CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells.

BACKGROUND: Metastasis is associated with poor prognosis for melanoma. The formation of metastases is a multi-step process, in which cancer cells can subsequently acquire the potential to intravasate into the blood or lymph vessels, disseminate through the circulation, extravasate through the endothelium and invade the connective tissue. There is increasing evidence that chemokines have a pivotal role in the dissemination and establishment of melanoma metastasis. METHODS: We isolated melanoma cells from melanoma metastasis and performed different migration assays and transendothelial resistance measurements of endothelial monolayers co-cultured with melanoma cells, in order to monitor barrier function and diapedesis and confirmed these results by confocal microscopy. RESULTS: We observed that tumour endothelial cells (ECs) secrete high levels of CXCL9 in all, and CXCL10 in most melanoma metastases. Migration studies revealed that low concentrations of these chemokines induce chemotaxis, whereas high concentrations induce spontaneous migration of melanoma cells (chemokinesis/chemorepulsion) and the disruption of the endothelial barrier, resulting in an accelerated transendothelial migration (TEM). Addition of anti-CXCL9 or anti-CXCR3 antibodies to the co-cultures delayed the TEM of melanoma cells. CONCLUSION: Our data represent novel mechanisms by which tumour cells in melanoma metastases might use the chemokine-expressing endothelium to leave the tumour and eventually to form additional metastases at distinct sites.

Refined candidate region specified by haplotype sharing for Escherichia coli F4ab/F4ac susceptibility alleles in pigs.

Infection of the small intestine by enterotoxigenic Escherichia coli F4ab/ac is a major welfare problem and financial burden for the pig industry. Natural resistance to this infection is inherited as a Mendelian recessive trait, and a polymorphism in the MUC4 gene segregating for susceptibility/resistance is presently used in a selection programme by the Danish pig breeding industry. To elucidate the genetic background involved in E. coli F4ab/ac susceptibility in pigs, a detailed haplotype map of the porcine candidate region was established. This region covers approximately 3.7 Mb. The material used for the study is a three generation family, where the founders are two Wild boars and eight Large White sows. All pigs have been phenotyped for susceptibility to F4ab/ac using an adhesion assay. Their haplotypes are known from segregation analysis using flanking markers. By a targeted approach, the candidate region was subjected to screening for polymorphisms, mainly focusing on intronic sequences. A total of 18 genes were partially sequenced, and polymorphisms were identified in GP5, CENTB2, APOD, PCYT1A, OSTalpha, ZDHHC19, TFRC, ACK1, MUC4, MUC20, KIAA0226, LRCH3 and MUC13. Overall, 227 polymorphisms were discovered in the founder generation. The analysis revealed a large haplotype block, spanning at least 1.5 Mb around MUC4, to be associated with F4ab/ac susceptibility.

Human clonal CD8 autoreactivity to an IGRP islet epitope shared between mice and men.

Type 1 diabetes (T1D) is a multifactorial disease characterized by the infiltration and subsequent destruction of the pancreatic insulin-producing beta cells by autoreactive T cells. CD8(+) T cells play an essential role in this beta cell destruction. However, little is known about the target antigens of CD8(+) T cells in human T1D patients. The aim of this study was to assess whether an epitope derived from the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), IGRP(265-273,) which has recently been identified as a target in non-obese diabetic (NOD) mice and is fully homologous to the human epitope, is a target of human diabetogenic CD8(+) T cells. We isolated a human CD8 T cell clone against this epitope, which confirms that this IGRP epitope is shared across species.

Dopamine D-1 and D-2 receptor agonists and antagonists and neuropeptide-induced excessive grooming.

The administration of the dopamine D-1 receptor antagonist, SCH 23390, but not of the dopamine D-2 receptor antagonist, sulpiride, suppressed the excessive grooming induced by a new environment or by various neuropeptides. In addition, administration of the dopamine D-1 agonist, SK & F 38393, induced excessive grooming but that of the dopamine D-2 agonist, quinpirole, did not. It is suggested that dopamine D-1 rather than D-2 receptor stimulation is an important mechanism underlying novelty-induced as well as neuropeptide-induced excessive grooming.

Zeitgeber induced modulation of activity patterns in nocturnal mammals (Chiroptera).

Changing the L:D intensity ratio of a synchronizing dark regime leads to characteristic modulations of the activity pattern of Chiroptera species. These modulations fit the predictions of WEVER'S oscillator model.