The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner.

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant KrasG12D-driven murine model of lung cancer. Using KrasG12D/+ Bok-/- mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in KrasG12D-driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using KrasG12D/+ Tp53Δ/Δ Bok-/- mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer

Energetic Stability and Its Role in the Mechanism of Ionic Transport in NASICON-Type Solid-State Electrolyte Li 1+ x Al x Ti 2– x (PO 4 ) 3

We apply high-temperature oxide melt solution calorimetry to assess the thermodynamic properties of the material Li1+xAlxTi2–x(PO4)3, which has been broadly recognized as one of the best Li-ion-conducting solid electrolytes of the NASICON family. The experimental results reveal large exothermic enthalpies of formation from binary oxides (ΔHf,ox°) and elements (ΔHf,el°) for all compositions in the range 0 ≤ x ≤ 0.5. This indicates substantial stability of Li1+xAlxTi2–x(PO4)3, driven by thermodynamics and not just kinetics, during long-term battery operation. The stability increases with increasing Al3+ content. Furthermore, the dependence of the formation enthalpy on the Al3+ content shows a change in behavior at x = 0.3, a composition near which the Li+ conductivity reaches the highest values. The strong correlation among thermodynamic stability, ionic transport, and clustering is a general phenomenon in ionic conductors that is independent of the crystal structure as well as the type of charge carrier. Therefore, the thermodynamic results can serve as guidelines for the selection of compositions with potentially the highest Li+ conductivity among different NASICON-type series with variable dopant contents

Vitamin D supplements and prevention of tuberculosis infection and disease

BACKGROUND: Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. METHODS: We randomly assigned children who had negative results for Mycobacterium tuberculosis infection, using the QuantiFERON-TB Gold In-tube assay (QFT), to receive a weekly oral dose of 14,000 IU vitamin D3 or placebo over 3 years. The primary outcome was the proportion of children having a positive QFT result at 3 years. Secondary outcomes included end-study vitamin D status and incidence of tuberculosis disease, acute respiratory infections and adverse events. RESULTS: 8851 participants underwent randomization (4418 to vitamin D, 4433 to placebo), of whom 95.6% had baseline serum 25-hydroxyvitamin D concentrations <20 ng/mL. Mean end-study 25-hydroxyvitamin D concentration in participants randomized to vitamin D vs. placebo was 31.0 vs. 10.7 ng/mL (95% CI for difference, 19.9 to 20.6 ng/mL), and 147 participants in the vitamin D group vs. 134 participants in the placebo group tested positive by QFT (adjusted risk ratio [aRR] 1.10, 95% CI 0.87 to 1.38, P=0.42). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and 25 children in the placebo group (aRR 0.87, 95% CI 0.49 to 1.55). 29 participants randomized to vitamin D and 34 randomized to placebo were hospitalized for treatment of acute respiratory infections (aRR 0.86, 95% CI 0.52 to 1.40). Incidence of adverse events did not differ significantly between study arms. CONCLUSIONS: Vitamin D supplementation did not reduce risk of tuberculosis infection, tuberculosis disease or acute respiratory infections among vitamin D-deficient schoolchildren in Mongolia