Future of combination therapy with dabrafenib and trametinib in metastatic melanoma.

Introduction: Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF(V600) mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.

Areas Covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib , and the combination thereof.

Operative and Perioperative Pulmonary Emboli.

Intraoperative and perioperative massive pulmonary emboli remain an unusual but well-established cause of death. Improved outcomes rely on a high index of suspicion, prompt recognition, and aggressive intervention. Surgical embolectomy outcomes have improved drastically since its inception as a technique at the turn of the previous century and should be used without hesitation during an intraoperative crisis in which pulmonary embolism has been determined to be the cause.

Making sense of current and emerging therapies in pancreatic cancer: balancing benefit and value.

Pancreatic cancer remains the fourth leading cause of cancer deaths in the United States with a dismal prognosis and a 5-year survival of less than 5% across all stages.(1) In 2014, there were approximately 46,420 new cases of pancreatic cancer with only 9% of patients having localized disease.(2) Given that the vast majority of patients present with advanced disease, much of the focus for drug development has been in the metastatic setting, which is evident with the advent of two combination chemotherapy regimens for this indication.

Fighting the force: Potential of homeobox genes for tumor microenvironment regulation.

Tumor cells exist in a constantly evolving stromal microenvironment composed of vasculature, immune cells and cancer-associated fibroblasts, all residing within a dynamic extracellular matrix. In this review, we examine the biochemical and biophysical interactions between these various stromal cells and their matrix microenvironment. While the stroma can alter tumor progression via multiple mechanisms, we emphasize the role of homeobox genes in detecting and modulating the mechanical changes in the microenvironment during tumor progression.

ASYMMETRIC CELL DIVISION: IMPLICATIONS FOR GLIOMA DEVELOPMENT AND TREATMENT.

Glioma is a heterogeneous disease process with differential histology and treatment response. It was previously thought that the histological features of glial tumors indicated their cell of origin. However, the discovery of continuous neuro-gliogenesis in the normal adult brain and the identification of brain tumor stem cells within glioma have led to the hypothesis that these brain tumors originate from multipotent neural stem or progenitor cells, which primarily divide asymmetrically during the postnatal period.

A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype.

Extracellular matrix (ECM) structure, composition, and stiffness have profound effects on tissue development and pathologies such as cardiovascular disease and cancer. Accordingly, a variety of synthetic hydrogel systems have been designed to study the impact of ECM composition, density, mechanics, and topography on cell and tissue phenotype. However, these synthetic systems fail to accurately recapitulate the biological properties and structure of the native tissue ECM.

The extracellular matrix modulates the hallmarks of cancer.

The extracellular matrix regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The extracellular matrix serves not only as the scaffold upon which tissues are organized but provides critical biochemical and biomechanical cues that direct cell growth, survival, migration and differentiation and modulate vascular development and immune function. Thus, while genetic modifications in tumor cells undoubtedly initiate and drive malignancy, cancer progresses within a dynamically evolving extracellular matrix that modulates virtually every behavioral facet of the tumor cells and cancer-associated stromal cells.

Extracellular matrix assembly: a multiscale deconstruction.

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.

The microenvironment matters.

The physical and biochemical properties of the microenvironment regulate cell behavior and modulate tissue development and homeostasis. Likewise, the physical and interpersonal cues a trainee receives profoundly influence his or her scientific development, research perspective, and future success. My cell biology career has been greatly impacted by the flavor of the scientific environments I have trained within and the diverse research mentoring I have received.

The development of potential antibody-based therapies for myeloma.

With optimal target antigen selection antibody-based therapeutics can be very effective agents for hematologic malignancies, but none have yet been approved for myeloma. Rituximab and brentuximab vedotin are examples of success for the naked antibody and antibody-drug conjugate classes, respectively. Plasma cell myeloma is an attractive disease for antibody-based targeting due to target cell accessibility and the complementary mechanism of action with approved therapies.

Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate.

Extracellular matrix (ECM) stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechanotransducer, in mammary epithelial tissue transformation and invasion.

Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.

Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC.

H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation.

Noncoding RNAs control critical cellular processes, although their contribution to disease remains largely unexplored. Dyskerin associates with hundreds of H/ACA small RNAs to generate a multitude of functionally distinct ribonucleoproteins (RNPs). The DKC1 gene, encoding dyskerin, is mutated in the multisystem disorder X-linked dyskeratosis congenita (X-DC).

Overview of randomized controlled treatment trials for clinically localized prostate cancer: implications for active surveillance and the United States preventative task force report on screening?

Prostate cancer and its management have been intensely debated for years. Recommendations range from ardent support for active screening and immediate treatment to resolute avoidance of screening and active surveillance. There is a growing body of level I evidence establishing a clear survival advantage for treatment of subsets of patients with clinically localized prostate cancer.

High-risk nonmuscle invasive bladder cancer: definition and epidemiology.

Purpose Of Review: Nonmuscle invasive bladder cancer represents a large majority of patients diagnosed with this disease. Precise definition and risk stratification are paramount in this group as high-risk patients have higher rates of progression and mortality and may benefit from early identification and aggressive treatment.

Recent Findings: The mainstay definitions of high-risk nonmuscle invasive bladder cancer are based on grade and stage.

The example of CaPSURE: lessons learned from a national disease registry.

Introduction: Although randomized controlled trials (RCTs) remain the gold standard for determining evidence-based clinical practices, large disease registries that enroll large numbers of patients have become paramount as a relatively cost-effective additional tool.

Methods: We highlight the advantages of disease registries focusing on the example of prostate cancer and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE™) registry.

Results: CaPSURE collects approximately 1,000 clinical and patient-reported variables, in over 13,000 men that are enrolled.