Differential Serum Peptidomics Reveal Multi-Marker Models That Predict Breast Cancer Progression.

Here, we assess how the differential expression of low molecular weight serum peptides might predict breast cancer progression with high confidence. We apply an LC/MS-MS-based, unbiased 'omics' analysis of serum samples from breast cancer patients to identify molecules that are differentially expressed in stage I and III breast cancer. Results were generated using standard and machine learning-based analytical workflows.

A natural product biflavonoid scaffold with anti-tryptase activity.

Tryptase is a serine protease that is released from mast cells during allergic responses. Tryptase inhibitors are being explored as treatments for allergic inflammation in the skin and respiratory system, most notably asthma. Here we report direct tryptase inhibition by natural product compounds.

Comparative transcriptomic analysis identifies distinct molecular signatures and regulatory networks of chondroclasts and osteoclasts.

Background: Chondroclasts and osteoclasts have been previously identified as the cells capable of resorbing mineralized cartilage and bone matrices, respectively. While both cell types appear morphologically similar, contain comparable ultrastructural features, and express tartrate-resistant acid phosphatase (TRAP), however, no information is available about the genomic similarities and differences between osteoclasts and chondroclasts.

Methods: To address this question, we laser captured homogeneous populations of TRAP-positive cells that interact with bone (osteoclasts) and TRAP-positive cells that interact with mineralized cartilage (chondroclasts) on the same plane from murine femoral fracture callus sections.

Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation.

Bone remodeling is achieved through the coupled activities of osteoclasts and osteoblasts that are controlled by many locally generated secreted factors, including WNT5A. While previous studies have demonstrated that osteoblast-derived WNT5A promotes osteoclastogenesis, the function of osteoclast-derived WNT5A on bone remodeling has remained unexplored. We examined the effects of osteoclast-derived WNT5A on bone homeostasis by utilizing the Cathepsin K-Cre (Ctsk-Cre) mouse to conditionally delete Wnt5a in mature osteoclasts.

Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34.

A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (20-93%, ave. = 59%). The straightforward synthesis involved sequential treatment of commercially-available acetonitrile derivatives with DMF-dimethylacetal (120 °C, 20 min), followed by treatment with NHNH·HBr (120 °C, 20 min), and 1,1,3,3-tetramethoxypropane or 2-aryl-substituted malondialdehdyes (120 °C, 20 min).

Resistance mechanisms and cross-resistance for a pyridine-pyrimidine amide inhibitor of microtubule polymerization.

Despite their clinical importance, drug resistance remains problematic for microtubule targeting drugs. D4-9-31, a novel microtubule destabilizing agent, has pharmacology that suggests it can overcome common resistance mechanisms and has been shown to remain efficacious in cell and animal models with acquired taxane resistance. To better understand resistance mechanisms and the breadth of cross-resistance with D4-9-31, this study examines the A2780 ovarian cancer cell line as it develops acquired resistance with continuous exposure to D4-9-31.

Articular cartilage protection in Ctsk mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix.

Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits.

Pharmacology and in vivo efficacy of pyridine-pyrimidine amides that inhibit microtubule polymerization.

Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors.

Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms.

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents.

A cellular automaton based on plasma membrane turnover accurately recapitulates cell mechanics during epithelial scattering.

Epithelial cells can be triggered to actively detach from epithelial tissues and become solitary, migratory and invasive. This process occurs repeatedly in development, where it is termed epithelial-mesenchymal transition (EMT), and can be recapitulated as epithelial scattering in cell culture models. Detachment of cell-cell junctions involves changes in contractile forces, actin cytoskeletal organization, changes in cell-substrate adhesion properties, surface presentation of cell-cell adhesion molecules, and gene expression.

Isolation and identification of compounds from Kalanchoe pinnata having human alphaherpesvirus and vaccinia virus antiviral activity.

Context: Kalanchoe pinnata (Lam.) Pers. (Crassulaceae) is a succulent plant that is known for its traditional antivirus and antibacterial usage.

Copy number analysis identifies tumor suppressive lncRNAs in human osteosarcoma.

Osteosarcoma (OS) has a high degree of chromosomal instability and total copy number (CN) changes. We examined 58 human OS samples including 40 primary tumors, 11 explants, and 7 cell lines using single nucleotide polymorphism (SNP) arrays, and revealed that 70% of the samples had one or more recurrent CN-neutral loss of heterozygosity (CNN‑LOH) also known as uniparental disomy (UPD). Importantly, 17% of the samples showed prominent homozygous deletion of 3q13.

Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation.

The periosteum contains multipotent skeletal progenitors that contribute to bone repair. The signaling pathways regulating the response of periosteal cells to fracture are largely unknown. Phosphatidylinositol-3 Kinase (PI3K), a prominent lipid kinase, is a major signaling protein downstream of several factors that regulate osteoblast differentiation.

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering.

Epithelial tissues use adherens junctions to maintain tight interactions and coordinate cellular activities. Adherens junctions are remodeled during epithelial morphogenesis, including instances of epithelial-mesenchymal transition, or EMT, wherein individual cells detach from the tissue and migrate as individual cells. EMT has been recapitulated by growth factor induction of epithelial scattering in cell culture.

Systematic Echocardiographic Evaluation of Mitral Valve Regurgitation for Transcatheter Edge-to-Edge Repair.

In patients with relevant mitral regurgitation (MR), transcatheter edge-to-edge repair (also called MitraClip) provides an alternative treatment option especially for inoperable or high-risk patients. In preparation for the procedure, echocardiography is the method of choice for assessment of mitral valve (MV) morphology and function and thus provides important information if successful treatment of MR can be accomplished by MitraClip. This review article provides structured and detailed guidance how to systematically assess functional and degenerative MR and MV pathology by echocardiography in order to select eligible patients for this procedure.

Small Molecules Revealed in a Screen Targeting Epithelial Scattering Are Inhibitors of Microtubule Polymerization.

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in the detachment of cell-cell junctions and initiation of cell migration. Instead of coordinating collective cell behavior within a tissue, cells become solitary and have few cell-cell interactions. Since epithelial scattering is recapitulated in cancer progression and since HGF signaling drives cancer metastasis in many cases, inhibitors of HGF signaling have been proposed to act as anticancer agents.

Effects of Mechanical Ventilation on Heart Geometry and Mitral Valve Leaflet Coaptation During Percutaneous Edge-to-Edge Mitral Valve Repair.

Objectives: This study sought to evaluate a ventilation maneuver to facilitate percutaneous edge-to-edge mitral valve repair (PMVR) and its effects on heart geometry.

Background: In patients with challenging anatomy, the application of PMVR is limited, potentially resulting in insufficient reduction of mitral regurgitation (MR) or clip detachment. Under general anesthesia, however, ventilation maneuvers can be used to facilitate PMVR.

The Implications of the Sequestosome 1 Mutation P392L in Patients with Paget's Disease in a United States Cohort.

Paget's disease of bone (PDB) is associated with a germline mutation in Sequestosome1/p62 (SQSTM1) found in ≤16 % of sporadic cases worldwide, and in 19-46 % of those studied with familial PDB. The P392L is the most prevalent mutation identified to date. This mutation by itself does not confer PDB or define the phenotype of PDB in a given person.

Role of Cbl-PI3K Interaction during Skeletal Remodeling in a Murine Model of Bone Repair.

Mice in which Cbl is unable to bind PI3K (YF mice) display increased bone volume due to enhanced bone formation and repressed bone resorption during normal bone homeostasis. We investigated the effects of disrupted Cbl-PI3K interaction on fracture healing to determine whether this interaction has an effect on bone repair. Mid-diaphyseal femoral fractures induced in wild type (WT) and YF mice were temporally evaluated via micro-computed tomography scans, biomechanical testing, histological and histomorphometric analyses.

Regulation of Osteoblast Migration Involving Receptor Activator of Nuclear Factor-kappa B (RANK) Signaling.

Bone remodeling requires osteoclast activation, resorption, and reversal, prior to osteoblast migration into the bone pit. The Receptor Activator of NF-κB (RANK) signaling pathway plays an important role in bone remodeling. Two components of the RANK signaling pathway, RANK Ligand (RANKL) and the decoy receptor Osteoprotegerin (OPG), are expressed predominantly on the surface of osteoblasts, while RANK is principally expressed on the surface of osteoclasts.

Winter warming as an important co-driver for Betula nana growth in western Greenland during the past century.

Growing season conditions are widely recognized as the main driver for tundra shrub radial growth, but the effects of winter warming and snow remain an open question. Here, we present a more than 100 years long Betula nana ring-width chronology from Disko Island in western Greenland that demonstrates a highly significant and positive growth response to both summer and winter air temperatures during the past century. The importance of winter temperatures for Betula nana growth is especially pronounced during the periods from 1910-1930 to 1990-2011 that were dominated by significant winter warming.

Epithelial-Mesenchymal Transition in Metastatic Cancer Cell Populations Affects Tumor Dormancy in a Simple Mathematical Model.

Signaling from the c-Met receptor tyrosine kinase is associated with progression and metastasis of epithelial tumors. c-Met, the receptor for hepatocyte growth factor, triggers epithelial-mesenchymal transition (EMT) of cultured cells, which is thought to drive migration of tumor cells and confer on them critical stem cell properties. Here, we employ mathematical modeling to better understand how EMT affects population dynamics in metastatic tumors.

Imatinib restores VASP activity and its interaction with Zyxin in BCR-ABL leukemic cells.

Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein.

Grasping with the Press of a Button: Grasp-selective Responses in the Human Anterior Intraparietal Sulcus Depend on Nonarbitrary Causal Relationships between Hand Movements and End-effector Actions.

Evidence implicates ventral parieto-premotor cortices in representing the goal of grasping independent of the movements or effectors involved [Umilta, M. A., Escola, L.

Cellular contractility changes are sufficient to drive epithelial scattering.

Epithelial scattering occurs when cells disassemble cell-cell junctions, allowing individual epithelial cells to act in a solitary manner. Epithelial scattering occurs frequently in development, where it accompanies epithelial-mesenchymal transitions and is required for individual cells to migrate and invade. While migration and invasion have received extensive research focus, how cell-cell junctions are detached remains poorly understood.