Expression of IGPR-1 in endothelial cells regulates cell survival

Angiogenesis is a physiological process by which new blood vessels develop from preexisting vasculature. The process of converting endothelial cells into fully developed blood vessels involves multiple coordinated cellular events that occur through the collaboration that exists between a variety of growth factors, receptors and adhesion molecules. The immunoglobulin-containing and proline rich receptor-1 (IGPR-1) is an IgSF containing adhesion molecule that has been recently identified as a novel regulator of angiogenesis in vitro. In this study, we provide evidence that IGPR-1 promotes cell survival in porcine aortic endothelial cells (PAE) and plays a role in the inhibition of p38 MAPK in vitro. Deletion of the extracellular domain of IGPR-1 abolished IGPR-1’s ability to inhibit phosphorylation of p38 MAPK and promote the survival of endothelial cells. Likewise, mutation of serines 186 (A186-IGPR-1) and 220 (A220-IGPR-1) on the cytoplasmic domain of IGPR-1 was also found to reduce both the promotion of cell survival and inhibition of p38 MAPK. These findings suggest that both domains of IGPR-1 are important for endothelial cell survival and the activation p38 MAPK

Energy transfer from an individual quantum dot to a carbon nanotube

A detailed understanding of energy transduction is crucial for achieving precise control of energy flow in complex, integrated systems. In this context, carbon nanotubes (CNTs) are intriguing model systems due to their rich, chirality-dependent electronic and optical properties. Here, we study the quenching of fluorescence from isolated quantum dots (QDs) upon approach of individual CNTs attached to atomic force microscope probes. Precision measurements of many different CNT/QD pairs reveal behavior consistent with resonant energy transfer between QD and CNT excitons via a Fohrster-like dipole-dipole coupling. The data reveal large variations in energy transfer length scales even though peak efficiencies are narrowly distributed around 96%. This saturation of efficiency is maintained even when energy transfer must compete with elevated intrinsic non-radiative relaxation rates during QD aging. These observations suggest that excitons can be created at different locations along the CNT length, thereby resulting in self-limiting behavior.Comment: 8 pages, 8 figures, with supplementary informatio

The role of BET proteins in castration-resistant prostate cancer dissemination

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen-deprivation therapy (ADT) and accumulated resistance mechanisms to evade androgen receptor (AR) suppression. Whereas the canonical androgen/AR signaling axis maintains prostate cell growth, differentiation and survival, in prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogenous, ADT-resistant tumor that culminates in prostate tumor cells transitioning from epithelial to mesenchymal states (EMT) and the development of metastatic castration-resistant prostate cancer (mCRPC). Here, we examined prostate cancer cell lines that model common CRPC subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and ExtraTerminal (BET – BRD2, BRD3 and BRD4) family of proteins, to test the hypothesis that each BET family member regulates EMT and underlying characteristics such as cell motility and invasiveness. We systematically manipulated the BET proteins and found that BRD4 regulates cell migration and invasion across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate cell migration and invasion in less aggressive models that retain AR expression or signaling. We determined that BRD4’s contribution to this process occurs through the transcriptional regulation of AHNAK, SNAI1 and SNAI2, which are EMT genes linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits EMT and metastatic potential. Overall, these results reveal a novel, BRD4-regulated EMT gene signature that may be targetable to treat metastatic castration-resistant prostate cancer

Using a sharp metal tip to control the polarization and direction of emission from a quantum dot

journal articleOptical antennas can be used to manipulate the direction and polarization of radiation from an emitter. Usually, these metallic nanostructures utilize localized plasmon resonances to generate highly directional and strongly polarized emission, which is determined predominantly by the antenna geometry alone, and is thus not easily tuned. Here we show experimentally that the emission polarization can be manipulated using a simple, nonresonant scanning probe consisting of the sharp metallic tip of an atomic force microscope; finite element simulations reveal that the emission simultaneously becomes highly directional. Together, the measurements and simulations demonstrate that interference between light emitted directly into the far field with that elastically scattered from the tip apex in the near field is responsible for this control over polarization and directionality. Due to the relatively weak emitter-tip coupling, the tip must be positioned very precisely near the emitter, but this weak coupling also leads to highly tunable emission properties with a similar degree of polarization and directionality compared to resonant antennas

BRD4 regulates metastatic potential of castration-resistant prostate cancer through AHNAK

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen-deprivation therapy (ADT) and accumulated resistance strategies to evade androgen receptor (AR) suppression. In prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogeneous, ADT-resistant tumor. Here, we examined prostate cancer cell lines that model common castration-resistant prostate cancer (CRPC) subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and ExtraTerminal (BET) family of proteins. We found that BRD4 regulates cell migration across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate migration and invasion in less aggressive models that retain AR expression or signaling. BRD4, a co-regulator of gene transcription, controls migration and invasion through transcription of AHNAK, a large scaffolding protein linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits metastatic potential. Overall, these results reveal a novel BRD4-AHNAK pathway that may be targetable to treat metastatic CRPC (mCRPC). Implications: BRD4 functions as the dominant regulator of CRPC cell migration and invasion through direct transcriptional regulation of AHNAK, which together offer a novel targetable pathway to treat metastatic CRPC

BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment

Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling. The pathways by which tumor cells evade immune surveillance, immune therapies, and take advantage of antitumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment. Immune functions are abnormal in metabolic disease, and lessons learned from preclinical studies in lean and metabolically normal environments may not translate to patients with obesity and metabolic disease. This problem is made more urgent by the rising incidence of breast cancer among women who are not obese but who have metabolic disease and associated inflammation, a phenotype common in Asia. The somatic BET proteins, comprising BRD2, BRD3, and BRD4, are newcritical regulators of metabolism, coactivate transcription of genes that encode proinflammatory cytokines in immune cell subsets infiltrating the microenvironment, and could be important targets in breast cancer immunotherapy. These transcriptional coregulators are well known to regulate tumor cell progression, but only recently identified as critical for metabolism, metastasis, and expression of immune checkpoint molecules. We consider interrelationships among metabolism, inflammation, and breast cancer aggressiveness relevant to the emerging threat of breast cancer among women with metabolic disease, but without obesity

Tropical cyclone flow asymmetries induced by a uniform flow revisited

The article of record as published may be found at: http://dx.doi.org10.1002/2015MS000477We investigate the hypothesized effects of a uniform flow on the structural evolution of a tropical cyclone using a simple idealized, three-dimensional, convection-permitting, numerical model. The study addresses three outstanding basic questions concerning the effects of moist convection on the azimuthal flow asymmetries and provides a bridge between the problem of tropical cyclone intensification in a quiescent environment and that in the vertical shear over a deep tropospheric layer. At any instant of time, explicit deep convection in the model generates flow asymmetries that ten to mask the induced flow asymmetries predicted by the dry, slab boundary layer of Shapiro, whose results are frequently invoked as a benchmark for characterizing the boundary layer-induced vertical motion for a translating storm. In sets of ensemble experiment in which the initial low-level moisture field is randomly perturbed, time-averaged ensemble mean fields in the mature stage show a coherent asymmetry in the vertical motion rising into the eyewall and in the total (horizontal) wind speed just above the boundary layer. The maximum ascent occurs about 45 degrees to the left of the vortex motion vector, broadly in support of Shapiro's results, in which it occurs ahead of the storm, and consistent with one earlier more complex numerical calculation by Frank and Ritchie. The total wind asymmetry just above the boundary layer has a maximum in the forward right sector, which is in contrast to the structure effectively prescribed by Shapiro based on an inviscid dry symmetric vortex translating in a uniform flow where, in an Earth-relative frame, the maximum in on the right.G.L.T. and R.K.S. were supported in part by grant SM 30/23-1 from the German Research Council (DFG). R.K.S. is supported also by the Office of Naval Research Global under grant N62909-15-1-N021. M.T.M. acknowledges the supports of NSF grants AGS-0733380 and NSF AGS-0851077 and NASA grants NNH09AK561 and NNG09HG031Approved for public release; distribution is unlimited