Low Adherent Research Articles

Abstract 2820: LY2784544, a small molecule JAK2 inhibitor, induces apoptosis in inflammatory breast cancer spheres through targeting IL-6-JAK-STAT3 pathway

Abstract Inflammatory breast cancer (IBC) is more aggressive and deadly than other breast cancers (K Rowan. JNCI. 2009;101(19):1302-1304). IBC cells secrete angiogenic and vasculogenic growth factors, such as VEGF, bFGF, IL-6 and IL-8, resulting in a cluster of tumor cells, termed anembolus. Through maintaining cell-cell interactions, the IBC emboli can become resistant to “anoikis”, a cell death process following the loss of contact from their neighboring cells. It is hypothesized that this resistance may allow IBC cells to survive the migration through lymphatic vessels and facilitate development of skin and lymph node metastasis. With current therapy, the disease-free survival for IBC patients is only about 35% (SD Merajver et al. J Clin Oncol. 1997;15(8):2873-81). Clearly better therapy is needed for patients with IBC and insights may be gained from exploration of and subsequent interventions in the roles these growth factors play in the biology of IBC. In this study, we investigated the role of IL-6 in activating the signal transducer and activator of transcription 3 (STAT3), conferring resistance to anoikis, and promoting cell proliferation in IBC SUM-149 tumor spheres. Moreover, we targeted JAK2, a transducer of IL-6 signaling to STAT3, by a small molecule JAK2 inhibitor, LY2784544, to inhibit the IL-6-Stat3 pathway and induce apoptosis in SUM-149 tumor spheres. In brief, SUM-149 cells were grown to form tumor spheres under low adherence culture conditions. IL-6 mediated-Stat3 activation and the induction of the cleavage of PARP were evaluated by Western Blotting. Anoikis and cell viability were measured by calcein-AM accumulation and the expression of IL-6 was examined by RT-PCR. We found that exogenous IL-6 activated STAT3, conferred resistance to anoikis and promoted the cell proliferation in SUM-149 cells under the low adherent culture condition. Furthermore, the expression of IL-6 was increased by 50-fold in IBC tumor spheres as measured by RT-PCR. The autocrine production of IL-6 activated STAT3 and inhibited anoikis- induced apoptosis in SUM-149 tumor spheres. Very importantly, we showed that targeting JAK2 by LY2784544 potently inhibited the phosphorylation of STAT3 in a dose dependent manner with an IC50 of 0.25 µM. Blockage of this signal pathway by LY2784544 resulted in potent induction of apoptosis (EC50=0.49 µM). Taken together, these studies suggest the IL-6-JAK-STAT3 pathway may serve as a molecular signature of IBC and as a potential therapeutic target. LY2784544 is currently in clinical studies for the treatment of myeloid proliferative neoplasm indications and the results reported here support clinical investigation for the treatment of IBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2820. doi:10.1158/1538-7445.AM2011-2820

Association of cinacalcet adherence and costs in patients on dialysis

Objective:In addition to negative impacts on clinical effectiveness in treating secondary hyperparathyroidism, low adherence to cinacalcet may have negative impacts on healthcare costs. This study assessed the relationship between medication adherence and healthcare costs among US patients on dialysis given cinacalcet to manage secondary hyperparathyroidism.Methods:Retrospective cohort study of patients who were receiving dialysis with an initial cinacalcet prescription between January 2004 and April 2010 and who survived ≥12 months. Longitudinal, integrated medical, and pharmacy claims data from the MarketScan® database were used to calculate medication possession ratios (MPR) over 12 months and to examine the association of adherence with inpatient, outpatient, emergency room, outpatient medication, and total costs while controlling for patient characteristics, co-morbid medical conditions, and concomitant medication MPR in a multivariate regression model. Patients were dichotomized as adherent (<180 days refill gap) or non-adherent (≥180 day refill gap). Adherent patients were further dichotomized as low adherent (<0.8 MPR) and high adherent (≥0.8 MPR).Results:The final study cohort included 4923 patients. After 12 months, 46% were non-adherent, 27% were low adherent, and 28% were high adherent. Greater cinacalcet adherence was associated with significantly lower inpatient costs with cost-savings of a greater magnitude than the increased medication costs.Conclusions:This study demonstrated that low adherence to cinacalcet, which may be associated with undesirable clinical and health-economic outcomes, is common. Despite limitations inherent in retrospective studies of claims databases, such as unobserved confounding, non-discrimination between prescription fill and actual use, and not knowing the reasons for non-adherence, these results suggest that inpatient cost savings of $8899, more than offset higher medication costs of $5858 associated with increased cinacalcet adherence.

Adherence of Streptococcus pneumoniae to polystyrene plates, effect of serum on adhesion, and virulence in the gerbil otitis media model

The adherence of 11 pneumococcal strains to polystyrene was studied and expressed as the number of colony-forming units (CFU) recovered per 10 6 CFU of initial inoculum. Three strains were considered as strong adherent (>100 CFU/10 6), three as medium adherent (10–100 CFU/10 6), and five as low adherent (<10 CFU/10 6). All serotype 3 strains were low adherent whilst serotypes 23F and 19F behaved as strong or medium adherent. The impact of gerbil sera on adherence of six selected pneumococcal strains (one strong adherent, one medium adherent, and four low adherents) to abiotic material was also studied under two experimental conditions. In the presence of sera, the adherence ability of the strong, medium, and one low adherent strains decreased significantly. On the other hand, the adherence significantly increased in all strains when sera were removed following preincubation of bacteria exposed to sera, although such increase was statistically significant for five of them. Finally, the ability of two (one strong adherent and one low adherent) strains to induce otitis media in gerbils was also evaluated; the strong adherent strain behaved significantly more virulent than the less adherent in terms of ear damage and animal weight loss.