Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.

Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

Long Noncoding RNA ANROC on the INK4 Locus Functions to Suppress Cell Proliferation.

BACKGROUND/AIM: The INK4 locus encodes three important genes p15INK4B, p16INK4A, and ARF, which function to suppress oncogenesis, and a long noncoding RNA, ANRIL, which, in contrast, functions to promote oncogenesis. Herein, we report a fifth genetic element on the INK4 locus, a long noncoding RNA with unknown function named associated negative regulation of cell proliferation (ANROC), which played a role in the suppression of cell proliferation. MATERIALS AND METHODS: Following ANROC silencing in cells by siRNA, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and cell cycle analysis using flow cytometry were performed. RESULTS: ANROC expression was decreased by oncogenic RAS signalling. ANROC knockdown enhanced HeLa cell proliferation and induced cyclin B1 mRNA, which promotes G2/M progression of the cell cycle. Furthermore, flow cytometric analysis revealed that ANROC knockdown increased the percentage of cells in the S and G2/M phases of the cell cycle. CONCLUSION: ANROC functions to suppress cell cycle progression by suppressing cyclin B1 expression, thus inhibiting cell proliferation.

Diamond-like carbon coating under oleic acid lubrication: Evidence for graphene oxide formation in superlow friction.

The achievement of the superlubricity regime, with a friction coefficient below 0.01, is the Holy Grail of many tribological applications, with the potential to have a remarkable impact on economic and environmental issues. Based on a combined high-resolution photoemission and soft X-ray absorption study, we report that superlubricity can be realized for engineering applications in bearing steel coated with ultra-smooth tetrahedral amorphous carbon (ta-C) under oleic acid lubrication. The results show that tribochemical reactions promoted by the oil lubrication generate strong structural changes in the carbon hybridization of the ta-C hydrogen-free carbon, with initially high sp3 content. Interestingly, the macroscopic superlow friction regime of moving mechanical assemblies coated with ta-C can be attributed to a few partially oxidized graphene-like sheets, with a thickness of not more than 1 nm, formed at the surface inside the wear scar. The sp2 planar carbon and oxygen-derived species are the hallmark of these mesoscopic surface structures created on top of colliding asperities as a result of the tribochemical reactions induced by the oleic acid lubrication. Atomistic simulations elucidate the tribo-formation of such graphene-like structures, providing the link between the overall atomistic mechanism and the macroscopic experimental observations of green superlubricity in the investigated ta-C/oleic acid tribological systems.

Stereoselective synthesis of the C1-C29 part of amphidinol 3.

Stereoselective synthesis of the C1-C29 part of amphidinol 3 (AM3) was achieved. The C1-C20 part was assembled from three building blocks via regioselective cross metathesis to form the C4-C5 double bond and addition of an alkenyllithium and a lithium acetylide to two Weinreb amides followed by asymmetric reduction to form the C9-C10 and C14-C15 bonds, respectively. The C21-C29 part was synthesized via successive cross metathesis and oxa-Michael addition sequence to construct the 1,3-diol system at C25 and C27 and Brown asymmetric crotylation to introduce the stereogenic centers at C23 and C24. Coupling of the C1-C20 and C21-C29 parts was achieved by Julia-Kocienski olefination and regio- and stereoselective dihydroxylation of the C20-C21 double bond in the presence of the C4-C5 and C8-C9 double bonds to afford the C1-C29 part of AM3.