The Peripheral Lymphatic System Is Impaired by the Loss of Neuronal Control Associated with Chronic Spinal Cord Injury.

Spinal cord injury (SCI) is associated with venous vascular dysfunction below the level of injury, resulting in dysregulation of tissue fluid homeostasis in afflicted skin. The purpose of this study was to determine whether loss of neuronal control in chronic SCI also affects the skin lymphatic system. Morphology of lymphatics was characterized by immunohistochemistry and lymphatic gene expression profiles determined by DNA microarray analysis.

Cellular and molecular changes that predispose skin in chronic spinal cord injury to pressure ulcer formation.

Patients with spinal cord injury have a predisposition to develop pressure ulcers. Specific characteristics of the patients' skin potentially involved have not yet been identified. The purpose of this investigation was to determine whether loss of neuronal control affects cellular and molecular homeostasis in the skin.

Activation of human vascular endothelium in melanoma metastases induces ICAM-1 and E-selectin expression and results in increased infiltration with effector lymphocytes.

Lymphocytic infiltration into melanoma tissue is an important prerequisite for effective antitumoral immunity. However, analysis of human metastatic melanoma has shown that leucocyte adhesion receptor expression on melanoma blood vessels is very low or absent, thereby impairing the entry of cytotoxic lymphocytes into tumor tissue. We hypothesized that adhesion molecules can be induced on melanoma vasculature allowing better infiltration of cytotoxic lymphocytes.

A Prognostic Gene Signature Expressed in Primary Cutaneous Melanoma: Synergism With Conventional Staging.

Background: Current clinico-pathological American Joint Committee on Cancer (AJCC) staging of primary cutaneous melanoma is limited in its ability to determine clinical outcome, and complementary biomarkers are not available for routine prognostic assessment. We therefore adapted a gene signature, previously identified in fresh-frozen (FF) melanomas and adjacent stroma, to formalin-fixed paraffin-embedded (FFPE) melanomas. The aim was to develop a gene expression profiling (GEP) score to define patient survival probability at the time of first diagnosis.

CEACAM1 promotes melanoma metastasis and is involved in the regulation of the EMT associated gene network in melanoma cells.

We investigated the functional role of CEACAM1 in a spontaneous metastasis xenograft model of human melanoma in scid mice using BRAF wildtype MeWo cells with and without RNAi mediated knockdown of CEACAM1. Tumors from the xenograft model were subjected to whole genome expression analysis and metastasis was quantified histologically. Results and identified markers were verified using tissue samples of over 100 melanoma patients.

Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation.

Background: Melanoma is a heterogeneous malignancy. We set out to identify the molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes.

Methods: We examined transcriptome changes from benign states to early-, intermediate-, and late-stage tumors using a set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions.

Genomic Characterization of Dysplastic Nevi Unveils Implications for Diagnosis of Melanoma.

A well-defined risk factor and precursor for cutaneous melanoma is the dysplastic nevus. These benign tumors represent clonal hyperproliferation of melanocytes that are in a senescent-like state, but with occasional malignant transformation events. To portray the mutational repertoire of dysplastic nevi in patients with the dysplastic nevus syndrome and to determine the discriminatory profiles of melanocytic nevi (including dysplastic nevi) from melanoma, we sequenced exomes of melanocytic nevi including dysplastic nevi (n = 19), followed by a targeted gene panel (785 genes) characterization of melanocytic nevi (n = 46) and primary melanomas (n = 42).

Increased level of circulating U2 small nuclear RNA fragments indicates metastasis in melanoma patients.

Unlabelled: Background: Melanoma is the most aggressive skin cancer and, despite recent advances in therapy, about 20% of the patients die of their disease. Early relapse detection and monitoring of therapy response are crucial for efficient treatment of advanced melanoma. Thus, there is a need for blood-based biomarkers in melanoma management.

Cyclic mechanical strain induces TGFβ1-signalling in dermal fibroblasts embedded in a 3D collagen lattice.

Many tissues are constantly exposed to mechanical stress, e.g. shear stress in vascular endothelium, compression forces in cartilage or tensile strain in the skin.

Cutaneous and oral squamous cell carcinoma-dual immunosuppression via recruitment of FOXP3+ regulatory T cells and endogenous tumour FOXP3 expression?

Regulatory T cells (Tregs) are an essential component of the immune system, but are also involved in the suppression of anti-tumour immune responses. The study examines their immunoregulatory role including their transcription factor, FOXP3, in oral and cutaneous SCC. Tregs were detected by double-immunohistochemistry.

FBXW7 mutations in melanoma and a new therapeutic paradigm.

Background: Melanoma is a heterogeneous tumor with subgroups requiring distinct therapeutic strategies. Genetic dissection of melanoma subgroups and identification of therapeutic agents are of great interest in the field. These efforts will ultimately lead to treatment strategies, likely combinatorial, based on genetic information.

A tumor suppressor function for the lipid phosphatase INPP4B in melanocytic neoplasms.

The phosphoinositide-3 kinase (PI3K) pathway is deregulated in a significant proportion of melanomas, and PI3K pathway activation in combination with constitutively active mitogen-activated protein kinase signaling shows synergistic effects in the process of melanoma tumorigenesis. Recently, a tumor suppressor function for the lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) has been described in breast and prostate cancers, with impact on PI3K signaling output. Given the importance of PI3K pathway activity for melanoma formation and growth, we aimed to assess the role of INPP4B in melanocytic tumors.

Cyclic mechanical stress downregulates endothelin-1 and its responsive genes independently of TGFβ1 in dermal fibroblasts.

Mechanical forces are highly variable ranging from the ubiquitous gravity force to compression, fluid shear, torsion, tension and other forms. Mechanical forces act on cells and modulate their biological responses by regulating gene transcription, enzyme and growth factor activity. In soft connective tissues, formation of myofibroblasts strictly requires a mechanically loaded environment in addition to local transforming growth factor (TGF)-β activity, which itself can be modulated by the mechanical status of the environment.

The epidermal basement membrane is a composite of separate laminin- or collagen IV-containing networks connected by aggregated perlecan, but not by nidogens.

The basement membrane between the epidermis and the dermis is indispensable for normal skin functions. It connects, and functionally separates, the epidermis and the dermis. To understand the suprastructural and functional basis of these connections, heterotypic supramolecular aggregates were isolated from the dermal-epidermal junction zone of human skin.

Impact of thrombolysis on stroke outcome at 12 months in a population: the Bern stroke project.

Background And Purpose: Thrombolysis improves outcome of patients with acute ischemic stroke, but it is unknown whether thrombolysis has a measurable effect on long-term outcome in a defined population.

Methods: We prospectively assessed demographic data, management, and outcome of acute ischemic stroke patients admitted within 48 hours to 18 primary care hospitals of the canton of Bern (969 299 inhabitants) during 12 months. Blinded follow-up was obtained at 3 and 12 months.

Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV.

Motivation: The ability to detect copy-number variation (CNV) and loss of heterozygosity (LOH) from exome sequencing data extends the utility of this powerful approach that has mainly been used for point or small insertion/deletion detection.

Results: We present ExomeCNV, a statistical method to detect CNV and LOH using depth-of-coverage and B-allele frequencies, from mapped short sequence reads, and we assess both the method's power and the effects of confounding variables. We apply our method to a cancer exome resequencing dataset.

GAB2 amplifications refine molecular classification of melanoma.

Purpose: Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas. We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT.

Gab2-mediated signaling promotes melanoma metastasis.

Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.

Increased expression of the tumor suppressor PLZF is a continuous predictor of long-term survival in malignant melanoma patients.

Promyelocytic leukemia zinc finger (PLZF) is a transcriptional repressor and tumor suppressor inhibiting melanoma cell growth in vitro and in vivo in animal models. In this study, we analyzed the impact of in vivo primary tumor gene expression of PLZF on the long-term survival of malignant melanoma patients. PLZF expression was assessed by using DNA microarray and real-time polymerase chain reaction analysis of 41 primary malignant melanomas from patients with a defined histology and a close to 20-year clinical follow-up, of 29 melanoma metastases, and of 6 different melanoma cell lines.

Integrins as antimetastatic targets of RGD-independent snake venom components in liver metastasis [corrected].

Metastasis comprises several subsequent steps including local invasion and intravasation at the primary site, then their adhesion/arrest within the vessels of host organs followed by their extravasation and infiltration into the target organ stroma. In contrast to previous studies which have used aspartate-glycine-arginine (RGD) peptides and antibodies against integrins, we used rare collagen- and laminin-antagonizing integrin inhibitors from snake venoms to analyze the colonization of the liver by tumor cells both by intravital microscopy and in vitro. Adhesion of liver-targeting tumor cells to the sinusoid wall components, laminin-1 and fibronectin, is essential for liver metastasis.

Glycoconjugate profiling of primary melanoma and its sentinel node and distant metastases: implications for diagnosis and pathophysiology of metastases.

Aiming at more precise detection of melanoma cells in sentinel lymph nodes and better understanding of the mechanisms underlying metastatic spread, expression of L1, CEACAM1, and binding of the lectins HPA, ML-I and PNA, was assessed in benign nevi (n=12), primary melanomas (PTs: n=67), their corresponding sentinel lymph nodes (SLNs: n=40), and distant metastases (DMs: n=35). Sensitivity and specificity of CEACAM1 (95-97%; 66%) and L1 (90-93%; 100%) exceeded that of the standard markers MelanA, S100, and HMB45 in single marker use. Lectin binding was found in PTs and DMs (HPA: 69% and 77%; ML-I: 82% and 77%, respectively), but rarely in SLNMs (HPA: 20%, ML-I: 20%, PNA: 5%, respectively).

Inactivation of active and latent transforming growth factor beta by free thiols: potential redox regulation of biological action.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine with important roles in inflammation, wound repair, and cancer. Cells secrete TGF-beta as a latent protein complex, consisting of disulfide-bonded homodimers of growth factor and latency-associated propeptide. Latency regulates extracellular TGF-beta action by controlling the levels of active growth factor available.

Extracellular regulation of TGF-beta activity in wound repair: growth factor latency as a sensor mechanism for injury.

The transforming growth factor-beta (TGFbeta) family of growth factors are major regulators of wound repair, scar formation, and fibrosis. One of the prominent features of TGFbeta biology is the fact that this growth factor is secreted as a latent precursor, which may be directed to and stored at specific sites in the cellular microenvironment. Targeting and mobilization, and particularly extracellular activation of latent TGF-beta control the biological action of this growth factor.