Gene therapy for obstetric conditions

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy

Driving and use of the mobile phone: a study among 18 to 24-year-old

While we know that using the telephone when driving increases the risk of accidents and that 18 to 24 year-olds are a fringe of the population that is particularly affected by fatal accidents on the road, we lack information concerning the use of the mobile phone in this age group. This study carried out with 208 young drivers aims to gather data, analyses their behavior at the wheel with the mobile plus their beliefs and awareness of risk. Three contexts are focused on: stopping at the red light, driving during the rush hour and highways. The findings highlight the importance of messaging and the influence of the context on the use of the mobile. We observe an inverse effect between the speed and messaging. While young people declare they are aware of certain risks, it concerns more the risks penalties and accordingly they appear to be impervious to road safety campaigns concerning the mobile phone behind the wheel. On this subject few major differences are to be found between male and female drivers and between very young and young drivers. The use of the mobile while driving among 18 to 24-year-olds therefore presents universal characteristics of use from moment or the driver (male or female) is a little more experimented

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University

Malta : language, literacy and identity in a Mediterranean island society

Available documentation for the early modern period indicates that the Malta harbor towns achieved literacy earlier than the countryside. The Maltese townsmen lived on a trading route, and it was necessary for them to learn the lingua franca, as the language of trade in the Mediterranean. The educated elite were able to acquire fluent speaking knowledge, as well as the ability to write, Tuscan (a dialect then in the process of becoming standard Italian), while continuing to employ their local Maltese ‘dialect’ on numerous occasions. By and large, the erosion of the position of Maltese as the subordinate language was an inevitable by-product of this development. The Maltese language was able to attain the function of a literary language in the nineteenth century but it had no standard orthography until 1931 and was only adopted as Malta’s official language in 1964.peer-reviewe

Gender-based violence against women in contemporary France: domestic violence and forced marriage policy since the Istanbul Convention

ABSTRACT: In 2014, France ratified the Council of Europe’s Convention on Preventing and Combating Violence against Women and Domestic Violence (the Istanbul Convention) and passed the Law for Equality between Women and Men to bring French law into line with it. The Law for Equality between Women and Men situates the fight against violence against women within a broader context of the need to address inequalities between women and men. This is not new at the international level, but it is new to France. When the structural, transformative understandings of violence against women found in international texts are translated into national laws, policy documents and implementation on the ground, they might challenge widespread ideas about gender relations, or they might be diluted in order to achieve consensus. To what extent has French violence against women policy moved into line with UN and Council of Europe initiatives which present violence against women as both a cause and a consequence of gendered power relations? Have internationally accepted concepts of gender and gender-based violence been incorporated into French policy debates and, if so, how? What implications, if any, does all this have for the continued struggle in France and elsewhere to eliminate violence a gainst women? RÉSUMÉ: En 2014, la France a ratifié la Convention du Conseil de l’Europe sur la prévention et la lutte contre la violence à l’égard des femmes et la violence domestique (dite Convention d’Istanbul) et a adopté dans la foulée la loi pour l’égalité réelle entre les femmes et les hommes afin de mettre en conformité la législation française. Cette loi place la lutte contre la violence à l’égard des femmes dans un contexte de lutte contre les inégalités de genre. Si cela est loin d’être une nouveauté à l’échelle internationale, cela l’est en France. Lorsque les conceptions structurelles et transformatrices de la violence à l’égard des femmes présentes dans les textes internationaux sont traduites à l’échelle nationale en lois, documents d’orientation et mesures de mise en œuvre sur le terrain, elles peuvent alors remettre en question des idées largement répandues sur les rapports de genre, ou au contraire être édulcorées afin d’aboutir à un consensus. Dans quelle mesure la politique de la France relative à la violence à l’égard des femmes s’est-elle alignée sur les initiatives de l’ONU et du Conseil de l’Europe qui présentent ce type de violence comme étant à la fois une cause et une conséquence des rapports de force liés au genre? Le genre et la violence fondée sur le genre, qui sont des concepts internationalement reconnus, ont-ils été intégrés dans les débats politiques français, et si oui, de quelle manière? Quelles en sont les implications le cas échéant sur la poursuite, en France et ailleurs, de la lutte pour éliminer la violence à l’égard des femmes

Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature

This article is available open access through the publisher’s website at the link below. Copyright @ 2014 The American Society of Gene & Cell Therapy.Lentiviral vectors are widely used in basic research and clinical applications for gene transfer and long-term expression; however, safety issues have not yet been completely resolved. In this study, we characterized hepatocarcinomas that developed in mice 1 year after in utero administration of a feline-derived lentiviral vector. Mapped viral integration sites differed among tumors and did not coincide with the regions of chromosomal aberrations. Furthermore, gene expression profiling revealed that no known cancer-associated genes were deregulated in the vicinity of viral integrations. Nevertheless, five of the six tumors exhibited highly significant upregulation of E2F target genes, of which a majority are associated with oncogenesis, DNA damage response, and chromosomal instability. We further show in vivo and in vitro that E2F activation occurs early on following transduction of both fetal mice and cultured human hepatocytes. On the basis of the similarities in E2F target gene expression patterns among tumors and the lack of evidence implicating insertional mutagenesis, we propose that transduction of fetal mice with a feline lentiviral vector induces E2F-mediated major cellular processes that drive hepatocytes toward uncontrolled proliferation culminating in tumorigenesis.ISF, DFG, the Kamea Scientific Foundation, the European Research Council, the Lillyan & Alfy Nathan, Barbara Fox Miller, and Wolfson Foundations

Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy

BACKGROUND: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. METHODS: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. RESULTS: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05). CONCLUSION: Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment. British Journal of Cancer (2010) 103, 1407-1414. doi: 10.1038/sj.bjc.6605925 www.bjcancer.com Published online 5 October 2010 (C) 2010 Cancer Research U

Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression