MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers.

Adipose tissue metabolism is closely linked to insulin resistance, and differential fat distributions are associated with disorders like hypertension, diabetes, and cardiovascular disease. Adipose tissues vary in their impact on metabolic risk due to diverse gene expression profiles, leading to differences in lipolysis and in the production and release of adipokines and cytokines, thereby affecting the function of other tissues. In this paper, the roles of the various adipose tissues in obesity are summarized, with particular focus on mitochondrial function. In addition, we discuss how a functionally mitochondrial-targeted compound, the modified fatty acid tetradecylthioacetic acid (TTA), can influence mitochondrial function and decrease the size of specific fat depots.

Chemoresistance represents a major problem in the treatment of many malignancies. Overcoming this obstacle will require improved understanding of the mechanisms responsible for this phenomenon. The progenitor cell marker NG2/melanoma proteoglycan (MPG) is aberrantly expressed by various tumors, but its role in cell death signaling and its potential as a therapeutic target are largely unexplored. We have assessed cytotoxic druginduced cell death in glioblastoma spheroids from 15 patients, as well as in five cancer cell lines that differ with respect to NG2/MPG expression. The tumors were treated with doxorubicin, etoposide, carboplatin, temodal, cisplatin and tumor necrosis factor (TNF)a. High NG2/ MPG expression correlated with multidrug resistance mediated by increased activation of a3b1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated b1 integrin signaling revealing potent antitumor effects and further sensitized neoplastic cells to cytotoxic treatment in vitro and in vivo. Thus, as a novel regulator of the antiapoptotic response, NG2/MPG may represent an effective therapeutic target in several cancer subtypes.

Expanding knowledge, together with implementation of new techniques, has fuelled the area of translational medical research aiming at improving prognostication as well as prediction in cancer therapy. At the same time, new discoveries have revealed a biological complexity we were unaware of only a decade ago. Thus, we are faced with novel challenges with respect to how we may explore issues such as prognostication and predict drug resistance in vivo. While microarray analysis exploring expression of thousands of genes in concert represents a major methodological advancement, discoveries such as the finding of different mechanisms of epigenetic silencing, intronic mutations, that most gene transcripts in the human genome are subject to alternative splicing and that hypersplicing seems to be a tumour-related phenomenon, exemplifies a complex pathology that may not be explored with use of single analytical methods only. This paper discusses clinical settings for studying drug resistance in vivo together with a discussion of contemporary biology in this field. Notably, each individual parameter which has been found correlated to drug resistance in vivo so far represents either a direct drug target or a factor involved in DNA repair or apoptosis. On the basis of these findings, we suggest drug resistance may be explored on the basis of upfront biological hypotheses.