SUMMARY Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.

Zinc (Zn) is an essential trace mineral that regulates the expression and activation of biological molecules such as transcription factors, enzymes, adapters, channels, and growth factors, along with their receptors. Zn deficiency or excessive Zn absorption disrupts Zn homeostasis and affects growth, morphogenesis, and immune response, as well as neurosensory and endocrine functions. Zn levels must be adjusted properly to maintain the cellular processes and biological responses necessary for life. Zn transporters regulate Zn levels by controlling Zn influx and efflux between extracellular and intracellular compartments, thus, modulating the Zn concentration and distribution. Although the physiological functions of the Zn transporters remain to be clarified, there is growing evidence that Zn transporters are related to human diseases, and that Zn transporter-mediated Zn ion acts as a signaling factor, called "Zinc signal". Here we describe critical roles of Zn transporters in the body and their contribution at the molecular, biochemical, and genetic levels, and review recently reported disease-related mutations in the Zn transporter genes.

Cellular oxygen consumption is a determinant of intracellular oxygen levels. Because of the high demand of mitochondrial respiration during insulin secretion, pancreatic ␤-cells consume large amounts of oxygen in a short time period. We examined the effect of insulin secretion on cellular oxygen tension in vitro. We confirmed that Western blotting of pimonidazole adduct was more sensitive than immunostaining for detection of cellular hypoxia in vitro and in vivo. The islets of the diabetic mice but not those of normal mice were hypoxic, especially when a high dose of glucose was loaded. In MIN6 cells, a pancreatic ␤-cell line, pimonidazole adduct formation and stabilization of hypoxia-inducible factor-1␣ (HIF-1␣) were detected under mildly hypoxic conditions. Inhibition of respiration rescued the cells from becoming hypoxic. Glucose stimulation decreased cellular oxygen levels in parallel with increased insulin secretion and mitochondrial respiration. The cellular hypoxia by glucose stimulation was also observed in the isolated islets from mice. The MIN6 cells overexpressing HIF-1␣ were resistant to becoming hypoxic after glucose stimulation. Thus, glucose-stimulated ␤-cells can become hypoxic by oxygen consumption, especially when the oxygen supply is impaired.

Within the limitations of this study, from the viewpoint of energy absorption ability, the minimum thickness required for a mouthguard is 4 mm, which is generally too large from the viewpoint of player comfort. This finding indicates the necessity of improving the impact absorption ability of mouthguards by considering new designs and developing new materials.

Most impact force and impact energy absorption tests for mouthguards have used a steel ball in a drop-ball or the pendulum device. However, in reality most sports-related trauma is caused by objects other than the steel ball, e.g. various sized balls, hockey puck, or bat or stick. Also, the elasticity, the velocity and the mass of the object could change the degree and the extent of injuries. In this study, we attempted to measure the impact force from actual sports equipment in order to clarify the exact mechanism of dental-related sports injuries and the protective effects of mouthguards. The present study was conducted using the pendulum impact device and load cell. Impact objects were removable. Seven mobile impact objects were selected for testing: a steel ball, baseball, softball, field hockey ball, ice hockey puck, cricket ball, and wooden baseball bat. The mouthguard material used in this study was a 3-mm-thick Drufosoft (Dreve-Dentamid GmbH, Unna, Germany), and test samples were made of the one-layer type. The peak transmitted forces without mouthguard ranged from the smallest (ice hockey stick, 46.9 kgf) to the biggest (steel ball, 481.6 kgf). The peak transmitted forces were smaller when the mouthguard was attached than without it for all impact materials but the effect was significantly influenced by the object type. The steel ball showed the biggest (62.1%) absorption ability while the wooden bat showed the second biggest (38.3%). The other balls or the puck showed from 0.6 to 6.0% absorbency. These results show that it is important to test the effectiveness of mouthguards on specific types of sports equipment. In future, we may select different materials and mouthguard designs suitable for specific sports.