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Παρασκευή 3 Νοεμβρίου 2017

Conversations with French Medical Geneticists. A Personal Perspective on the Origins and Early Years of Medical Genetics in France

The history of the beginnings of medical genetics in France is discussed, based on the personal perspective provided by recorded interviews with 16 early French workers in the field. The weakness of French genetics overall up to the beginning of the Second World War meant that post-war medical genetics had to start from new, with its origins largely derived from the medical fields of child health and the prevention of genetic disorders, rather than from basic science. The key people responsible for initiating these developments were Robert Debré and Maurice Lamy at Hôpital Necker in Paris and those interviewed included a number of their colleagues and successors, including Jean Frézal, Pierre Maroteaux, Josué Feingold, André and Joelle Boué, and Jean-Claude Kaplan. A separate group of paediatricians, originally at Hôpital Trousseau under Raymond Turpin, including Jérôme Lejeune, Marthe Gautier and Roland Berger, was responsible for major advances in human cytogenetics. Outside Paris, workers were interviewed from Marseille, Strasbourg and Nancy, though not from Lyon, where Jacques-Michel Robert was an early pioneer, particularly of genetic counselling.

Challenges in the development of medical genetics in France included the advent of prenatal diagnosis with its ethical issues, the emergence of medical genetics as a distinct specialty from paediatrics, and its spread from Paris across France. These and other aspects are described by those interviewed from their own experiences, given in the 'supplementary material', while the full edited transcripts for most interviews are accessible on the Web (http://ift.tt/2gZRksj).

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'The early history of medical genetics in France is discussed in the context of recorded interviews with 16 early workers in the field, based principally but not exclusively in Paris. These origins and early years show considerable differences between France and other countries that are of international interest and deserve a more comprehensive study than the personal perspective given here can provide. Further recorded interviews with key workers across France still living will be of particular importance.



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Inhibition of PI3K/Akt/mTOR overcomes cisplatin resistance in the triple negative breast cancer cell line HCC38

Abstract

Background

Widely established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Classical chemotherapy remains the systemic treatment option. Cisplatin has been tested in TNBC but bears the disadvantage of resistance development. The purpose of this study was to identify resistance mechanisms in cisplatin-resistant TNBC cell lines and select targeted therapies based on these findings.

Methods

The TNBC cell lines HCC38 and MDA-MB231 were subjected to intermittent cisplatin treatment resulting in the 3.5-fold cisplatin-resistant subclone HCC38CisR and the 2.1-fold more resistant MDA-MB231CisR. Activation of pro-survival pathways was explored by immunostaining of phospho-receptor tyrosine kinases. Targeted therapies (NVP-AEW541, lapatinib and NVP-BEZ235) against activated pathways were investigated regarding cancer cell growth and cisplatin sensitivity.

Results

In HCC38CisR and MDA-MB231CisR, phosphorylation of epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) was observed. In HCC38CisR, treatment with NVP-AEW541 increased potency of lapatinib almost seven-fold, but both compounds could not restore cisplatin sensitivity. However, the dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 acted synergistically with cisplatin in HCC38CisR and fully restored cisplatin sensitivity. Similarly, NVP-BEZ235 increased cisplatin potency in MDA-MB231CisR. Furthermore, NVP-AEW541 in combination with lapatinib restored cisplatin sensitivity in MDA-MB231CisR.

Conclusion

Simultaneous inhibition of EGFR and IGF1R in cisplatin-resistant TNBC cell lines was synergistic regarding inhibition of proliferation and induction of apoptosis. Co-treatment with NVP-BEZ235 or with a combination of NVP-AEW541 and lapatinib restored cisplatin sensitivity and may constitute a targeted treatment option for cisplatin-resistant TNBC.



http://ift.tt/2zuABsG

Factors associated with the high prevalence of oesophageal cancer in Western Kenya: a review

Abstract

Oesophageal carcinoma (OC) is highly prevalent in Western Kenya especially among the members of the Kalenjin community who reside in the Northern and Southern areas of the Rift Valley. Previous authors have suggested potential association of environmental and genetic risk factors with this high prevalence. The environmental factors that have been suggested include contamination of food by mycotoxins and/or pesticides, consumption of traditional alcohol (locally referred to "Busaa" and "Chan'gaa"), use of fermented milk ("Mursik"), poor diet, tobacco use and genetic predisposition. The aim of this paper is to critically examine the potential contribution of each of the factors that have been postulated to be associated with the high prevalence of the disease in order to establish the most likely cause. We have done this by analyzing the trends, characteristics and behaviours that are specifically unique in the region, and corroborated this with the available literature.

From our findings, the most plausible cause of the high incidence of OC among the Kalenjin community is mycotoxins, particularly fumonisins from the food chain resulting from poor handling of cereals; particularly maize combined with traditional alcohol laced with the toxins interacting synergistically with other high-risk factors such as dietary deficiencies associated alcoholism and viral infections, especially HPV. Urgent mitigating strategies should be developed in order to minimize the levels of mycotoxins in the food chain.



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Issue Information – TOC



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Large population study quantifies chances of pregnancy after cancer treatment



http://ift.tt/2zbpWjg

First person: Maura L. Gillison, MD, PhD



http://ift.tt/2j0D9HF

More cancers diagnosed at an early stage after increases in health insurance coverage



http://ift.tt/2zctdz9