The mechanisms of compromised mitochondrial function under various pathological conditions, including hypoxia, remain largely unknown. Recent studies have shown that microRNA-210 (miR-210) is induced by hypoxia under the regulation of hypoxia-inducible factor-1a and has an important role in cell survival under hypoxic microenvironment. Hence, we hypothesized that miR-210 has a role in regulating mitochondrial metabolism and investigated miR-210 effects on mitochondrial function in cancer cell lines under normal and hypoxic conditions. Our results demonstrate that miR-210 decreases mitochondrial function and upregulates the glycolysis, thus make cancer cells more sensitive to glycolysis inhibitor. miR-210 can also activate the generation of reactive oxygen species (ROS). ISCU (iron-sulfur cluster scaffold homolog) and COX10 (cytochrome c oxidase assembly protein), two important factors of the mitochondria electron transport chain and the tricarboxylic acid cycle have been identified as potential targets of miR-210. The unique means by which miR-210 regulates mitochondrial function reveals an miRNAmediated link between microenvironmental stress, oxidative phosphorylation, ROS and iron homeostasis.

Loss of intraepidermal nerve fibers (IENFs) has been speculated to play a critical role in the development of various neuropathies. In this study, the density of IENFs were studied over time during the induction of Taxol-induced chemoneuropathy and compared with the changes in IENFs in animals co-treated with Taxol plus the protective agent minocycline. Rats were injected (i.p.) with 2mg/kg of Taxol every other day for 4 injections (Days 1, 3, 5, and 7). Minocycline (25 mg/kg) was given in a separate group of rats 24 hours prior to the first dose of Taxol and every day for the next 9 days (Days 0 through 9). Animals were tested for mechanical paw withdrawal thresholds prior to any drug administrations and again on Days 7, 14, and 30. Immunohistochemistry using the pan-neuronal marker PGP9.5 was performed on glabrous skin of the hind-paw foot pad to stain for IENFs also on Days 7, 14, and 30. The results show that Taxol-treated animals developed mechanical sensitivity and corresponding IENF loss. Animals receiving minocycline plus Taxol showed no hyperalgesia or loss of IENFs. This study confirms, for the first time, that a loss of IENFs occurs as a neuropathy develops, and further shows a protection against both IENF loss and hyperalgesia with minocycline treatment.

Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.

Electronic monitoring demonstrated that only one-fourth of the patients had an adherence rate ≥80%. Polypharmacy and depression were associated with non-adherence.

The mammalian target of rapamycin (mTOR) pathway plays important roles in regulating nutrient metabolism and promoting the growth and survival of cancer cells, which exhibit increased glycolysis for ATP generation. In this study, we tested the hypothesis that inhibition of the mTOR pathway and glycolysis would synergistically impact the energy metabolism in cancer cells and may serve as an effective therapeutic strategy to kill malignant cells. Using human lymphoma cells and leukemia cells, we demonstrated that the combination of rapamycin, an mTOR inhibitor, with a glycolytic inhibitor produced synergistic cytotoxic effect, as evidenced by apoptosis and cell growth inhibition assays. Mechanistic studies showed that inhibition of the mTOR pathway by rapamycin alone sufficiently suppressed the phosphorylation of the downstream molecules p70S6K and 4E-BP-1, but only caused a moderate cytostatic effect. Combination of mTOR inhibition and blockage of glycolysis synergistically suppressed glucose uptake and severely depleted cellular ATP pools, leading to significant enhancement of cell killing. In contrast, combination of rapamycin and ara-C did not increase cytotoxicity in vitro. Our findings suggest that targeting mTOR pathway in combination with inhibition of glycolysis may be an effective therapeutic strategy for hematological malignancies. This mechanismbased drug combination warrants further investigation in preclinical and clinical settings.