PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate.

Tumor-associated inflammation mediates the development of a systemic immunosuppressive milieu that is a major obstacle to effective treatment of cancer. Inflammation has been shown to promote the systemic expansion of immature myeloid cells which have been shown to exert immunosuppressive activity in laboratory models of cancer as well as cancer patients. Consequentially, significant effort is underway toward the development of therapies that decrease tumor-associated inflammation and immunosuppressive cells.

Altered sphingolipid metabolism in patients with metastatic pancreatic cancer.

Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to identify perturbations in pancreatic cancer patient samples. Thus, we utilized a mass spectrometry-based lipidomic approach, focused towards the sphingolipid class of lipids, to quantify changes in human pancreatic cancer tumor and plasma specimens.

Selective integrin subunit reduction disrupts fibronectin extracellular matrix deposition and fibrillin 1 gene expression.

Integrins are transmembrane receptors that can specifically bind extracellular matrix (ECM) proteins. Assembly of the ECM protein fibronectin into fibrils has been shown to be a cell-mediated process that requires integrins. Like fibronectin, fibrillin 1 is an ECM glycoprotein that can assemble into fibrils, but the role of integrins in fibril formation is not understood.

Osteosarcoma in a Marfan patient with a novel premature termination codon in the FBN1 gene.

Osteosarcoma is a malignant neoplasm of mesenchymal origin that is presumed to arise from osteoblasts. Considered a rare tumor, approximately 1000 cases of osteosarcoma are diagnosed in the United States each year, and osteosarcoma of the foot is rarer still. Marfan syndrome (MFS) is a rare genetic disorder that affects 1 in 5000 individuals and is caused by mutations in the fibrillin 1 (FBN1) gene.

Bone and soft connective tissue alterations result from loss of fibrillin-2 expression.

Fibrillins 1, 2 and 3 make up a family of genes that encode large, cysteine-rich extracellular matrix glycoproteins found in connective tissues, lung, blood vessels and other extensible tissues. Fibrillins 1 and 2 have both overlapping as well as separate distributions in human embryonic and adult tissues. Fibrillin-containing microfibrils are known to modulate morphogenetic events by proper targeting of growth factors to the extracellular matrix.

Human embryonic and mesenchymal stem cells express different nuclear proteomes.

Human embryonic stem cells (hESCs) are characterized by their immortality and pluripotency. Human mesenchymal stem cells (hMSC), on the other hand, have limited self-renewal and differentiation capabilities. The underlying molecular differences that account for this characteristic self-renewal and plasticity are, however, poorly understood.

Arg-Gly-Asp-containing domains of fibrillins-1 and -2 distinctly regulate lung fibroblast migration.

Development of the extracellular matrix is a critical feature of alveolar formation and actively involves pulmonary interstitial fibroblasts. The elastic fiber network is an interconnected system of load-bearing fibers that also influences the behavior of adjacent cells, particularly the interstitial lung fibroblasts (LF). We hypothesized that discrete domains of fibrillins-1 and -2 interact with LF integrins and direct their migration in the presence of platelet-derived growth factor (PDGF)-A.

Tendon injury response: assessment of biomechanical properties, tissue morphology and viability following flexor digitorum profundus tendon transection.

Insertion site injuries of the flexor digitorum profundus (FDP) tendon often present for delayed treatment. Apart from gross observations made at the time of surgery, the changes that occur in the flexor tendon stump during the interval from injury to repair are unknown. These changes may include tendon softening and loss of viability, which may contribute to the poor outcomes observed clinically and experimentally.

Identification of a major microfibril-associated glycoprotein-1-binding domain in fibrillin-2.

Using yeast two-hybrid, ligand blotting, and solid phase binding assays, we have shown that microfibril-associated glycoprotein-1 (MAGP-1) interacts with the 8-cysteine motif of fibrillin-2 encoded by exon 24. Binding to this sequence was demonstrated for full-length MAGP-1 as well as for the MAGP-1 matrix-binding domain encoded by exons 7 and 8. The matrix-binding domain, but not the full-length protein, also bound to regions of fibrillin-2 defined by exons 16 and 17, exon 20, and exons 23 and 24.

Tendon cell array isolation reveals a previously unknown fibrillin-2-containing macromolecular assembly.

Within tendon, between collagen fascicles, cells are organized in linear arrays surrounded by a specialized environment of extracellular matrix (ECM) proteins that are largely unidentified. Our goal was to identify interfascicular, pericellular ECM components and provide additional resolution to the organization of the pericellular matrix. To this end, we employed a combination of enzymatic digestion, mechanical disruption, and differential sedimentation to demonstrate for the first time that it possible to liberate living linear tendon cell arrays from whole tendon.

Fibrillin-1 and -2 contain heparin-binding sites important for matrix deposition and that support cell attachment.

Fibrillin-1 and -2 are large modular extracellular matrix glycoproteins found in many vertebrate organ systems and are known to be key components of the elastic fibre. In the present study, we identify a new heparin-binding region in fibrillin-2 between exons 18 and 24. Additionally, we have narrowed the location of heparin-binding activity previously identified in fibrillin-1 to the last 17 residues of the mature proteolytically processed protein.

Tendon cells produce gelatinases in response to type I collagen attachment.

Cells that carry out wound healing must be able to perform catabolic as well as anabolic functions. As the tendon is a tissue rich in extracellular matrix (ECM) proteins, we hypothesized that cells which participate in tendon healing should be able to produce proteases that would allow the remodeling of such a tissue. To this end, we assessed the ability of endotenon cells isolated from canine flexor digitorum profundus tendon and from surrounding parietal sheath to produce the gelatinases MMP-2 and MMP-9.

Distribution of the elastic fiber and associated proteins in flexor tendon reflects function.

The elastic fiber is known to be an important component of skin, lung, and vasculature. Much less is known about the distribution of elastin and elastic fiber-related proteins in connective tissues, yet genetic defects of elastic fiber constituents can lead to deficiencies in these tissues. For the first time, we determine the distribution of elastin, fibrillins 1 and 2, and microfibril-associated glycoproteins (MAGPs) 1 and 2 in the flexor digitorum profundus (FDP) tendon.