Summary Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. TNFα/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of hedgehog pathway, has been observed in EAC. In this study, we found that activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by mTOR pathway inhibitor enhances the killing effects of the hedgehog pathway inhibitor. Together, our results established a crosstalk between mTOR/S6K1 and the hedgehog pathways, which provides not only a mechanism for SMO-independent Gli1 activation but also a rationale for combination therapy for EAC.

beta-catenin plays an important role in development and homeostasis. Deregulated beta-catenin is involved in oncogenesis. In this study, we found that beta-catenin can physically complex with NF-kappa B, resulting in a reduction of NF-kappa B DNA binding, transactivation activity, and target gene expression. Repressed NF-kappa B activity is found in human colon cancer cells in which beta-catenin is activated. Importantly, activated beta-catenin was found to inhibit the expression of NF-kappa B target genes, including Fas and TRAF1. Furthermore, a strong inverse correlation was identified between the expression levels of beta-catenin and Fas in colon and breast tumor tissues, suggesting that beta-catenin regulates NF-kappa B and its targets in vivo. Thus, beta-catenin may play an important role in oncogenesis through the crossregulation of NF-kappa B.

Summary Kinetochores bind and regulate the plus-ends of microtubules during mitosis. These attachments must be tight enough to move chromosomes, while the microtubule end both remains dynamic and repositions within the attachment pocket so that connections are maintained during depolymerization. Hec1/Ndc80 (Hec1) is a subunit of the four-protein Ndc80 complex, which is an important structural component of the kinetochore [1-3]. Kinetochores are unable to bind microtubules after Hec1 knockdown [2,4]; however, because the Ndc80 complex has structural roles, it is unclear if Hec1 directly mediates kinetochore microtubule attachments. Hec1 has a microtubule-binding site composed of both an unstructured N-terminal tail and a calponin homology domain [5-7]. Here we show that, surprisingly, the N-terminal tail is sufficient for microtubule binding affinity in vitro. The interaction is salt sensitive and the positively charged Hec1 tail is unable to bind microtubules lacking negatively charged tails. We have replaced the endogenous Hec1 subunit with a mutant lacking the N-terminal tail. These cells assemble kinetochores properly but are unable to congress chromosomes, generate tension across sister kinetochores, or establish cold-stable kinetochore-microtubule attachments. Our data argue that the highest affinity interactions between kinetochores and microtubules are ionic attractions between two unstructured domains. We discuss the importance of this finding for models of repositioning of microtubules in the kinetochore during depolymerization.

Overexpression of HER-2/neu correlates with poor survival of breast and ovarian cancer patients and induces resistance to tumor necrosis factor (TNF), which causes cancer cells to escape from host immune defenses. The mechanism of HER-2/neu-induced TNF resistance is unknown. Here we report that HER-2/neu activates Akt and NF-B without extracellular stimulation. Blocking of the Akt pathway by a dominant-negative Akt sensitizes the HER-2/neu-overexpressing cells to TNF-induced apoptosis and inhibites IB kinases, IB phosphorylation, and NF-B activation. Our results suggested that HER-2/neu constitutively activates the Akt/ NF-B anti-apoptotic cascade to confer resistance to TNF on cancer cells and reduce host defenses against neoplasia.

Abstract-We discuss a fundamentally new approach for the measurement of electric (E) fields that will lead to the development of a broadband, direct SI-traceable, compact, selfcalibrating E-field probe (sensor). This approach is based on the interaction of radio frequency (RF) fields with alkali atoms excited to Rydberg states. The RF field causes an energy splitting of the Rydberg states via the Autler-Townes effect and we detect the splitting via electromagnetically induced transparency (EIT). In effect, alkali atoms placed in a vapor cell act like an RFto-optical transducer, converting an RF E-field strength measurement to an optical frequency measurement. We demonstrate the broadband nature of this approach by showing that one small vapor cell can be used to measure E-field strengths over a wide range of frequencies: 1 GHz to 500 GHz. The technique is validated by comparing experimental data to both numerical simulations and far-field calculations for various frequencies. We also discuss various applications, including: a direct traceable measurement, the ability to measure both weak and strong field strengths, compact form factors of the probe, and sub-wavelength imaging and field mapping.Keywords: atom based metrology, Autler-Townes splitting, broadband sensor and probe, electrical field measurements and sensor, EIT, sub-wavelength imaging, Rydberg atoms