used to elicit host antibody response against cell surface proteins expressed on metastatic variants. In this study, a new monoclonal antibody (MoAb), LY1, that is highly specific for the 7GP and T1P26 variants, was isolated. LY1 identifies a membrane protein of Mr 55,000 on melanoma variants with epitopes that were resistant to sugar-cleaving enzymes. Immunostaining cells from variants by LY1 showed that staining is distributed to the cell periphery with high labeling intensity at the cell-to-cell contact points. This MoAb significantly inhibited invasion of metastatic variants through a reconstituted basement membrane (Matrigel) in vitro. Moreover, tumor growth of melanoma variants was dramatically affected in vivo with this MoAb. In vitro studies indicate that the LY1 MoAb does not inhibit chemotactic migration of the metastatic variants, the adhesion of tumor cells to vitronectin, collagen IV, fibronectin, and laminin, or cell proliferation. Expression of this antigen is high in human striated muscle, heart, spleen, brain, and lung and absent in kidney, liver, and pancreas. Using 59 fixed, paraffin-embedded archival tissues of human melanomas and nevi, LY1-reactive cells were not observed in melanocytes, nevi, or radial growth phase primary melanomas. In sharp contrast, LY1 selectively stained melanocytes derived from the vertical growth phase of many primary melanomas and metastatic melanomas. These results provide evidence that the Mr 55,000 protein expressed by selected variants with increased metastatic properties in vivo plays a functionally important role in determining metastasis. This molecule may represent a new metastatic risk marker in human melanoma and may be of biological importance in the identification of fatal metastatic subpopulations that have acquired competence for metastasis production.

[Characteristics of 2F2-F1 distorsion products in adults with normal hearing]. / Caractéristiques du produit de distorsion 2F2-F1 chez l'homme normo-entendant.

Acoustic distorsion products (ADP) are otoemissions which the cochlea emits in response to stimulation by two pure frequencies, f1 and f2. ADP 2f1-f2 has been widely studied, however little work has been reported on ADP 2f2-f1. We performed a study in 34 adults with normal hearing to determine the normal values (incidence and amplitude) of ADP and compared them with the ADP 2f1-f2. Two f2/f1 ratios were used (1.22 and 1.12). Different behaviors were observed between the two types of ADP. These results suggest that the mechanisms generating the two ADP are different and that, consequently, ADP 2f2-f1 should have clinical implications different than ADP 2f1-f2.

[Frontal cerebral abscess, a rare complication of nasosinusal polyposis. Apropos of a case]. / Abcès cérébral frontal, complication rare de la polypose nasosinusienne. A propos d'une observation.

Sinusonasal polyposis is frequent but usually benign. A 77-year-old woman with an history of sinusonasal polyps, presented with fever and neurologic impairment. Radiologic imaging showed a polypoïd mass filling the nose and sinuses, eroding the ethmoïd bone, progressing intracranially, and causing brain abscess. The literature is reviewed, according to the relations between brain abscess development and nasal polyposis, with emphasis on intracranial extension of sinusonasal polyps. Treatment of the nasal polyps, usually based on the use of local or general corticosteroïds, can avoid this serious complication.

[Unilateral paralysis of the lower cranial nerves caused by lesion of the internal carotid artery]. / Paralysie unilatérale des derniers nerfs crâniens par lésion de l'artère carotide interne.

We report two cases of unilateral, isolated lower cranial nerves (IX, X, XI and XII) palsy: both were due to a lesion of the internal carotid artery in the para-pharyngeal space (a dissection and a pseudoaneurysm). The diagnosis was based upon magnetic resonance imaging and selective angiography. The normality of the external carotid artery on angiography led to the hypothesis of a direct compression of the lower cranial nerves in the para-pharyngeal space, rather than an ischemia of these nerves.

[Painful ophthalmoplegia caused by chronic sphenoid sinusitis. Contribution of imaging]. / Ophtalmoplégie douloureuse par sinusite sphénoïdale chronique. Apport de l'imagerie.

Sphenoid sinusitis is a rare, often misdiagnosed, potentially lifethreatening infection. We report two cases of chronic sphenoid sinusitis presenting as painful ophthalmoplegia. We emphasize the difficulty of the diagnosis due to the deep-seated position of the cavity. The availability of CT and MRI should allow an early diagnosis. Attention has to be paid to the sphenoid sinus on every cranial image. In the chronic as well as in the acute form, the treatment is an emergency. Surgery procedures should be considered when antibiotics are inefficient. Sphenoid sinusitis must be considered in the diagnosis of painful ophthalmoplegia.

[Patients excluded from voice restoration after total laryngectomy]. / Les exclus de la restauration vocale après laryngectomie totale.

Concerning 73 radical laryngectomy operations carried out at the Hôpital Tenon in the period between july 1985 and july 1989, the authors studied the mode of vocal restoration used and the patient population not benefitting from any of the procedures used. Esophageal voice was utilized initially in 19 patients; a tracheo-esophageal fistula (surgical shunt or puncture with Blom-Singer prosthesis) was created during laryngectomy in 19 patients, and secondary tracheo-esophageal puncture was performed in 13 others. Twenty patients had no vocal restoration operation performed. In a large number of the patients, the tracheo-esophageal fistulas restored a normal voice. In the end, 38% of the laryngectomized patients did not have their voice restored. The various causes for such a high percentage of exclusions that are discernable are discussed. Lack for motivation on the part of the patients is a major reason, irrespective of the technique used.

[Dysphagia in oculopharyngeal myopathies. Report of 7 cases]. / La dysphagie au cours des myopathies oculo-pharyngées. A propos de sept cas.

Swallowing disorders have been studied in seven patients with oculopharyngeal myopathy. All patients presented with symptoms dominated by solid food dysphagia and false passages. Two of them had a considerably deteriorated general and pulmonary condition. Manometry demonstrates a decrease in pharyngeal populsion in six patients but does not detect any anomaly in the function of the upper sphincter of the esophagus. Three patients were operated with myotomy of the cricopharyngeus. The procedure led to the disappearance of the disorders in two of them, while it was a failure in the third. Swallowing disorders, the difficulties of manometric exploration and the role of myotomy are discussed in this article.

[Monitoring of thyroid function in patients treated for cancer of the upper respiratory and digestive tract]. / Surveillance de la fonction thyroïdienne des patients traités pour cancer des voies aéro-digestives supérieures (VADS).

A study was carried out at Hôpital Boucicaut to determine the incidence of iatrogenic biological thyroid dysfunction in patients treated for cancer of the upper digestive and respiratory tracts, and to define the risk profile (tumor localisations, practical therapeutical procedures). Two studies were conducted: a prospective on including 18 patients and a retrospective one including 58 patients. Only partial results are currently available. They permit emphasizing the frequency of biological thyroid dysfunction associated both with combination surgical and radiotherapeutical regimens and radiotherapy or radiotherapy alone for the treatment of lesions of the piriform sinus, although they fail to provide conclusive evidence regarding the real frequency of this type pathology or the time of its occurrence.

Rapid suppression of alpha 1-fetoprotein gene transcription by dexamethasone in developing rat liver.

The administration of glucocorticosteroid hormones to newborn rats interrupts selectively (and reversibly, if the hormone is withdrawn) the hepatic production of alpha 1-fetoprotein (AFP). This results from a decreased concentration of AFP mRNA in the liver [Bélanger, L., Frain, M., Baril, P., Gingras, M.C., Bartkowiak, J., & Sala-Trepat, J.M. (1981) Biochemistry 20, 6665]. We have delineated further the mechanism and time course of this hormonal action in 4-day-old rats treated with dexamethasone (DEX). DNA from a recombinant plasmid containing a 578-bp insert of rat AFP cDNA was used to develop a cell-free nuclear run-off system and directly assess AFP gene transcription activity. Five minutes after DEX injection, AFP gene transcription activity is unchanged, but after 30 min, it drops to 25% that of the control; this correlates with the time required for translocation of DEX receptors to the nucleus. Dose-response curves also show that the degree of AFP gene suppression is closely correlated with the amount of DEX receptor translocated to the nucleus. The nuclear concentration of AFP mRNA, monitored by dot-blot hybridization, decreases to undetectable levels within 48 h, whereas that of albumin mRNA increases slightly, which indicates the selectivity of DEX action. These results show that DEX suppresses AFP gene expression at the transcriptional level and suggest a direct negative action of DEX-receptor complexes on the AFP chromatin transcription unit.

Oncodevelopmental and hormonal regulation of alpha 1-fetoprotein gene expression.

The main features of the oncodevelopmental biology of alpha 1-fetoprotein (AFP) are reviewed. Progress made in the molecular biology of AFP gene regulation is discussed and we present our recent data on the mechanisms of AFP suppression by glucocorticoid hormones. The relationship between AFP gene transcription and cell replication is examined, and it is suggested that the degree of methylation of the AFP gene (or of co-methylated regulatory DNA sequences) conditions its response to hormones.