Hypoxia increases the levels of ADAM12 in a Notch-dependent manner, leading to increased ectodomain shedding of HB-EGF and subsequent promotion of invadopodia formation.

Tks5 is a scaffold protein and Src substrate involved in cell migration and matrix degradation through its essential role in invadosome formation and function. We have previously described that Tks5 is fundamental for zebrafish neural crest cell migration in vivo. In the present study, we sought to investigate the function of Tks5 in mammalian development by analyzing mice mutant for sh3pxd2a, the gene encoding Tks5. Homozygous disruption of the sh3pxd2a gene by gene-trapping in mouse resulted in neonatal death and the presence of a complete cleft of the secondary palate. Interestingly, embryonic fibroblasts from homozygous gene-trap sh3pxd2a mice lacked only the highest molecular weight band of the characteristic Tks5 triplet observed in protein extracts, leaving the lower molecular weight bands unaffected. This finding, together with the existence of two human Expressed Sequence Tags lacking the first 5 exons of SH3PXD2A, made us hypothesize about the presence of a second alternative transcription start site located in intron V. We performed 5′RACE on mouse fibroblasts and isolated a new transcript of the sh3pxd2a gene encoding a novel Tks5 isoform, that we named Tks5β. This novel isoform diverges from the long form of Tks5 in that it lacks the PX-domain, which confers affinity for phosphatidylinositol-3,4-bisphosphate. Instead, Tks5β has a short unique amino terminal sequence encoded by the newly discovered exon 6β; this exon includes a start codon located 29 bp from the 5'-end of exon 6. Tks5β mRNA is expressed in MEFs and all mouse adult tissues analyzed. Tks5β is a substrate for the Src tyrosine kinase and its expression is regulated through the proteasome degradation pathway. Together, these findings indicate the essentiality of the larger Tks5 isoform for correct mammalian development and the transcriptional complexity of the sh3pxd2a gene.

Intratumoral hypoxia is a common feature of solid tumors. Recent advances in cancer biology indicate that hypoxia is not only a consequence of unrestrained tumor growth, but also plays an active role in promoting tumor progression, malignancy, and resistance to therapy. Hypoxia signaling is mediated by the hypoxia-inducible factors (HIFs), which are not only stabilized under hypoxia, but also by activated oncogenes or inactivated tumor suppressors under normoxia. Hypoxia is a prominent feature of the tumor microenvironment of pancreatic tumors, also characterized by the presence of a fibrotic reaction that promotes, and is also modulated by, hypoxia. As the mechanisms by which hypoxia signaling impacts invasion and metastasis in pancreatic cancer are being elucidated, hypoxia is emerging as a key determinant of pancreatic cancer malignancy as well as an important target for therapy. Herein we present an overview of recent advances in the understanding of the impact that hypoxia has in pancreatic cancer invasion and metastasis.

In the era of increasing antibiotic resistance, development of new agents that could provide therapeutic options for difficult to treat pathogens is vital. Dalbavancin is a new lipoglycopeptide recently approved by the US FDA for the treatment of acute bacterial skin and skin structure infections. A derivative of the older glycopeptide class, chemical structure alterations resulted in a molecule with a similar mechanism of action, however, with a comparatively increased activity as reflected by organism MICs. These modifications also resulted in an antibiotic with distinctive properties that allow for once-weekly dosing in the treatment of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and drug resistant Streptococcus spp. As the first of these long acting compounds, understanding the pharmacokinetic and pharmacodynamic properties of agents like dalbavancin is essential for determining a place in therapy.

Pseudomonas aeruginosa is a common infection in immunocompromised patients. However, it can also cause severe infections in otherwise healthy individuals. We describe pseudomonal bacteraemia in a 6-month-old boy with significant obstruction of the nasopharynx by pseudomonal debris, which we termed pseudomembranous nectrotising pharyngitis. To prevent aspiration and suffocation, early recognition and removal of the obstruction by endoscopy is recommended.