Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

[Prolonged therapeutic hypothermia after pericardial effusion drain surgery]. / Hipotermia terapéutica prolongada tras cirugía de drenaje de derrame pericárdico.

Therapeutic hypothermia is an effective treatment for neurological protection after out-of-hospital cardiac arrest, and may also be beneficial for in-hospital cardiac arrest. Its use is limited in post-surgical patients due to the risk of specific complications, particularly bleeding. There are significant differences among previous publications regarding the time to reach the target temperature and the duration of therapy, so the optimal strategy is not yet established. We present the case of a patient who suffered a perioperative cardiac arrest related to a pericardial tamponade, and who underwent therapeutic hypothermia for 48h.

Black esophagus (acute esophageal necrosis) after spinal anesthesia.

Acute esophagic necrosis or black esophagus is an uncommon clinical entity that owes its name to the endoscopic view of the necrotic esophageal mucosa. It is always related with a critical medical condition and usually has an ischemic etiology. We report the first case of acute esophageal necrosis after a spinal anesthetic for partial hip joint arthroplasty. We discuss the underlying pathophysiological mechanisms.

[Chronic medications in the preoperative period: should they be stopped?]. / Medicación crónica durante el preoperatorio: ¿suspender o no suspender?

As different specialists are becoming increasingly involved in the preoperative management of our patients (for two main reasons; Primary Care doctors have to perform minor surgical procedures, and as coordination between Primary Care and In-hospital Care is more and more necessary in order to improve their outcomes), we believe that an update is needed as regards the management of chronic medications in this period. We will try to review the current literature dealing with the recommendations about withdrawing or continuing these drugs.

Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer.

The Kruppel-like factor (KLF) proteins are multitasked transcriptional regulators with an expanding tumor suppressor function. KLF2 is one of the prominent members of the family because of its diminished expression in malignancies and its growth-inhibitory, pro-apoptotic and anti-angiogenic roles. In this study, we show that epigenetic silencing of KLF2 occurs in cancer cells through direct transcriptional repression mediated by the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2). Binding of EZH2 to the 5'-end of KLF2 is also associated with a gain of trimethylated lysine 27 histone H3 and a depletion of phosphorylated serine 2 of RNA polymerase. Upon depletion of EZH2 by RNA interference, short hairpin RNA or use of the small molecule 3-Deazaneplanocin A, the expression of KLF2 was restored. The transfection of KLF2 in cells with EZH2-associated silencing showed a significant anti-tumoral effect, both in culture and in xenografted nude mice. In this last setting, KLF2 transfection was also associated with decreased dissemination and lower mortality rate. In EZH2-depleted cells, which characteristically have lower tumorigenicity, the induction of KLF2 depletion 'rescued' partially the oncogenic phenotype, suggesting that KLF2 repression has an important role in EZH2 oncogenesis. Most importantly, the translation of the described results to human primary samples demonstrated that patients with prostate or breast tumors with low levels of KLF2 and high expression of EZH2 had a shorter overall survival.