Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice

A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness. We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3-HER2 (p< 0.001) expression was found in human breast tumors. Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression

Diphyllobothriasis, Brazil

Cases of human diphyllobothriasis have been reported worldwide. Only 1 case in Brazil was diagnosed by our institution from January 1998 to December 2003. By comparison, 18 cases were diagnosed from March 2004 to January 2005. All patients who became infected ate raw fish in sushi or sashimi

The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression

BACKGROUND: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. METHODS AND RESULTS: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. CONCLUSION: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression

Evaluation du rôle de la neurotensine et de ses récepteurs dans la progression tumorale humaine et perspectives cliniques associées

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Discussing alcohol use with the GP: a qualitative study.

BACKGROUND: Despite most GPs recognising their role in the early diagnosis of alcohol use disorder (AUD), only 23% of GPs routinely screen for alcohol use. One reason GPs report for not screening is their relationship with patients; questions regarding alcohol use are considered a disturbance of a relationship built on mutual trust. AIM: To analyse the feelings and experiences of patients with AUD concerning early screening for alcohol use by GPs. DESIGN & SETTING: A qualitative study of patients ( = 12) with AUD in remission or treatment, recruited from various medical settings. METHOD: Semi-structured interviews were conducted, audiorecorded, and transcribed verbatim. The authors conducted an inductive analysis based on grounded theory. The analysis was performed until theoretical data saturation was reached. RESULTS: The participants experienced AUD as a chronic, destructive, and shameful disease. The participants expected their GPs to play a primary role in addressing AUD by kind listening, and providing information and support. If the GPs expressed a non-judgmental attitude, the participants could confide in them; this moment was identified as a key milestone in their trajectory, allowing relief and a move toward treatment. The participants thought that any consultation could be an opportunity to discuss alcohol use and noted that such discussions required a psychological and benevolent approach. CONCLUSION: The participants felt fear or denial from the GPs, even though they felt that discussing alcohol use is part of the GP's job. The participants requested that GPs adopt non-judgmental attitudes and kindness when approaching the subject of alcohol use

Gymnotic delivery and gene silencing activity of reduction-responsive siRNAs bearing lipophilic disulfide-containing modifications at 2′-position

International audienceModified oligoribonucleotides used as siRNAs bearing biolabile disulfide-containing groups at some 2'-positions were synthesized following a post-synthesis transformation of solid-supported 2'-O-acetylthiomethyl RNA, previously described. Thus, the reduction-responsive and lipophilic benzyldithiomethyl (BnSSM) modification was introduced at different locations into siRNAs targeting the Ewing sarcoma EWS-Flil protein. Thermal stability, serum stability and response to glutathione treatment of modified siRNAs were thoroughly investigated. Among 17 modified siRNAs, significant gene silencing activities were demonstrated for the 8 most stable siRNAs in serum (half-life > 1 h) when using a transfection reagent. Of special interest, two naked 2'-O-BnSSM siRNAs transfection exhibited a remarkable gene silencing activity after 24 h incubation. These inhibitions are consistent with an efficient gymnotic delivery demonstrated by the presence of the corresponding fluorescent siRNAs within cells

Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression

International audienceEmerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the high-affinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients

Evolution of dissolved and particulate chromophoric materials during the VAHINE mesocosm experiment in the New Caledonian coral lagoon (south-west Pacific)

In the framework of the VAHINE project, we investigated the spectral characteristics and the variability of dissolved and particulate chromophoric materials throughout a 23-day mesocosm experiment conducted in the south-west Pacific at the mouth of the New Caledonian coral lagoon (22 degrees 29.073 S-166 degrees 26.905 E) from 13 January to 4 February 2013. Samples were collected in a mesocosm fertilized with phosphate at depths of 1, 6 and 12m and in the surrounding waters. Light absorption coefficients of chromophoric dissolved organic matter (CDOM) [a(g) (lambda)] and particulate matter [a(p) (lambda)] were determined using a point-source integrating-cavity absorption meter (PSICAM), while fluorescent DOM (FDOM) components were determined from excitation-emission matrices (EEMs) combined with parallel factor analysis (PARAFAC). The evolutions of a(g) (lambda) and a(p) (lambda) in the mesocosm were similar to those of total chlorophyll a concentration, Synechococcus spp. and picoeukaryote abundances, bacterial production, particulate organic nitrogen and total organic carbon concentrations, with roughly a decrease from the beginning of the experiment to days 9-10, and an increase from days 9-10 to the end of the experiment. In the surrounding waters, the same trend was observed but the increase was much less pronounced, emphasizing the effect of the phosphate fertilization on the mesocosm's plankton community. Correlations suggested that both Synechococcus cyanobacteria and heterotrophic bacteria were strongly involved in the production of CDOM and absorption of particulate matter. The increase in phytoplankton biomass during the second part of the experiment led to a higher contribution of particulate material in the absorption budget at 442 nm. The three FDOM components identified (tryptophan-, tyrosine-and ultraviolet C (UVC) humic-like fluorophores) did not follow the evolution of CDOM and particulate matter, suggesting they were driven by different production/degradation processes. Finally, the results of this work support the idea there is indirect coupling between the dynamics of N-2 fixation and that of chromophoric material via the stimulation of Synechococcus bloom

Neurotensin Receptor 1 Determines the Outcome of Non-Small Cell Lung Cancer

International audiencePurpose: This study aimed to investigate the role of the neurotensin/neurotensin receptor I (NTSR1) complex in non-small cell lung cancer (NSCLC) progression. Experimental Design: The expression of neurotensin and NTSR1 was studied by transcriptome analysis and immunohistochemistry in two series of 74 and 139 consecutive patients with pathologic stage I NSCLC adenocarcinoma. The findings were correlated with clinic-pathologic features. Experimental tumors were generated from the malignant human lung carcinoma cell line A459, and a subclone of LNM35, LNM-R. The role of the neurotensin signaling system on tumor growth and metastasis was investigated by small hairpin RNA-mediated silencing of NTSR1 and neurotensin. Results: Transcriptome analysis carried out in a series of 74 patients showed that the positive regulation of NTSR1 put it within the top 50 genes related with relapse-free survival. Immunohistochemistry revealed neurotensin-and NTSR1-positive staining in 60.4% and 59.7% of lung adenocarcinomas, respectively. At univariate analysis, NTSR1 expression was strongly associated with worse 5-year overall survival rate (P = 0.0081) and relapse-free survival (P = 0.0024). Multivariate analysis showed that patients over 65 years of age (P = 0.0018) and NTSR1 expression (P = 0.0034) were independent negative prognostic factors. Experimental tumor xenografts generated by neurotensin-and NTSR1-silenced human lung cancer cells revealed that neurotensin enhanced primary tumor growth and production of massive nodal metastasis via autocrine and paracrine regulation loops. Conclusion: NTSR1 expression was identified as a potential new prognostic biomarker for surgically resected stage I lung adenocarcinomas, as NTSR1 activation was shown to participate in lung cancer progression

Correlation of the subpopulation co-expressing NT and NT1 receptor with the major prognosis factors.

<p>Correlation of the subpopulation co-expressing NT and NT1 receptor with the major prognosis factors.</p