Background The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment. Discussion Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer. Conclusions Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.

An equivalent circuit grid (ECG) model is proposed to analyse the time-varying characteristics of no-insulation (NI) ReBCO pancake coils. In the model, each turn of the coil is subdivided into fine elements in the azimuthal direction, and each element is equivalent to a circuit parameter. Then, the coil is equivalent to a circuit grid. A math model based on Kirchhoff’s law is proposed to solve the circuit grid model. The distribution of the electrical current inside the NI coil is analysed for the charging and discharging process. A finite element method (FEM) model is coupled to calculate the magnetic field induced by the coil. To validate the model, a double pancake (DP) coil is fabricated by coated conductor ReBCO tapes. Charging and discharging tests are performed on the coil at 77 K. The results from simulations and experiments exhibit a good agreement. Then, this model is used for more studies on the current distribution inside the NI coil in the charging and discharging process. The charging and discharging delay of NI coil is analysed and explained by the model. The model can also be applied to partial insulated (PI) coils and magnets consisting of NI coils.

Crowdfunding is an innovative strategy for financing a new business venture from the general public instead of seeking funds in traditional ways, such as issuing bonds or bank lending. This study aims to identify the determinants affecting the success of a crowdfunding campaign and how different measurements for crowdfunding success, different crowdfunding models, and the selection of subdivided determinants influence the determinants’ impacts on crowdfunding success. We set the disciplines in the search strategy to select studies related to crowdfunding success. Ultimately, 94 empirical papers are selected to reveal the different findings for the determinants of crowdfunding success; based on this information, we construct an integrated framework for future research. There has been much research on project- and creator-related factors; however, many of these factors have inconsistent relationships with crowdfunding success due to varying measurements of success. In particular, different measurements used within the same study for determinants or crowdfunding success may also produce inconsistent results. In addition, different crowdfunding models of a project have been found to induce additional findings. Our review of the determinants of crowdfunding success and the definitions of the determinants, as well as the proposed integrated framework, can help focus future work on relatively new or unique determinants rarely addressed in the existing literature. This work provides practical implications for both theory and practice, and directions for future research.

Oncogenic Pim-1 kinase is upregulated in multiple solid cancers, including human pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with few useful treatment options. Pim-1 is also transcriptionally induced upon oncogenic K-Ras-mediated transformation of the human pancreatic ductal epithelial (HPDE) cell model of PDAC. Given the near ubiquitous presence of mutant K-Ras in PDAC and its critical role in this disease, we wished to study the effects of oncogenic K-Ras signaling on Pim-1 expression, as well as the role of Pim-1 in growth transformation of PDAC cells. Pim-1 protein levels were upregulated in both PDAC cell lines and patient tumor tissues. Furthermore, ectopic oncogenic K-Ras increased Pim-1 expression in human pancreatic nestin-expressing (HPNE) cells, a distinct immortalized cell model of PDAC. Conversely, shRNA-mediated suppression of oncogenic K-Ras decreased Pim-1 protein in PDAC cell lines. These results indicate that oncogenic K-Ras regulates Pim-1 expression. The kinase activity of Pim-1 is constitutively active. Accordingly, shRNA-mediated suppression of Pim-1 in K-Ras-dependent PDAC cell lines decreased Pim-1 activity, as measured by decreased phosphorylation of the pro-apoptotic protein Bad and increased expression of the cyclin-dependent kinase inhibitor p27Kip1. Biological consequences of inhibiting Pim-1 expression included decreases in both anchorage-dependent and -independent cell growth, invasion through Matrigel and radioresistance as measured by standard clonogenic assays. These results indicate that Pim-1 is required for PDAC cell growth, invasion and radioresistance downstream of oncogenic K-Ras. Overall, our studies help to elucidate the role of Pim-1 in PDAC growth transformation and validate Pim-1 kinase as a potential molecular marker for mutated K-Ras activity.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 5-year survival rate of only 6%. Although the cytosine analog gemcitabine is the drug commonly used to treat PDAC, chemoresistance unfortunately renders the drug ineffective. Thus, strategies that can decrease this resistance will be essential for improving the dismal outcome of patients suffering from this disease. We previously observed that oncogenic Pim-1 kinase was aberrantly expressed in PDAC tissues and cell lines and was responsible for radioresistance. Furthermore, members of the Pim family have been shown to reduce the efficacy of chemotherapeutic drugs in cancer. Therefore, we attempted to evaluate the role of Pim-3 in chemoresistance of PDAC cells. We were able to confirm upregulation of the Pim-3 oncogene in PDAC tissues and cell lines versus normal samples. Biological consequences of inhibiting Pim-3 expression with shRNA-mediated suppression included decreases in anchorage-dependent growth, invasion through Matrigel and chemoresistance to gemcitabine as measured by caspase-3 activity. Additionally, we were able to demonstrate that Pim-1 and Pim-3 play overlapping but non-identical roles as it relates to gemcitabine sensitivity of pancreatic cancer cells. To further support the role of Pim-3 suppression in sensitizing PDAC cells to gemcitabine, we used the pharmacological Pim kinase inhibitor SGI-1776. Treatment of PDAC cells with SGI-1776 resulted in decreased phosphorylation of the proapoptotic protein Bad and cell cycle changes. When SGI-1776 was combined with gemcitabine, there was a greater decrease in cell viability in the PDAC cells versus cells treated with either of the drugs separately. These results suggest combining drug therapies that inhibit Pim kinases, such as Pim-3, with chemotherapeutic agents, to aid in decreasing chemoresistance in pancreatic cancer.