Recent reports indicate a broad spectrum of antileukemic activity for arsenic trioxide (As 2 O 3 ) due to its ability to induce apoptosis via intracellular production of reactive oxygen species (ROS). Despite its potent apoptotic mechanism, As 2 O 3 is not equally effective in all leukemic cells, which has prompted a search for agents enhancing As 2 O 3 efficacy. Recently, evidence has been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may sensitize tumor cells to ROSinducing anticancer agents. The aim of our investigation was to evaluate whether DHA enhances As 2 O 3 -mediated apoptosis in As 2 O 3 -resistant HL-60 cells. While 1 M As 2 O 3 or 25 M DHA reduced cell viability to 85.8% ؎ 2.9% and 69.2% ؎ 3.6%, combined treatment with As 2 O 3 and DHA reduced viability to 13.0% ؎ 9.9% with a concomitant increase of apoptosis. Apoptotic cell death was preceded by collapse of the mitochondrial membrane potential, increased expression of proapoptotic B-cell lymphoma protein-2-associated X protein (Bax), and caspase-3 activation. Importantly, the combined effect of As 2 O 3 and DHA was associated with increased production of intracellular ROS and toxic lipid peroxidation products and was abolished by the antioxidant vitamin E or when oleic acid (a nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and toxic lipid peroxidation products most likely constitute the key mediators contributing to the combined effect of As 2 O 3 and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of As 2 O 3 and suggest that the combination of As 2 O 3 and DHA could be more broadly applied in leukemia therapy.

It has been shown that the polyunsaturated fatty acid docosahexaenoic acid (DHA) can sensitize various tumor cells to reactive oxygen species (ROS)-inducing anticancer agents. Recently, we demonstrated that DHA also enhances the apoptotic effect of clinically achievable concentrations (1-2 M) of arsenic trioxide (As 2 O 3 ) in several As 2 O 3 -resistant human leukemic cell lines via a ROS-dependent mechanism. The aim of the present study was to evaluate whether this combined effect of As 2 O 3 and DHA is also applicable to Several studies have shown that exogenous polyunsaturated fatty acids (PUFAs) may sensitize tumor cells to reactive oxygen species (ROS)-inducing anticancer drugs both in vitro and in vivo. [1][2][3][4][5][6][7] It has been shown that the susceptibility of PUFAs to lipid peroxidation is of pivotal importance for this drug-enhancing effect. 2,4,7 The ROS-generating anticancer drug arsenic trioxide (As 2 O 3 ) has been used for the treatment of several types of leukemia with remarkable clinical success. 8 -12 Although several mechanisms of action have been proposed for the antileukemic activity of As 2 O 3 , the generation and accumulation of ROS most likely constitutes the key mechanism responsible for its cytotoxic action. 13,14 However, clinically achievable concentrations (1-2 M) of As 2 O 3 are not effective in all tumor types. 15 Hence, investigations to enhance the effect of As 2 O 3 without increasing its concentration have been impelled. 16,17 Recently, we showed that the PUFA docosahexaenoic acid (DHA) enhances the apoptotic effect of clinically achievable concentrations (1 M) of As 2 O 3 in As 2 O 3 -resistant leukemia cells. 18 The combined effect of As 2 O 3 and DHA was due to the induction of apoptosis and associated with accumulation of intracellular ROS and increased production of toxic lipid peroxidation products. Importantly, the combined effect of As 2 O 3 and DHA was not restricted to one type of leukemia cells, but was effective in cells derived from several hematologic malignancies. As a consequence, we hypothesized that the combined effect of As 2 O 3 /DHA treatment may also be applicable to solid tumor cells that are known to be intrinsically less sensitive to As 2 O 3 . To elucidate whether a possible enhancing effect of DHA was PUFA-specific and to define the relationship between enhanced lipid peroxidation and increased As 2 O 3 toxicity, we also tested the effects of oleic acid (OA), a nonperoxidizable monounsaturated fatty acid, on As 2 O 3 -mediated apoptosis. Finally, we also determined the efficacy of As 2 O 3 and DHA in the presence of the lipophilic antioxidant vitamin E. MATERIAL AND METHODS ChemicalsNinety-nine percent pure cis-4,7,10,13,16,19-DHA and cis-9-OA, dl-␣-tocopherol (vitamin E) and As 2 O 3 (Sigma Chemical, St. Louis, MO) were prepared as stock solutions and dissolved to the respective working concentrations with complete culture medium before use as described previously. 18

Digitalisation is changing all areas of our daily life. This changing environment requires new competences from physicians in all specialities. This study systematically surveyed the knowledge, attitude, and interests of medical students. These results will help further develop the medical curriculum, as well as increase our understanding of future physicians by other healthcare market players. A web-based survey consisting of four sections was developed: Section one queried demographic data, section two assessed the current digital health knowledge of medical students, section three queried their attitudes about the future impact of digital health in medicine and section four assessed the recommendations medical students have for the medical curriculum in terms of digital health. This survey was distributed to all (11,978) student at all public Austrian medical schools. A total of 8.4% of the medical student population started the survey. At the knowledge self-assessment section, the medical students reached mean of 11.74 points (SD 4.42) out of a possible maximum of 32 (female mean 10.66/ SD 3.87, male mean 13.34/SD 4.50). The attitude section showed that students see digitalisation as a threat, especially with respect to the patient–physician relationship. The curriculum recommendation section showed a high interest for topics related to AI, a per study year increasing interest in impact of digital health in communication, as well as a decreasing interest in robotic related topics. The attitude towards digital health can be described as sceptical. To ensure that future physicians keep pace with this development and fulfil their responsibility towards the society, medical schools need to be more proactive to foster the understanding of medical students that digital health will persistently alter the medical practice.

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