The COOH-Terminal Peptide of Platelet Factor-4 Variant (CXCL4L1/PF-4var47-70) Strongly Inhibits Angiogenesis and Suppresses B16 Melanoma Growth In vivo.

Chemokines influence tumor growth directly or indirectly via both angiogenesis and tumor-leukocyte interactions. Platelet factor-4 (CXCL4/PF-4), which is released from alpha-granules of activated platelets, is the first described angiostatic chemokine. Recently, it was found that the variant of CXCL4/PF-4 (CXCL4L1/PF-4var) could exert a more pronounced angiostatic and antitumoral effect than CXCL4/PF-4. However, the molecular mechanisms of the angiostatic activities of the PF-4 forms remain partially elusive. Here, we studied the biological properties of the chemically synthesized COOH-terminal peptides of CXCL4/PF-4 (CXCL4/PF-4(47-70)) and CXCL4L1/PF-4var (CXCL4L1/PF-4var(47-70)). Both PF-4 peptides lacked monocyte and lymphocyte chemotactic activity but equally well inhibited (25 nmol/L) endothelial cell motility and proliferation in the presence of a single stimulus (i.e., exogenous recombinant fibroblast growth factor-2). In contrast, when assayed in more complex angiogenesis test systems characterized by the presence of multiple mediators, including in vitro wound-healing (2.5 nmol/L versus 12.5 nmol/L), Matrigel (60 nmol/L versus 300 nmol/L), and chorioallantoic membrane assays, CXCL4L1/PF-4var(47-70) was found to be significantly (5-fold) more angiostatic than CXCL4/PF-4(47-70). In addition, low (7 mug total) doses of intratumoral CXCL4L1/PF-4var(47-70) inhibited B16 melanoma growth in mice more extensively than CXCL4/PF-4(47-70). This antitumoral activity was predominantly mediated through inhibition of angiogenesis (without affecting blood vessel stability) and induction of apoptosis, as evidenced by immunohistochemical and fluorescent staining of B16 tumor tissue. In conclusion, CXCL4L1/PF-4var(47-70) is a potent antitumoral and antiangiogenic peptide. These results may represent the basis for the design of CXCL4L1/PF-4var COOH-terminal-derived peptidomimetic anticancer drugs. Mol Cancer Res; 8(3); 322-34

Biological Activity of CXCL8 Forms Generated by Alternative Cleavage of the Signal Peptide or by Aminopeptidase-Mediated Truncation

Posttranslational modification of chemokines is one of the mechanisms that regulate leukocyte migration during inflammation. Multiple natural NH(2)-terminally truncated forms of the major human neutrophil attractant interleukin-8 or CXCL8 have been identified. Although differential activity was reported for some CXCL8 forms, no biological data are available for others.status: publishe

Urban yellow fever outbreak-Democratic Republic of the Congo, 2016: Towards more rapid case detection.

BackgroundBetween December 2015 and July 2016, a yellow fever (YF) outbreak affected urban areas of Angola and the Democratic Republic of the Congo (DRC). We described the outbreak in DRC and assessed the accuracy of the YF case definition, to facilitate early diagnosis of cases in future urban outbreaks.Methodology/principal findingsIn DRC, suspected YF infection was defined as jaundice within 2 weeks after acute fever onset and was confirmed by either IgM serology or PCR for YF viral RNA. We used case investigation and hospital admission forms. Comparing clinical signs between confirmed and discarded suspected YF cases, we calculated the predictive values of each sign for confirmed YF and the diagnostic accuracy of several suspected YF case definitions. Fifty seven of 78 (73%) confirmed cases had travelled from Angola: 88% (50/57) men; median age 31 years (IQR 25-37). 15 (19%) confirmed cases were infected locally in urban settings in DRC. Median time from symptom onset to healthcare consultation was 7 days (IQR 6-9), to appearance of jaundice 8 days (IQR 7-11), to sample collection 9 days (IQR 7-14), and to hospitalization 17 days (IQR 11-26). A case definition including fever or jaundice, combined with myalgia or a negative malaria test, yielded an improved sensitivity (100%) and specificity (57%).Conclusions/significanceAs jaundice appeared late, the majority of cases were diagnosed too late for supportive care and prompt vector control. In areas with known local YF transmission, a suspected case definition without jaundice as essential criterion could facilitate earlier YF diagnosis, care and control

Intradermal air pouch leukocytosis as an in vivo test for nanoparticles

Jennifer Vandooren,1 Nele Berghmans,1 Chris Dillen,1 Ilse Van Aelst,1 Isabelle Ronsse,1 Liron Limor Israel,2 Ina Rosenberger,3 Jörg Kreuter,3 Jean-Paul Lellouche,2 Shulamit Michaeli,4 Erica Locatelli,5 Mauro Comes Franchini,5 Miren K Aiertza,6 Laura Sánchez-Abella,6 Iraida Loinaz,6 Dylan R Edwards,7 Louis Shenkman,8 Ghislain Opdenakker1 1Rega Institute for Medical Research, University of Leuven, Leuven, Belgium; 2Department of Chemistry and Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 3Institut für Pharmazeutische Technologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany; 4The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel; 5Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy; 6New Materials Department, Fundación CIDETEC, San Sebastián, Spain; 7School of Biological Sciences, University of East Anglia, Norwich, UK; 8Tel Aviv University, Ramat Aviv, Tel Aviv, Israel Abstract: The need for test systems for nanoparticle biocompatibility, toxicity, and inflammatory or adaptive immunological responses is paramount. Nanoparticles should be free of microbiological and chemical contaminants, and devoid of toxicity. Nevertheless, in the absence of contamination, these particles may still induce undesired immunological effects in vivo, such as enhanced autoimmunity, hypersensitivity reactions, and fibrosis. Here we show that artificial particles of specific sizes affect immune cell recruitment as tested in a dermal air pouch model in mice. In addition, we demonstrate that the composition of nanoparticles may influence immune cell recruitment in vivo. Aside from biophysical characterizations in terms of hydrodynamic diameter, zeta potential, concentration, and atomic concentration of metals, we show that – after first-line in vitro assays – characterization of cellular and molecular effects by dermal air pouch analysis is straightforward and should be included in the quality control of nanoparticles. We demonstrate this for innate immunological effects such as neutrophil recruitment and the production of immune-modulating matrix metalloproteases such as MMP-9; we propose the use of air pouch leukocytosis analysis as a future standard assay. Keywords: nanoparticles, biocompatibility, toxicity, air pouch, immunologyA Letter to the Editor has been received and published for this article

Increased Rotavirus Prevalence in Diarrheal Outbreak Precipitated by Localized Flooding, Solomon Islands, 2014

Flooding on 1 of the Solomon Islands precipitated a nationwide epidemic of diarrhea that spread to regions unaffected by flooding and caused >6,000 cases and 27 deaths. Rotavirus was identified in 38% of case-patients tested in the city with the most flooding. Outbreak potential related to weather reinforces the need for global rotavirus vaccination