The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation.

The Ras-extracellular signal-regulated kinase (Ras-ERK) and phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) signaling pathways are the chief mechanisms for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling conduits activated by different stimuli, yet even early experiments hinted that they might intersect to regulate each other and co-regulate downstream functions. The extent of this cross-talk and its significance in cancer therapeutics are now becoming clear.

ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex.

Cell movement begins with a leading edge protrusion, which is stabilized by nascent adhesions and retracted by mature adhesions. The ERK-MAPK (extracellular signal-regulated kinase-mitogen-activated protein kinase) localizes to protrusions and adhesions, but how it regulates motility is not understood. We demonstrate that ERK controls protrusion initiation and protrusion speed. Lamellipodial protrusions are generated via the WRC (WAVE2 regulatory complex), which activates the Arp2/3 actin nucleator for actin assembly. The WRC must be phosphorylated to be activated, but the sites and kinases that regulate its intermolecular changes and membrane recruitment are unknown. We show that ERK colocalizes with the WRC at lamellipodial leading edges and directly phosphorylates two WRC components: WAVE2 and Abi1. The phosphorylations are required for functional WRC interaction with Arp2/3 and actin during cell protrusion. Thus, ERK coordinates adhesion disassembly with WRC activation and actin polymerization to promote productive leading edge advancement during cell migration.

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax.

The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins. Antibodies directed against TOM22 or an antisense knockdown of the expression of TOM22 specifically inhibited the association of Bax with mitochondria and prevented Bax-dependent apoptosis. In yeast, a haploid strain for TOM22 exhibited a decreased expression of TOM22 and mitochondrial association of ectopically expressed human Bax. Our data provide a new perspective on the mechanism of association of Bax with mitochondria as it involves a classical import pathway.

Reconstruction of axillary contractures with thoracodorsal perforator island flap.

The axilla is one of the most frequently sites affected by contractures after severe burns. These contractures often cause cosmetic problems and functional deficiency. A variety of therapeutic methods such as skin grafting, Z-plasties, local flaps, island flaps, and free flaps, have been reported for treatment of the contractures. Each has its own advantages and drawbacks. In this clinical study we report 15 cases of post burn axillary contractures treated with thoracodorsal perforator-based cutaneous flaps. The flaps were harvested in range of sizes up to as large as 27 cmx15 cm. All flaps survived completely without even marginal necrosis. The donor sites were closed primarily except in one case who needed a small skin graft. Satisfactory improvement in shoulder abduction was obtained. The range of abduction was on average 46.6+/-19.3 degrees before the operations and 159+/-12.4 degrees after the operations. Cosmetic results were satisfactory from the patient's point of view. The thoracodorsal perforator flap can be safely raised to meet any size required even in the most severe contractures. The donor site scar may be considered as acceptable considering the advantages of the flap. We strongly recommend this flap as the treatment of choice in releasing challenging axillary contractures.

[The dynamics of two-layer graft acoustic properties at different times after myringoplasty]. / Dinamika akusticheskikh svoistv dvukhsloinogo transplantata v razlichnye sroki posle miringoplastiki.

A two-year follow-up tympanometric results have been analysed for 40 patients subjected to myringoplasty. Ultrathin allocartilage was used as one of the transplant components. The static compliance of the neotympanic membrane seemed to change in a wide range, but the changes did not affect hearing. The formation of an adequate neotympanic membrane takes place by the end of the second year after the operation.

[Trends in body weight in the population of the Czech Republic]. / Vývoj telesné hmotnosti v populaci Ceské republiky.

The authors investigated the development of body weight of the population from six districts in the Czech Republic participating in the international WHO project MONICA. The examinations were made within the framework of epidemiological studies of risk factors of IHD in 1985 and 1988 in 1% independent population samples (range 25-64 years). The mean values of body mass index, BMI, increased in the above three-year period in men from 26.9 to 27.5 (p less than 0.001) in women from 26.9 to 27.4 (n. s.). The prevalence of obesity increased during the same period from 19.9% to 25.4% (p less than 0.001) in men and from 33.8% to 35.7% (n. s.) in women. In all decades of men and women there was a rising trend of body weight and increasing prevalence of obesity. With regard to the adverse effects of overweight on health and life span, the authors consider prevention of obesity as one of the foremost tasks of preventive medicine.

Changes in size, morphology and weight of human anterior teeth during the fetal period.

The changes in size and weight of the calcified portions of the crowns of deciduous anterior teeth (maxillary and mandibular central and lateral incisors and canines) in human fetuses aged 5-10 months were studied. Relating the weight and size of each tooth to fetal age provided quantitative information on the rate of crown development in each of these teeth. There is a good correlation between crown height and fetal age. At the corresponding ages the length of the maxillary central incisor is greater than that of the maxillary lateral incisor which is greater than that of the maxillary canine. A similar pattern is found in the mandibular teeth. Generally, with the exception of a few mandibular central incisors, no type of anterior tooth crown has reached its final length before birth.

Development of enamel in human fetal teeth.

The present study concerns enamel development in human fetal teeth. Chemical analysis and the appearance of developing enamel from maxillary and mandibular central and lateral incisors of human fetuses aged from five to nine mo distinguished two main stages during this period of development. The first stage corresponded to the production of forming enamel, which was soft, translucent, and partially mineralized, and the second to the maturation or secondary mineralization of enamel. The enamel at this stage appeared opaque when dried. The transition of forming enamel to maturing enamel was accompanied by a decrease in protein concentration, a distinct change in amino-acid composition, and a rise in the concentration of calcium and phosphate. Ultraviolet and chloronaphthalene inhibition studies revealed that the third and final stage in enamel development, the mature hard enamel, was generally absent, but was found in a very small percentage of maxillary and mandibular central incisors from nine- and ten-month-old fetuses, at the incisal tip. In both maxillary and mandibular canine teeth, only the forming stage in enamel development was observed during the fetal period. Further studies relating the length of each zone in enamel to fetal age provided information relative to the timing and rate of enamel development in each tooth.