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Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt's lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound's therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.

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Age-related health decline has been attributed to the accumulation of senescent cells recognized in vivo by p16(Ink4a) expression. The pharmacological elimination of p16(Ink4a)-positive cells from the tissues of mice was shown to extend a healthy lifespan. Here, we describe a population of mesenchymal cells isolated from mice that are highly p16(INK4a)-positive are proficient in proliferation but lack other properties of cellular senescence. These data, along with earlier reports on p16(Ink4a)-positive macrophages, indicate that p16(Ink4a)-positive and senescent cell populations only partially intersect, therefore, extending the list of potential cellular targets for anti- aging therapies.

Demands for improved fuel efficiency and reduced CO 2 emissions of diesel engines have been the driving force for car industry in the past decades. One way to achieve this would be by using thermal spraying to apply a thermal insulation layer on parts of the engine's combustion chamber. A candidate thermal spray process to give coatings with appropriate properties is suspension plasma spray (SPS). SPS, which uses a liquid feedstock for the deposition of finely structured columnar ceramic coatings, was investigated in this work for application in light-duty diesel engines. In this work, different spray processes and materials were explored to achieve coatings with optimized microstructure on the head of aluminum pistons used in diesel engine cars. The functional properties of the coatings were evaluated in single-cylinder engine experiments. The influence of thermo-physical properties of the coatings on their functional properties has been discussed. The influence of different spray processes on coating formation on the complex piston head profiles has been also discussed. The results show that SPS can be a promising technique for producing coatings on parts of the combustion chamber, which can possibly lead to higher engine efficiency in light-duty diesel engines. Keywords diesel engines Á fuel efficiency Á microstructure Á suspension plasma spraying Á surface engineering Á thermal barrier coatings & Wellington Uczak de Goes wellington.uczak

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