Molecular pathogenesis and therapeutic strategies of human osteosarcoma

Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies. Born out of these and similar investigations, a variety of emerging therapies are now undergoing various phases of OS clinical testing. They broadly include angiogenesis inhibitors, drugs that act on the bone microenvironment, receptor tyrosine kinase inhibitors, immune system modulators, and other radio- or chemo-sensitizing agents. As new forms of drug delivery are being developed simultaneously, the possibility of targeting tumors locally while minimizing systemic toxicityis is seemingly more achievable now than ever. In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.     

Anthropometrical and physiological determinants of performance in French West Indian monofin swimmers: a first approach

To characterise the anthropometrical and physiological parameters of French West Indian monofin swimmers, seven French West Indian male competitors underwent anthropometrical measurements and physiological testing. The results were analysed in relation with their performances during national and international events (from 50- to 1500-m). We found that both anthropometrical and physiological (aerobic and anaerobic components) factors contributed to the performances of these swimmers. The results demonstrated that certain parameters consistently contributed to the global performance: aerobic parameters (maximal oxygen uptake and the second ventilatory threshold, R (2) = 0.72 and 0.69, respectively), anaerobic parameters (power obtained with the counter-movement jump [R (2) = 0.58] and the force-velocity test [R (2) = 0.54]), leg volume (V1, R (2) = 0.54) and perimeter (P1, R (2) = 0.64), and fat and lean body mass (R (2) = 0.76 and 0.62, respectively). Further studies are needed to compare these determinants of performance in French West Indian and European swimmers and to investigate how they contribute to swimming technique.     

IGFBP5 domains exert distinct inhibitory effects on the tumorigenicity and metastasis of human osteosarcoma

Osteosarcoma (OS) is the most common primary malignancy of bone. We investigated the roles of insulin-like growth factor binding protein 5 (IGFBP5) domains in modulating OS tumorigenicity and metastasis. The N-terminal (to a lesser extent the C-terminal) domain inhibited cell proliferation and induced apoptosis while the C-terminal domain inhibited cell migration and invasion. The Linker domain had no independent effects. In vivo, the N-terminal domain decreased tumor growth without affecting pulmonary metastases while the C-terminal domain inhibited tumor growth and metastases. In summary, the N- and C-terminal domains modulated OS tumorigenic phenotypes while the C-terminal domain inhibited OS metastatic phenotypes.     

Specific pulmonary responses during the cycle-run succession in triathletes

The aim of the present study was to investigate the relationship between alterations in pulmonary function (i.e., diffusing capacity for carbon monoxide and pulmonary volumes) and the ventilatory response elicited during the cycle-run succession in triathletes. Ten well-trained triathletes performed three exercises: 1) 30 min cycling plus 20 min of running, termed the cycle-run succession; 2) 30 min cycling; and 3) 20 min running. Before and 10 min after each trial, the triathletes underwent pulmonary function testing, including spirometry and diffusing capacity for carbon monoxide. During all trials, ventilatory data were collected every minute using an automated breath-by-breath system. The ventilatory response was significantly higher in the run subsequent to cycling as compared with the run performed independently (P<0.001). There was no change in pulmonary volumes before and after exercises; however, the diffusing capacity for carbon monoxide and the transfer coefficient were similarly decreased (P<0.05) after cycling and the cycle-run succession, but not decreased after running. The increase in minute ventilation in the run segment of the cycle-run succession versus in running alone was significantly correlated with the decrease in diffusing capacity for carbon monoxide measured after versus before the cycle-run succession (P<0.01). This same increase in ventilation was also correlated with the decrease in diffusing capacity measured after the cycle-run succession versus after cycling alone (P<0.03). These results suggest the possibility that the DLCO decrease contributes in part to the ventilatory increase noted in the run after cycling during the cycle-run succession of the triathlon.     

Physiological responses of sickle cell trait carriers during exercise

Growing evidence suggests that physiological responses during exercise in sickle cell trait (SCT) carriers might differ from persons with normal haemoglobin. Epidemiological and experimental results support the view that SCT carriers could be advantaged in certain anaerobic activities, but the underlying physiological and bio-cellular mechanisms remain unknown. Maximal aerobic physical fitness (i.e. maximal oxygen consumption and maximal aerobic power) is not affected by SCT; however, recent studies suggest that SCT carriers could be characterized by a lesser aerobic capacity. Discrepancies are frequently reported in the literature concerning lactate metabolism during exercise in this population. While some studies observed higher blood lactate concentration during exercise in individuals carrying SCT compared with subjects with normal haemoglobin, others described lower concentration, which suggests a paradoxical lower lactate production by exercising muscles and/or greater ability to clear circulating lactate in SCT carriers. One of the most debated topics is the clinically benign condition of SCT, particularly during strenuous exercise. SCT carriers are usually involved in physical exercise without developing medical complications; however, several authors have presented case reports of SCT carriers who have collapsed and died unexpectedly during or after exercise. Blood rheological, haemostatic and vascular adhesion mechanism abnormalities in combination with environmental factors, such as heat strain, might play a role in the occurrence of these fatal scenarios. Several physiological differences have been observed between SCT carriers and non-SCT carriers, which make it necessary to consider the former as a specific population in response to exercise.     

Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behçet's disease

Objective

Behçet's disease is a chronic, relapsing, multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers and by ocular, articular, vascular, and central nervous system involvement. The tumor necrosis factor α (TNFα) pathway is likely involved in the pathophysiology of Behçet's disease. One of the 2 TNFα receptors is TNF receptor superfamily 1A (TNFRSF1A). We searched for R92Q TNFRSF1A mutations in patients with Behçet's disease.

Methods

A search for TNFRSF1A mutations was performed by polymerase chain reaction amplification of the TNFRSF1A gene, followed by denaturing high‐performance liquid chromatography scanning.

Results

Among the 74 unrelated European patients with Behçet's disease, 5 (6.8%) carried the R92Q TNFRSF1A mutation. The frequency of the R92Q mutation in patients with Behçet's disease was significantly higher than that in controls (P = 0.006 by Fisher's exact test). Deep vein thrombosis was significantly associated with the R92Q mutation (P = 0.001 [with Bonferroni adjustment for multiple comparisons]). Among the 30 patients with thrombosis, 10 had cerebral thrombophlebitis. None of these patients had the R92Q mutation. Among the 20 patients with Behçet's disease who had extracranial deep vein thrombosis, 6 had the R92Q mutation, whereas 14 did not (P < 0.0001)

Conclusion

The R92Q mutation in patients with Behçet's disease is associated with an increased risk of extracranial venous thrombosis. This new finding may help in understanding the complex prothrombotic state in patients with Behçet's disease.