LNK (SH2B3): paradoxical effects in ovarian cancer.

LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers

The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA- MB- 231 cells in correlation with reduced activation of the survival pathway NF kappa B, as a consequence of diminished I kappa B and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NF kappa B activity and transcriptional downregulation of AP-1. NF kappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NF kappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NF kappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright (c) 2007 S. Karger AG, Basel

Compressional-mode giant resonances in deformed nuclei

AbstractBackground-free inelastic scattering spectra have been obtained for the Sm isotopes with 400 MeV α particles at forward angles (including 0°) to investigate the effect of deformation on the compressional-mode giant resonances. The strength distributions for the isoscalar giant resonances (L⩽3) have been extracted for the spherical nucleus 144Sm and the deformed nucleus 154Sm. We have observed that the effects of deformation are different for the low- and high-excitation-energy components of the isoscalar giant dipole resonance in 154Sm. Evidence for the theoretically predicted coupling between the isoscalar dipole resonance and the high-energy octupole resonance is reported

Evidence-based guidelines and decision support services: a discussion and evaluation in triple assessment of suspected breast cancer

Widespread health service goals to improve consistency and safety in patient care have prompted considerable investment in the development of evidence-based clinical guidelines. Computerised decision support (CDS) systems have been proposed as a means to implement guidelines in practice. This paper discusses the general concept in oncology and presents an evaluation of a CDS system to support triple assessment (TA) in breast cancer care. Balanced-block crossover experiment and questionnaire study. One stop clinic for symptomatic breast patients. Twenty-four practising breast clinicians from United Kingdom National Health Service hospitals. A web-based CDS system. Clinicians made significantly more deviations from guideline recommendations without decision support (60 out of 120 errors without CDS; 16 out of 120 errors with CDS, P<0.001). Ignoring minor deviations, 16 potentially critical errors arose in the no-decision-support arm of the trial compared with just one (P=0.001) when decision support was available. Opinions of participating clinicians towards the CDS tool became more positive after they had used it (P<0.025). The use of decision support capabilities in TA may yield significant measurable benefits for quality and safety of patient care. This is an important option for improving compliance with evidence-based practice guidelines

Cost of Community Integrated Prevention Campaign for Malaria, HIV, and Diarrhea in Rural Kenya

BACKGROUND: Delivery of community-based prevention services for HIV, malaria, and diarrhea is a major priority and challenge in rural Africa. Integrated delivery campaigns may offer a mechanism to achieve high coverage and efficiency. METHODS: We quantified the resources and costs to implement a large-scale integrated prevention campaign in Lurambi Division, Western Province, Kenya that reached 47,133 individuals (and 83% of eligible adults) in 7 days. The campaign provided HIV testing, condoms, and prevention education materials; a long-lasting insecticide-treated bed net; and a water filter. Data were obtained primarily from logistical and expenditure data maintained by implementing partners. We estimated the projected cost of a Scaled-Up Replication (SUR), assuming reliance on local managers, potential efficiencies of scale, and other adjustments. RESULTS: The cost per person served was $41.66 for the initial campaign and was projected at$31.98 for the SUR. The SUR cost included 67% for commodities (mainly water filters and bed nets) and 20% for personnel. The SUR projected unit cost per person served, by disease, was $6.27 for malaria (nets and training),$15.80 for diarrhea (filters and training), and $9.91 for HIV (test kits, counseling, condoms, and CD4 testing at each site). CONCLUSIONS: A large-scale, rapidly implemented, integrated health campaign provided services to 80% of a rural Kenyan population with relatively low cost. Scaling up this design may provide similar services to larger populations at lower cost per person

Silencing cytokeratin 18 gene inhibits intracellular replication of Trypanosoma cruzi in HeLa cells but not binding and invasion of trypanosomes

<p>Abstract</p> <p>Background</p> <p>As an obligatory intracellular parasite, <it>Trypanosoma cruzi</it>, the etiological agent of Chagas' disease, must invade and multiply within mammalian cells. Cytokeratin 18 (CK18) is among the host molecules that have been suggested as a mediator of important events during <it>T. cruzi</it>-host cell interaction. Based on that possibility, we addressed whether RNA interference (RNAi)-mediated down regulation of the CK18 gene could interfere with the parasite life cycle <it>in vitro</it>. HeLa cells transiently transfected with CK18-RNAi had negligible levels of CK18 transcripts, and significantly reduced levels of CK18 protein expression as determined by immunoblotting or immunofluorescence.</p> <p>Results</p> <p>CK18 negative or positive HeLa cells were invaded equally as well by trypomastigotes of different <it>T. cruzi </it>strains. Also, in CK18 negative or positive cells, parasites recruited host cells lysosomes and escaped from the parasitophorous vacuole equally as well. After that, the growth of amastigotes of the Y or CL-Brener strains, was drastically arrested in CK18 RNAi-treated cells. After 48 hours, the number of amastigotes was several times lower in CK18 RNAi-treated cells when compared to control cells. Simultaneous staining of parasites and CK18 showed that in HeLa cells infected with the Y strain both co-localize. Although the amastigote surface protein-2 contains the domain VTVXNVFLYNR previously described to bind to CK18, in several attempts, we failed to detect binding of a recombinant protein to CK-18.</p> <p>Conclusion</p> <p>The study demonstrates that silencing CK18 by transient RNAi, inhibits intracellular multiplication of the Y and CL strain of <it>T. cruzi </it>in HeLa cells, but not trypanosome binding and invasion.</p