Five new cases of juvenile renal cell carcinoma with translocations involving Xp11.2: a cytogenetic and morphologic study

Two cases of renal cell carcinoma (RCC) carrying a t(X;1)(p11.2;q21) in a 12-year-old boy and a 14 year-old girl, two cases with a t(X;1)(p11.2;p34) in a 9-year-old boy and a 31-year-old woman, and one case with a t(X;17)(p11.2;q25) in a 15-year-old boy are reported. Two are likely papillary RCC, with clear or slightly eosinophilic cells, and two to a clear cell RCC; one shows a mixture of papillary and clear cell RCC architecture. Renal cell carcinomas with translocations involving Xp11.2 form a specific entity characterized by subtle pathologic features and younger age of occurrence, especially for those with the t(X;17).     

Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB

We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling.     

A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts

Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its beta-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor.     

Genetically modified organisms: a new threat to food safety

This article analyzes all of the food safety-related aspects related to the use of genetically modified organisms into agriculture and food. A discussion is provided as to the uncertainties related to the insertion of foreign genes into organisms, providing examples of unforeseen, undesirable effects and of instabilities of the organisms thus artificially fabricated. Data is then provided from both official agencies as well as existing literature questioning the accuracy and reliability of the risk analyses as to these organisms being harmless to health and discusses the almost total lack of scientific studies analyzing the health safety/dangerousness of transgenic foods. Given all these unknowns, other factors must be taken into account, particularly genetic contamination of the non-genetically modified crops, which is now starting to become widespread in some parts of the world. Not being able of reversing the situation in the even of problems is irresponsible. Other major aspects are the impacts on the environment (such as insects building up resistances, the loss of biodiversity, the increase in chemical products employed) with indirect repercussions on health and/or future food production. Lastly, thoughts for discussion are added concerning food safety in terms of food availability and food sovereignty, given that the transgenic seed and related agrochemicals market is currently cornered by five large-scale transnational companies. The conclusion entails an analysis of biotechnological agriculture's contribution to sustainability.     

Liver arterialization improves hepatocytes ultrastructure in rats with portacaval shunts

The effect of arterialization (ART) of the distal stump of the portal vein after portacaval shunt (PCS) on bile formation and liver ultrastructure was assessed. ART using the left gastric artery was performed in male Wistar rats. Animals were sacrificed 3 weeks later. ART prevented body and liver atrophy. However, the liver weight to body weight ratio was significantly decreased when compared to sham PCS (2.5±0.36 vs 3.22±0.15). Reduction in total bile secretion (μl/min) seen following PCS is reversed by ART. ART partly corrected hepatocyte size atrophy and the major ultrastructural abnormalities, namely the irregularity of the nucleus and the dilatation of the nuclear envelope and of the rough endoplasmic reticulum appearing after PCS. However, mitochondria remained swollen, deformed, and enlarged with scission figures. No lesions in connection with ART were seen. This result confirms, at the ultrastructural level, the beneficial effect of ART in PCS.     

Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families

Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast-ovarian cancers. However, BRCA1 germline mutations are found much less frequently than expected, especially as standard PCR-based mutation detection approaches focus on point and small gene alterations. In order to estimate the contribution of large gene rearrangements to the BRCA1 mutation spectrum, we have extensively analysed a series of 120 French breast-ovarian cancer cases. Thirty-eight were previously found carrier of a BRCA1 point mutation, 14 of a BRCA2 point mutation and one case has previously been reported as carrier of a large BRCA1 deletion. The remaining 67 cases were studied using the BRCA1 bar code approach on combed DNA which allows a panoramic view of the BRCA1 region. Three additional rearrangements were detected: a recurrent 23.8 kb deletion of exons 8-13, a 17.2 kb duplication of exons 3-8 and a 8.6 kb duplication of exons 18-20. Thus, in our series, BRCA1 large rearrangements accounted for 3.3% (4/120) of breast-ovarian cancer cases and 9.5% (4/42) of the BRCA1 gene mutation spectrum, suggesting that their screening is an important step that should be now systematically included in genetic testing surveys.