Targeting Sphingosine Kinase 2 as a Treatment for Cholangiocarcinoma

Cholangiocarcinoma (CCA) has a high mortality rate and its occurrence is rising. This increase prompts the need for improved CCA treatments. Studies have suggested that CCA is highly reliant on the sphingosine-1-phosphate-receptor-2 (S1PR2) and sphingosine kinase 2 (SphK2). Recently, a competitive SphK2 inhibitor, ABC294640, has been approved for clinical trial. ABC294640 has the potential to treat CCA, which is support by a phase I clinical study that was able to temporarily treat a patient suffering from metastasized CCA with ABC294640. To determine the viability of ABC294640 as a treatment for CCA, this study focused on determining the effects of ABC294640 on rat CCA cell lines. We found that ABC294640 inhibited the growth and migration of CCA and CAFs cells. The growth and count of 3-D organotypic co-culture of CCA and CAFs, which forms the “duct-like” structures, were reduced by ABC294640. The potential of inhibiting SphK2 as a treatment for CCA is supported by our finding of increased expression of S1PR2 and SphK2 in CCA patient liver samples. In conclusion, ABC294640 represents a potential therapeutic agent for CCA

A Mechanistic Study of Thioester Hydrolysis with Heavy Atom Kinetic Isotope Effects

The carbonyl-C, carbonyl-O, and leaving-S kinetic isotope effects (KIEs) were determined for the hydrolysis of formylthiocholine. Under acidic conditions, ¹³<i>k</i>_obs = 1.0312, ¹⁸<i>k</i>_obs = 0.997, and ³⁴<i>k</i>_obs = 0.995; for neutral conditions, ¹³<i>k</i>_obs = 1.022, ¹⁸<i>k</i>_obs = 1.010, and ³⁴<i>k</i>_obs = 0.996; and for alkaline conditions, ¹³<i>k</i>_obs = 1.0263, ¹⁸<i>k</i>_obs = 0.992, and ³⁴<i>k</i>_obs = 1.000. The observed KIEs provided helpful insights into a qualitative description of the bond orders in the transition state structure

Recurring slope lineae in equatorial regions of Mars

The presence of liquid water is a requirement of habitability on a planet. Possible indicators of liquid surface water on Mars include intermittent flow-like features observed on sloping terrains. These recurring slope lineae are narrow, dark markings on steep slopes that appear and incrementally lengthen during warm seasons on low-albedo surfaces. The lineae fade in cooler seasons and recur over multiple Mars years. Recurring slope lineae were initially reported to appear and lengthen at mid-latitudes in the late southern spring and summer and are more common on equator-facing slopes where and when the peak surface temperatures are higher. Here we report extensive activity of recurring slope lineae in equatorial regions of Mars, particularly in the deep canyons of Valles Marineris, from analysis of data acquired by the Mars Reconnaissance Orbiter. We observe the lineae to be most active in seasons when the slopes often face the sun. Expected peak temperatures suggest that activity may not depend solely on temperature. Although the origin of the recurring slope lineae remains an open question, our observations are consistent with intermittent flow of briny water. Such an origin suggests surprisingly abundant liquid water in some near-surface equatorial regions of Mars