PO-278 Assessment of the influence of stellate cells on primary pancreatic cancer cell growth and drug resistance in a spheroid model: MET inhibitors to the rescue

Introduction Pancreatic ductal adenocarcinoma has one of the lowest 5 year survival rates among all cancers and it is going to be the 2nd leading cause of cancer death in 2030. Drug resistance and early metastasis are among the main causes of this dismal prognosis and tumour microenvironment may give a considerable contribution to this aggressive behaviour. Pancreatic stellate cells (PSCs) are the main source of cancer-associated fibroblasts in stroma, and are suspected to induce drug resistance by paracrine secretion of hepatocyte growth factor (HGF) and activation of the MET receptor in cancer cells. Material and methods We first examined the effect of human PSC conditioned medium on the growth and drug resistance of six different primary cell cultures isolated from PDAC patients by sulforhodamine B (SRB) assay growing as monolayers. Further, we developed a spheroid 3D-co-culture with PDAC5-SSEA4 and immortalised or primary PSC cells and examined the effects of different drugs by luciferase assay, immunofluoresence and confocal microscopy. Results and discussions Conditioned medium of stimulated PSC cells, i.e., primed with PDAC conditioned medium, gave growth advantage to different primary PDAC cells and made them several times more resistant to gemcitabine and oxaliplatin. PDAC5-SSEA4/PSC spheroids were much more resistant to gemcitabine and oxaliplatin compared to PDAC5-SSEA4 spheroids. However, MET inhibitors such as tivantinib and PHA-665752 were equally effective in homo and heterospheroids. Of note, immortalised and primary PSC cells had similar influences on the behaviour of PDAC cells in spheroids. Conclusion We successfully developed a 3D-spheroid model to evaluate the interaction of primary PDAC cells with PSCs. Pharmacological studies provided evidence that spheroids containing PSCs are much more resistant to cytotoxic drugs. Conversely MET inhibitors seem to be valuable tools to overcome the drug resistance of PDAC cells caused by the presence of PSC cells

Cost-effectiveness of stereotactic large-core needle biopsy for nonpalpable breast lesions compared to open-breast biopsy

This paper demonstrates that the introduction of large-core needle biopsy (LCNB) replacing needle-localised breast biopsy (NLBB) for nonpalpable (screen-detected) breast lesions could result in substantial cost savings at the expense of a possible slight increase in breast cancer mortality. The cost-effectiveness of LCNB and NLBB was estimated using a microsimulation model. The sensitivity of LCNB (0.97) and resource use and costs of LCNB and NLBB were derived from a multicentre consecutive cohort study among 973 women who consented in getting LCNB and NLBB, if LCNB was negative. Sensitivity analyses were performed. Replacing NLBB with LCNB would result in approximately six more breast cancer deaths per year (in a target population of 2.1 million women), or in 1000 extra life-years lost from breast cancer (effect over 100 years). The total costs of management of breast cancer (3% discounted) are estimated at £4676 million with NLBB; introducing LCNB would save £13 million. The incremental cost-effectiveness ratio of continued NLBB vs LCNB would be £12 482 per additional life-year gained (3% discounted); incremental costs range from £-21 687 (low threshold for breast biopsy) to £74 378 (high sensitivity of LCNB)

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)

The provocative lumbar facet joint

Low back pain is the most common pain symptom experienced by American adults and is the second most common reason for primary care physician visits. There are many structures in the lumbar spine that can serve as pain generators and often the etiology of low back pain is multifactorial. However, the facet joint has been increasingly recognized as an important cause of low back pain. Facet joint pain can be diagnosed with local anesthetic blocks of the medial branches or of the facet joints themselves. Subsequent radiofrequency lesioning of the medial branches can provide more long-term pain relief. Despite some of the pitfalls associated with facet joint blocks, they have been shown to be valid, safe, and reliable as a diagnostic tool. Medial branch denervation has shown some promise for the sustained control of lumbar facet joint-mediated pain, but at this time, there is insufficient evidence that it is a wholly efficacious treatment option. Developing a universal algorithm for evaluating facet joint-mediated pain and standard procedural techniques may facilitate the performance of larger outcome studies. This review article provides an overview of the anatomy, pathophysiology, diagnosis, and treatment of facet joint-mediated pain

Synthesis of 2-azidoethyl α-d-mannopyranoside orthogonally protected and selective deprotections

4 páginas, 1 figura, 2 esquemas.We present the synthesis of a fully orthogonally protected mannosyl glycoside 1 and the corresponding methods for selective deprotections. Mannosyl glycoside 1 contains a functionalized linker at the anomeric position to allow for the attachment of carbohydrate units to scaffolds in order to prepare carbohydrate multivalent systems.We would like to thank FIS (PI030093), for financial supportPeer reviewe