Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer.

Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.

DGG-300273, a novel WNT/ß-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/ß-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/ß-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/ß-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

Hypocapnia attenuates, and nitrous oxide disturbs the cerebral oximetric response to the rapid introduction of desflurane.

The aim of this study was to develop a nonlinear mixed-effects model for the increase in cerebral oximetry (rSO(2)) during the rapid introduction of desflurane, and to determine the effect of hypocapnia and N(2)O on the model. Twelve American Society of Anesthesiologist physical status class 1 and 2 subjects were allocated randomly into an Air and N(2)O group. After inducing anesthesia, desflurane was then increased abruptly from 4.0 to 12.0%. The PET(CO2), PET(DESF) and rSO(2) were recorded at 12 predetermined periods for the following 10 min. The maximum increase in rSO(2) reached +24-25% during normocapnia. The increase in rSO(2) could be fitted to a four parameter logistic equation as a function of the logarithm of PET(DESF). Hypocapnia reduced the maximum response of rSO(2), shifted the EC(50) to the right, and increased the slope in the Air group. N(2)O shifted the EC(50) to the right, and reduced the slope leaving the maximum rSO(2) unchanged. The N(2)O-effects disappeared during hypocapnia. The cerebrovascular reactivity of rSO(2) to CO(2) is still preserved during the rapid introduction of desflurane. N(2)O slows the response of rSO(2). Hypocapnia overwhelms all the effects of N(2)O.

Difficult endotracheal intubation due to an undiagnosed epiglottic cyst :A case report.

An epiglottic cyst is a common form of laryngeal cysts which are rare causes of upper airway obstruction. A congenital laryngeal cyst always causes neonatal respiratory distress, but an acquired cyst shows very wide spectrum of symptoms such as no specific complaints, dysphagia, respiratory difficulty, or even death according to its size, location, or age. From anesthesiologists' point of view, an asymptomatic undiagnosed laryngeal cyst is a major concern. Unexpectedly, it can cause difficult airway such as 'cannnot intubate' or 'cannot intubate and cannot ventilate' situation during anesthesia. Recently we discovered an undiagnosed epiglottic cyst obscuring laryngeal inlet, leading to difficult intubation during general anesthesia for decompression and fusion of lumbar vertebrae. Fortunately, mask ventilation was possible, and after failed attempts of direct laryngoscopy, we could perform oral fiberoptic bronchoscope-aided intubation. He was discharged 10 days later with no harmful events.

Pulmonary edema during hysteroscopic surgery: Three cases report.

Hysteroscopic surgery has become a routine gynecologic procedure. The advantages are associated with more accurate removal of lesion, its short operating time, rapid post-operative recovery and low morbidity. However, there are potentially serious complications which can be occured during and following hysteroscopic surgery. The complications are uterine perforation, fluid overload and electrolyte disturbance due to intravasation and absorption of uterine distention media, hemorrhage and, rarely, gas or air embolism. We experienced pulmonary edema during hysteroscopic surgery in three consecutive patients. Therefore, we report these cases of fluid overload with uterine distention media resulting acute pulmonary edema during hysteroscopic surgery.