MMP8 increases tongue carcinoma cell-cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5.

Matrix metalloproteinases (MMPs) modify bioactive factors via selective processing or degradation resulting in tumour-promoting or tumour-suppressive effects, such as those by MMP8 in various cancers. We mapped the substrates of MMP8 to elucidate its previously shown tumour-protective role in oral tongue squamous cell carcinoma (OTSCC). MMP8 overexpressing (+) HSC-3 cells, previously demonstrated to have reduced migration and invasion, showed enhanced cell-cell adhesion. By analysing the secretomes of MMP8 + and control cells with terminal amine isotopic labelling of substrates (TAILS) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS), we identified 36 potential substrates of MMP8, including FXYD domain-containing ion transport regulator 5 (FXYD5). An anti-adhesive glycoprotein FXYD5 has been previously shown to predict poor survival in OTSCC. Cleavage of FXYD5 by MMP8 was confirmed using recombinant proteins. Furthermore, we detected a loss of FXYD5 levels on cell membrane of MMP8 + cells, which was rescued by inhibition of the proteolytic activity of MMP8. Silencing (si) FXYD5 increased the cell-cell adhesion of control but not that of MMP8 + cells. siFXYD5 diminished the viability and motility of HSC-3 cells independent of MMP8 and similar effects were seen in another tongue cancer cell line, SCC-25. FXYD5 is a novel substrate of MMP8 and reducing FXYD5 levels either with siRNA or cleavage by MMP8 increases cell adhesion leading to reduced motility. FXYD5 being a known prognostic factor in OTSCC, our findings strengthen its potential as a therapeutic target.

Severe pelvic fracture-related bleeding in pediatric patients: does it occur?

PURPOSE: Pediatric pelvic fractures are rare and less likely to cause hemodynamic instability than similar injuries in adult patients. The associated injuries are common, and they have a major impact on mortality. The aim of the present study was to evaluate the risk of life-threatening hemorrhage associated with unstable pelvic fractures in children. METHODS: We identified retrospectively all pediatric pelvic fractures (ring and acetabulum) treated at Helsinki University Central Hospital during a 10-year period (1998-2007). Stable A-type fractures (fractures not involving the pelvic ring) were excluded. All available pre- and in-hospital medical records were reviewed. The collected data consisted of patient characteristics, mechanisms of injury, vital signs, laboratory tests, care given, other injuries diagnosed, and the 30-day survival rate. RESULTS: There were 71 (40 males) pediatric patients (median age 14, range 1-16 years) with unstable pelvic fractures; 66 pelvic ring and 5 acetabulum fractures. The most common mechanism of injury was traffic accident (69%). Four patients had life-threatening bleeding. All had fracture of a mature pelvic ring, but the source of massive bleeding was pelvic ring fracture in only two patients (2.8% of all patients). No acetabulum fracture-related major pelvic bleeding was observed. One patient (age 16 years) required emergency surgery and angioembolization for pelvic bleeding. No life-threatening pelvic bleeding was seen among patients with immature bony pelvis. Pelvic ring fractures were surgically treated in 25 patients. Two patients died from head injuries (overall mortality 2.8%), but there were no bleeding-related deaths. CONCLUSIONS: We conclude that life-threatening bleeding from pelvic or acetabular fractures in pediatric patients is rare (2.8%), and does not contribute to the overall mortality.

Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer.

Squamous cell carcinoma (SCC) of the tongue is the most common cancer in the oral cavity and has a high mortality rate. A total of 90 mobile tongue SCC samples were analysed for Bryne's malignancy scores, microvascular density, and thickness of the SCC sections. In addition, the staining pattern of cyclooxygenase-2, alphavbeta6 integrin, the laminin-5 gamma2-chain, and matrix metalloproteinases (MMPs) -2, -7, -8, -9, -20, and -28 were analysed. The expression of MMP-8 (collagenase-2) was positively associated with improved survival of the patients and the tendency was particularly prominent in females. No sufficient evidence for a correlation with the clinical outcome was found for any other immunohistological marker. To test the protective role of MMP-8 in tongue carcinogenesis, MMP-8 knockout mice were used. MMP-8 deficient female mice developed tongue SCCs at a significantly higher incidence than wild-type mice exposed to carcinogen 4-Nitroquinoline-N-oxide. Consistently, oestrogen-induced MMP-8 expression in cultured HSC-3 tongue carcinoma cells, and MMP-8 cleaved oestrogen receptor (ER) alpha and beta. According to these data, we propose that, contrary to the role of most proteases produced by human carcinomas, MMP-8 has a protective, probably oestrogen-related role in the growth of mobile tongue SCCs.

Cervicocephalic kinesthetic sensibility in patients with whiplash injury.

This study investigated cervicocephalic kinesthetic sensibility in patients with whiplash injury and the effects of a rehabilitation programme. Fourteen patients with a whiplash injury and 34 healthy subjects participated in this study. The ability to appreciate both movement and the position of the head with respect to the trunk was investigated. Active head repositioning was significantly less precise in the whiplash subjects compared to the control group. Repositioning was more precise in whiplash subjects after the 5-week rehabilitation programme. There was no correlation between error of repositioning in patients and pain intensity. It is probable that cervicocephalic kinesthesia is linked to sensory information from the extensive muscular and articular proprioceptive system. A flexion-extension injury to the neck may result in dysfunction of this system.