The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms

The mitogen-activated protein kinase (MAPK) and PI3K pathways are regulated by extensive crosstalk, occurring at different levels. In tumors, transactivation of the alternate pathway is a frequent "escape" mechanism, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity. Here we show that, in the M14 melanoma model, simultaneous inhibition of both MEK and mammalian target of rapamycin (mTOR) achieves synergistic effects at suboptimal concentrations, but becomes frankly antagonistic in the presence of relatively high concentrations of MEK inhibitors. This observation led to the identification of a novel crosstalk mechanism, by which either pharmacologic or genetic inhibition of constitutive MEK signaling restores phosphatase and tensin homolog (PTEN) expression, both in vitro and in vivo, and inhibits downstream signaling through AKT and mTOR, thus bypassing the need for double pathway blockade. This appears to be a general regulatory mechanism and is mediated by multiple mechanisms, such as MAPK-dependent c-Jun and miR-25 regulation. Finally, PTEN upregulation appears to be a major effector of MEK inhibitors' antitumor activity, as cancer cells in which PTEN is inactivated are consistently more resistant to the growth inhibitory and anti-angiogenic effects of MEK blockade.     

Diabetic Hand Infections: Factors at Presentation Influencing Amputation and Number of Surgical Procedures

Background Diabetic hand infections are associated with significant morbidity and disability. Amputations cause permanent disability, and multiple surgical procedures lead to morbidity. Diabetic foot infections have been well-studied but literature on hand infections is limited. We undertook a retrospective study of patients with diabetic hand infections operated at our center to study the factors at presentation with significant association with amputation and number of surgical procedures. Patients and Methods Demographic data of 51 patients was collected. The six parameters, namely, duration of diabetes, “onset of symptoms to presentation” interval, presence of comorbidities, HbA1c level, random blood sugar (RBS) levels at admission, and culture characteristics were selected for statistical analysis to find a relationship with the two outcome variables: number of procedures done and need for amputation. Results On bivariate analysis, Gram-negative infection was found to have a significant relationship with the need for multiple of procedures ( p = 0 . 014). The mean difference between the “onset of symptoms to presentation” interval between the amputation/non-amputation groups (2.9 days, p = 0 . 04) and the multiple procedures/non-multiple procedure groups (4.4 days, p = 0 . 02) was found to be statistically significant. Presence of comorbidities, long duration of diabetes, HbA1c, and RBS levels at admission did not show any statistically significant association with the two outcome variables studied. Conclusion In the present study, we found that infection with Gram-negative organisms is significantly related to the need for multiple surgical procedures. A delay in presentation can influence the risk of amputation as well as multiple procedures. Institution of early appropriate care is important to get a good outcome.     

Pseudarthrosis of cervical rib: an unusual cause of thoracic outlet syndrome

Thoracic outlet syndrome is uncommon in adolescence. Cervical rib fracture is an extremely rare cause of thoracic outlet syndrome in this age group. We report an unusual case of thoracic outlet syndrome in a 14-year-old girl caused by pseudarthrosis of the cervical rib. A magnetic resonance imaging scan showed significant compression of the brachial plexus by the pseudarthrosis mass. Excision of the cervical rib through a supraclavicular approach gave excellent results in this case.