Colchicine promotes atherosclerotic plaque stability independently of inflammation.

Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans -differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

Recent Advancements in the Fabrication of Functional Nanoporous Materials and Their Biomedical Applications.

Functional nanoporous materials are categorized as an important class of nanostructured materials because of their tunable porosity and pore geometry (size, shape, and distribution) and their unique chemical and physical properties as compared with other nanostructures and bulk counterparts. Progress in developing a broad spectrum of nanoporous materials has accelerated their use for extensive applications in catalysis, sensing, separation, and environmental, energy, and biomedical areas. The purpose of this review is to provide recent advances in synthesis strategies for designing ordered or hierarchical nanoporous materials of tunable porosity and complex architectures. Furthermore, we briefly highlight working principles, potential pitfalls, experimental challenges, and limitations associated with nanoporous material fabrication strategies. Finally, we give a forward look at how digitally controlled additive manufacturing may overcome existing obstacles to guide the design and development of next-generation nanoporous materials with predefined properties for industrial manufacturing and applications.

Mechanically stressed cancer microenvironment: Role in pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in the world due to its insensitivity to current therapies and its propensity to metastases from the primary tumor mass. This is largely attributed to its complex microenvironment composed of unique stromal cell populations and extracellular matrix (ECM). The recruitment and activation of these cell populations cause an increase in deposition of ECM components, which highly influences the behavior of malignant cells through disrupted forms of signaling. As PDAC progresses from premalignant lesion to invasive carcinoma, this dynamic landscape shields the mass from immune defenses and cytotoxic intervention. This microenvironment influences an invasive cell phenotype through altered forms of mechanical signaling, capable of enacting biochemical changes within cells through activated mechanotransduction pathways. The effects of altered mechanical cues on malignant cell mechanotransduction have long remained enigmatic, particularly in PDAC, whose microenvironment significantly changes over time. A more complete and thorough understanding of PDAC's physical surroundings (microenvironment), mechanosensing proteins, and mechanical properties may help in identifying novel mechanisms that influence disease progression, and thus, provide new potential therapeutic targets.

Recent advances in the design of Hedgehog pathway inhibitors for the treatment of malignancies.

INTRODUCTION: The Hedgehog (Hh) signaling pathway is known to be dysregulated in several forms of cancer. Hence, specifically targeting this signaling cascade is a valid and promising strategy for successful therapeutic intervention. Several components within the Hh pathway have been proven to be druggable; however, challenges in the discovery and development process for small molecules targeting this pathway have been identified. AREAS COVERED: This review details both the current state and future potential of Hh pathway inhibitors as anticancer chemotherapeutics that target a variety of human malignancies. EXPERT OPINION: The initial development of Hh pathway inhibitors focused on small-molecule antagonists of Smoothened, a transmembrane protein that is a key regulator of pathway signaling. More recently, efforts to identify and develop inhibitors of pathway signaling that function through alternate mechanisms have been increasing. However, none of these have advanced into clinical trials. Further, early evidence suggesting the broad application of Hh pathway inhibitors as a monotherapy in a wide range of human cancers has not been validated. The potential for Hh pathway inhibitors as combination therapy has demonstrated promising preclinical results. However, more research to identify rational drug combinations to fully explore the potential of this anticancer drug class is warranted.

Hedgehog pathway inhibitors: a patent review (2009--present).

INTRODUCTION: The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents. AREAS COVERED: This review surveys the recent patent literature (2009 - 2012) for Hh pathway inhibitors as treatments for a variety of human malignancies. EXPERT OPINION: To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling. While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified. Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo. The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling.