SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2′deoxycytidine to increase SPARC expression and improve therapy response

Poor clinical outcomes in cancer can often be attributed to inadequate response to chemotherapy. Strategies to overcome either primary or acquired chemoresistance may ultimately impact on patients' survival favourably. We previously showed that lower levels of SPARC were associated with therapy-refractory colorectal cancers (CRC), and that upregulating its expression enhances chemo-sensitivity resulting in greater tumour regression in vivo. Here, we examined aberrant hypermethylation of the SPARC promoter as a potential mechanism for repressing SPARC in CRCs and whether restoration of its expression with a demethylating agent 5-Aza-2′deoxycytidine (5-Aza) could enhance chemosensitivity. Initially, the methylation status of the SPARC promoter from primary human CRCs were assessed following isolation of genomic DNA from laser capture microdissected specimens by direct DNA sequencing. MIP101, RKO, HCT 116, and HT-29 CRC cell lines were also used to evaluate the effect of 5-Aza on: SPARC promoter methylation, SPARC expression, the interaction between DNMT1 and the SPARC promoter (ChIP assay), cell viability, apoptosis, and cell proliferation. Our results revealed global hypermethylation of the SPARC promoter in CRCs, and identified specific CpG sites that were consistently methylated in CRCs but not in normal colon. We also demonstrate that SPARC repression in CRC cell lines could be reversed following exposure to 5-Aza, which resulted in increased SPARC expression, leading to a significant reduction in cell viability (by an additional 39% in RKO cells) and greater apoptosis (an additional 18% in RKO cells), when combined with 5-FU in vitro (in comparison to 5-FU alone). Our exciting findings suggest potential diagnostic markers of CRCs based on specific methylated CpG sites. Moreover, the results reveal the therapeutic utility of employing demethylating agents to improve response through augmentation of SPARC expression

A simple model of international joint venture distributorships: the American-Kuwaiti experience

The paper develops an analytical model for analyzing international joint venture distributorships in marketing channels selling highly differentiated industrial products. Regarding four alternative forms of demand functions, profits of channel members and consumer welfare under the joint venture arrangement are compared with those under the classic vertical integrated and decentralized structures. Furthermore, optimal allocation of joint venture benefits is discussed and the influence of attitude towards risk and bargaining power have been examined. A case study from international marketing is presented in relation to the theoretical work developed herein. It describes the events that have lead to the formation of a joint venture between an American manufacturer and a Kuwaiti distributor as well as the factors that have contributed to its termination. Implications of the research and its findings to management are also discussed.business strategy case study distribution joint ventures marketing optimization

Follow the Leaders: competition in the Brazilian Auto Financing Sector

This study seeks to understand the competitive pattern and strategy of the firms in the Brazilian automobile financing market. First, we analyzed the strong segmentation observed in this market, determining market niches. We then estimated reaction functions to price changes. The results indicated that the three largest companies in the sector have a strong influence on interest rate setting within the entire segment. This phenomenon characterizes the competition of this sector as the leader-follower type, rather than Bertrand competition, the latter of which is often expected in the banking sector and it demonstrates the existence of the leading firms' market power

Optimal Duration of Magazine Promotions

The planning of promotions and other marketing events frequently requires manufacturers to make decisions about the optimal duration of these activities. Yet manufacturers often lack the support tools for decision making. We assume that customer decisions at the aggregated level follow a state-dependent Markov process. On the basis of the expected economic return associated with dynamic response to stimuli, we determine the ideal length of marketing events using dynamic programming optimization and apply the model to a complex promotion event. Results suggest that this methodology could help managers in the publishing industry to plan the optimal duration of promotion events. Copyright Springer Science + Business Media, Inc. 2005optimal duration of promotion events, Markovian process, dynamic programming,

Returns to product promotion when consumers are learning how to consume

Consumer skills, Learning by consuming, Consumer socialization, Product promotion, Returns to advertising, D11, M37, C63,