The CCL3 Family of Chemokines and Innate Immunity Cooperate In Vivo in the Eradication of an Established Lymphoma Xenograft by Rituximab

The therapeutic mAb rituximab induced the expression of the CCL3 and CCL4 chemokines in the human lymphoma line BJAB following binding to the CD20 Ag. Induction of CCL3/4 in vitro was specific, was observed in several cell lines and freshly isolated lymphoma samples and also took place at the protein level in vitro and in vivo. To investigate the role of these beta-chemokines in the mechanism of action of rituximab, we synthesized a N-terminally truncated CCL3 molecule CCL3(11\u201370), which had antagonist activity on chemotaxis mediated by either CCL3 or BJAB supernatant. We also set up an established s.c. BJAB tumor model in athymic mice. Rituximab, given weekly after tumors had reached 250 mm2, led to complete disappearance of the lymphoma within 2\u20133 wk. Treatment of mice with cobra venom factor showed that complement was required for rituximab therapeutic activity. Treatment of BJAB tumor bearing mice every 2 days with the CCL3(11\u201370) antagonist, starting 1 wk before rituximab treatment, had no effect on tumor growth by itself, but completely inhibited the therapeutic activity of the Ab. To determine whether CCL3 acts through recruitment/activation of immune cells, we specifically depleted NK cells, polymorphonuclear cells, and macrophages using mAbs, clodronate treatment, or Rag2\u2013/\u2013c\u2013/\u2013 mice. The data demonstrated that these different cell populations are involved in BJAB tumor eradication. We propose that rituximab rapidly activates complement and induces beta-chemokines in vivo, which in turn activate the innate immunity network required for efficient eradication of the bulky BJAB tumor

Venting and seepage systems associated with mud volcanoes and mud diapirs in the southern Tyrrhenian Sea

High resolution swath bathymetry and backscatter data, seismic CHIRP profiles, multibeam water column acoustic measurements and sediment samples were collected on a cold seep province in the southeastern Tyrrhenian Sea, at a water depth of 500-1000. m. The mud volcanoes, characterized by a high backscatter signature, are the site of gas venting at the seafloor that formed a 630-m-high plume in the water column. The mud volcanoes feature a precipitation of iron-oxy-hydroxide crusts and pyritized and Sulfur burrows in the sub-surface and authigenic siderites, also cementing burrows, further down, showing a sharp transition from the oxic zone toward the sulfate-methanogenic zone.The mud flows are characterized by an intermediate backscatter seafloor and by the presence of gas in the sediment only 2. m below the seafloor. The mud flows consist of 1-m-thick drapes of water-rich mud extending downslope from the mud volcanoes. They act as sealing layers that prevent large fluxes of gas venting at the seafloor (low venting) and favor oxic conditions close to the sediment-water interface and the abundant precipitation of post-oxic siderites a few meters below the seafloor.The mud diapirs are characterized by a low backscatter seafloor and large fields of pockmarks. In coincidence with the normal faults, organogenic carbonate crusts form at or very close to the seafloor and are associated with chemosymbiontic bivalves (lucinids). The youngest shells are AMS radiocarbon dated 640-440. BP, suggesting that the seepage activity may have been clogged by the carbonates, only very recently.Similarities between the normal faults in the study area and the tectonic setting of the inland Calabrian Arc show that normal faults can control the location of fluid pathways and, probably, also the rising of the mud diapir

Magnesium deficiency promotes a pro-atherogenic phenotype in cultured human endothelial cells via activation of NFkB.

Contains fulltext : 87400.pdf (publisher's version ) (Closed access)Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of atherosclerosis, partly through the activation of the transcription factor NFkB. Several data indicate that magnesium deficiency caused by prolonged insufficient intake and/or defects in its homeostasis may be a missing link between diverse cardiovascular risk factors and atherosclerosis. Here we report that endothelial cells cultured in low magnesium rapidly activate NFkB, an event which is prevented by exposure to the anti-oxidant trolox. It is well known that NFkB activation correlates with marked alterations of the cytokine network. In the present study, we show that exposure of endothelial cells to low magnesium increases the secretion of RANTES, interleukin 8 and platelet derived growth factor BB, all important players in atherogenesis. Moreover, we describe the increased secretion of matrix metalloprotease-2 and -9 and of their inhibitor TIMP-2. Interestingly, by zymography we show that metalloprotease activity predominated over the inhibitory effect of TIMP-2. These results indicate that low magnesium promotes endothelial dysfunction by inducing pro-inflammatory and pro-atherogenic events.1 november 201