Purpose Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer. Experimental Design We conducted a retrospective study of diabetic patients with pancreatic cancer treated at MD Anderson Cancer Center. Information on diabetes history including treatment modalities and clinical outcome of pancreatic cancer was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan Meier plot, log-rank test, and Cox proportional hazards regression models. Results Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n=117) and those who had not (n=185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the nonmetformin group (P=0.004, χ2 test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the nonmetformin group (P=0.004, log-rank test). Metformin users had a 32% lower risk of death; the hazard ratio (95% confidence interval) was 0.68 (0.52–0.89) in a univariate model (P=0.004), 0.64 (0.48–0.86) after adjusting for other clinical predictors (P=0.003), and 0.62 (0.44–0.87) after excluding insulin users (P=0.006). Metformin use was significantly associated with longer survival in patients with non-metastatic disease only. Conclusions Our finding that metformin use was associated with improved outcome of diabetic patients with pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population.

Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative, "triple-negative" breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.

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How does the brain represent the passage of time at the subsecond scale? Although different conceptual models for time perception have been proposed, its neurophysiological basis remains unknown. We took advantage of a visual duration illusion produced by stimulus novelty to link changes in cortical activity in monkeys with distortions of duration perception in humans. We found that human subjects perceived the duration of a subsecond motion pulse with a novel direction longer than a motion pulse with a repeated direction. Recording from monkeys viewing identical motion stimuli but performing a different behavioral task, we found that both the duration and amplitude of the neural response in the middle temporal area of visual cortex were positively correlated with the degree of novelty of the motion direction. In contrast to previous accounts that attribute distortions in duration perception to changes in the speed of a putative internal clock, our results suggest that the known adaptive properties of neural activity in visual cortex contributes to subsecond temporal distortions.

The PI3K pathway plays an important role in key cellular functions such as cell growth, proliferation and survival. Genetic and epigenetic alterations in different pathway components lead to aberrant pathway activation and have been observed in high frequencies in various tumor types. Consequently, significant effort has been made to develop antineoplastic agents targeting different nodes in this pathway. Additionally, PI3K pathway status may have predictive and prognostic implications, and may contribute to drug resistance in tumor cells. This article provides an overview of our current knowledge of the PI3K pathway with an emphasis on its application in cancer treatment.