JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer

We developed an analytic strategy that correlates gene expression and clinical outcomes as a means to identify novel candidate oncogenes operative in breast cancer. This analysis, followed by functional characterization, resulted in the identification of Jumonji Domain Containing 6 (JMJD6) protein as a novel driver of oncogenic properties in breast cancer.

Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells

Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy.

Multi-Level Wordline Driver for Low Power SRAMs in Nano-Scale CMOS Technology

In this paper, a multi-level wordline driver scheme is presented to improve SRAM read and write stability while lowering power consumption during hold operation. The proposed circuit applies a shaped wordline voltage pulse during read mode and a boosted wordline pulse during write mode. During read, the applied shaped pulse is tuned at nominal voltage for short period of time, whereas for the remaining access time, the wordline voltage is reduced to a lower level. This pulse results in improved read noise margin without any degradation in access time which is explained by examining the dynamic and nonlinear behavior of the SRAM cell. Furthermore, during hold mode, the wordline voltage starts from a negative value and reaches zero voltage, resulting in a lower leakage current compared to conventional SRAM. Our simulations using TSMC 65nm process show that the proposed wordline driver results in 2X improvement in static read noise margin while the write margin is improved by 3X. In addition, the total leakage of the proposed SRAM is reduced by 10% while the total power is improved by 12% in the worst case scenario of a single SRAM cell. The total area penalty is 10% for a 128Kb standard SRAM array.

Multi-level wordline driver for robust SRAM design in nano-scale CMOS technology

In this paper, a multi-level wordline driver scheme is presented to improve 6T-SRAM read and write stability. The proposed wordline driver generates a shaped pulse during the read mode and a boosted wordline during the write mode. During read, the shaped pulse is tuned at nominal voltage for a short period of time, whereas for the remaining access time, the wordline voltage is reduced to save the power consumption of the cell. This shaped wordline pulse results in improved read noise margin without any degradation in access time for small wordline load. The improvement is explained by examining the dynamic and nonlinear behavior of the SRAM cell. Furthermore, during the hold mode, for a short time (depending on the size of boosting capacitance), wordline voltage becomes negative and charges up to zero after a specific time that results in a lower leakage current compared to conventional SRAM. The proposed technique results in at least 2× improvement in read noise margin while it improves write margin by 3× for lower supply voltages than 0.7 V. The leakage power for the proposed SRAM is reduced by 2% while the total power is improved by 3% in the worst case scenario for an SRAM array. The main advantage of the proposed wordline driver is the improvement of dynamic noise margin with less than 2.5% penalty in area. TSMC 65 nm technology models are used for simulations.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.

RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.

CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230-42. ©2015 AACR.