Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit

Cyclic oxidation of coated and uncoated single-crystal nickel-based superalloy MC2 analyzed by continuous thermogravimetry analysis

The previously developed cyclic thermogravimetry analysis (CTGA) [Monceau D, Poquillon D. Oxid Met 2004;61:143–163] method is applied to the cyclic oxidation at 1150 C of a NiCoCrAlYTa-coated and an uncoated single-crystal nickel-based superalloy MC2. A new procedure to correct the buoyancy effect is proposed in order to evaluate the amount of oxide formed during the heating periods, which can be important for alloys forming fast-growing transient oxides or during cycling with slow heating rates. It is shown that cyclic thermogravimetry is an useful technique for uantifying the oxidation resistance of an industrial alloy. Moreover, the behaviour of the alloy is better described with CTGA than with a classic cyclic gravimetric test, because both isothermal oxidation kinetics and spalling behaviour are assessed independently. In the present case, it is shown clearly that the NiCoCrAlYTa coating greatly improves the cyclic oxidation resistance without decreasing the isothermal oxidation kinetics. Finally, the use of CTGA for performance and time-of-life evaluations is demonstrated