Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing

The molecular circuitries controlling the process of skin wound healing have gained new significant insights in recent years. This knowledge is built on landmark studies on skin embryogenesis, maturation, and differentiation. Furthermore, the identification, characterization, and elucidation of the biological roles of adult skin epithelial stem cells and their influence in tissue homeostasis have provided the foundation for the overall understanding of the process of skin wound healing and tissue repair. Among numerous signaling pathways associated with epithelial functions, the PI3K/Akt/mTOR signaling route has gained substantial attention with the generation of animal models capable of dissecting individual components of the pathway, thereby providing a novel insight into the molecular framework underlying skin homeostasis and tissue regeneration. In this review, we focus on recent findings regarding the mechanisms involved in wound healing associated with the upregulation of the activity of the PI3K/Akt/mTOR circuitry. This review highlights critical findings on the molecular mechanisms controlling the activation of mTOR, a downstream component of the PI3K–PTEN pathway, which is directly involved in epithelial migration and proliferation. We discuss how this emerging information can be exploited for the development of novel pharmacological intervention strategies to accelerate the healing of critical size wounds.     

Associations of self-esteem,dysfunctional beliefs and coping style with depression in patients with schizophrenia: A preliminary survey

Psychological models of depression in schizophrenia have proposed that cognitive structures (e.g., self-esteem, dysfunctional beliefs) may have a role in the development and maintenance of depression. However, it has not been clear what the characteristics of these cognitive structures were in people with schizophrenia and whether they have an independent association with depression, especially in those from a Chinese cultural background. The present investigation examined 133 people with schizophrenia and 50 healthy controls and indicated that compared to the controls people with schizophrenia showed lower self-esteem, higher levels of dysfunctional beliefs and negative coping styles. Multiple linear regression analysis revealed that only low frustration tolerance, problem solving and self-blame were found to be the independent correlates of depression in schizophrenia. Results are discussed with the view of clinical implications of cognitive formulation and therapy for schizophrenia in China.     

Technique Selection of Bricker or Wallace Ureteroileal Anastomosis in Ileal Conduit Urinary Diversion: A Strategy Based on Patient Characteristics

Objectives

This study was designed to establish an individualized selection strategy for the two most common types of ureteroenteric anastomotic techniques (Bricker and Wallace anastomosis) used in ileal conduit (IC) diversion.

Methods

Patients who underwent IC diversion after radical cystectomy for transitional cell carcinoma between January 2009 and December 2011 were prospectively collected. The choice of anastomosis type (Bricker vs. Wallace) was successively based on tumor characteristics, ureteral anomalies, and ureteral length after retrosigmoidal tunneling.

Results

Ninety-nine patients were enrolled in the final study. Fifty-three patients underwent Bricker anastomosis, and 46 underwent Wallace anastomosis. Ureteral stricture developed in 6 (6.1 %) patients and the overall stricture rate for all ureters was 3.1 % (6/196). Strictures occurred at an average of 13.3 months after surgery and were predominately located in the left ureter (66.7 %, 4/6). The difference in the ureter stricture rates between the two groups was not statistically significant: 3.8 % (4/104) and 2.2 % (2/92) for Bricker and Wallace, respectively (p = 0.686). There were no significant differences in age, sex, body mass index (BMI), prevalence of pelvic radiation therapy, length of stay, follow-up time, or time to stricture between the two techniques. Patients in whom stricture developed had a significantly higher mean BMI compared with those without stricture (25.2 vs. 23.3 kg/m², respectively; p = 0.008).

Conclusions

Our preliminary outcomes demonstrate that this selection strategy of Bricker vs. Wallace anastomosis seems to be clinically reliable, providing an acceptable low ureteral stricture rate of 3.1 %. However, the potential advantage for oncologic control of this strategy is needed to further confirm.     

A Comparative Study of Electron Radiation Responses of Pu2Zr2O7 and La2Zr2O7: An ab initio Molecular Dynamics Study

In this study, the response of Pu₂Zr₂O₇ and La₂Zr₂O₇ to electronic radiation is simulated, employing an ab initio molecular dynamics method. It is shown that Pu₂Zr₂O₇ undergoes a crystalline-to-amorphous structural transition with 0.3% electronic excitation, while for La₂Zr₂O₇, the structural amorphization occurs with 1.2% electronic excitation. During the microstructural evolution, the anion disorder further drives cation disorder and eventually results in the structural amorphization of Pu₂Zr₂O₇ and La₂Zr₂O₇. The difference in responses to electron radiation between Pu₂Zr₂O₇ and La₂Zr₂O₇ mainly results from the strong correlation effects between Pu 5f electrons and the smaller band gap of Pu₂Zr₂O₇. These results suggest that Pu₂Zr₂O₇ is less resistant to amorphization under local ionization rates that produce a low level of electronic excitation, since the level of the concentration of excited electrons is relatively low in Pu₂Zr₂O₇. The presented results will advance the understanding of the radiation damage effects of zirconate pyrochlores.     

Oral iron chelators--development and application

Iron chelation therapy is the only therapeutic approach that leads to enhanced iron excretion in beta-thalassaemia major and other transfusion-dependent patients. Although desferrioxamine has been used in such treatment over the last three decades, it is not an ideal drug due to its poor oral availability. Consequently extensive research effort has been directed towards the identification of non-toxic, orally active iron chelators. An ideal candidate must possess a range of critical physicochemical and biological properties, such as high selectivity and affinity for iron(III), tightly controlled distribution and metabolic profiles and low toxicity. Unfortunately, hexadentate ligands are generally associated with poor oral bioavailability, whereas many tridentate and bidentate molecules are orally active. The tridentate triazoles have been investigated for clinical potential; they are readily absorbed from the gastrointestinal tract and promote iron excretion with high efficacy. In similar fashion, several bidentate hydroxypyridinones have been demonstrated to possess potential as oral chelating agents.     

Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection

Maternally administered recombinant human granulocyte colony- stimulating factor (rhG-CSF) has been shown to cross the placenta and induce a peripheral neutrophilia and increases in the marrow and spleen neutrophil storage pools in fetal and newborn rats. In the present study, we have used this model system to investigate the efficacy of prenatally administered rhG-CSF on neonatal defense to a lethal challenge with Group B-beta hemolytic Streptococcus (GBS). Pregnant rats were injected with rhG-CSF twice daily beginning 6 days before parturition. At birth, all pups were infected with a dose of GBS that is lethal for 90% of infected pups (LD90). Survival was monitored daily for 5 days. Survival of infected pups from saline-treated mothers beyond 60 hours after infection was 10%. No difference in survival was observed among pups from mothers treated 2 and 4 days before parturition. In contrast, we determined that survival was 82.5% among infected pups from mothers treated for 6 days before parturition with rhG-CSF. Our results demonstrate that maternal administration of rhG- CSF augments neonatal defenses against a lethal bacterial challenge.     

Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation

The effects of granulocyte-macrophage colony-stimulating factor (GM- CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T- cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM- CSF responsive cell type, thymic AC and T cells were examined for GM- CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single- cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.