BACKGROUND Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches. MATERIALS AND METHODS ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa). RESULTS NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells. CONCLUSION NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.

During February and March 2010, the New York State Department of Health investigated secondary and tertiary vaccinia contact transmission from a military vaccinee to 4 close contacts. Identification of these cases underscores the need for strict adherence to postvaccination infection control guidance to avoid transmission of the live virus.

BACKGROUND Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. METHODS ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. RESULTS Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. CONCLUSION Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.

Much of the previous research on children's understanding of intentions confounded intentions with desires. Intentions and desires are different, in that a desire can be satisfied in a number of ways, but an intention must be satisfied by carrying out the intended action. Children 3 through 7 years of age and adults were presented with situations in which intentions were satisfied but desires were not, or vice versa, in a story-comprehension task (N = 71) and a target-hitting game (N = 45). Although 3- and 4-year-olds were unable to differentiate desires and intentions consistently, 5- and 7-year-olds often matched the adult pattern. Younger children's difficulties in understanding intentions are discussed in terms of their use of a desire-outcome matching strategy and the representational complexities of intentions.

Human actions and movements can be caused by psychological states (e.g. beliefs and desires), physical forces (e.g. gravity) and biological processes (e.g. reflexes). In three studies we explored young children's understanding of the causes of human movements in order to examine their ability to differentiate and coordinate psychological, physical and biological reasoning to account for the activities of one single entity--a human being. In Study 1, 4-year-olds explained characters' voluntary actions, mistakes, physically-caused and biologically-caused behaviors and movements. Children gave psychological explanations for the intended actions and mistakes, but biological and physical explanations for the biologically-caused and physically-caused movements. Studies 2 and 3 extended the investigation to younger children (3-year-olds), encompassed a greater variety of items, and used several converging methods in order to examine children's judgments and explanations. Consistently, 3- and 4-year-olds gave appropriately different responses and explanations to the different item types. These findings show that far from viewing people in strictly psychological terms, young children evidence multiple causal-explanatory construals of human behavior. We discuss the implications of these findings for children's everyday psychological, physical, and biological theories. One implication of the findings is that young children do not assume a match between entities and theories (persons-psychology, objects-physics). If they do not, this raises the question of what information they use to decide which explanatory system fits which events.

In a series of 4 studies, we explored preschoolers' understanding of thought bubbles. Very few 3-year-olds or 4-year-olds we tested knew what a thought-bubble depiction was without instruction. But, if simply told that the thought bubble "shows what someone is thinking," the vast majority of 3-year-olds and 4-year-olds easily understood the devices as depicting thoughts generally and individual thought contents specifically. In total, these children used thought-bubble depictions to ascertain the contents of characters' thoughts in a variety of situations; appropriately distinguished such depictions from mere associated actions or objects; described thought bubbles in the language of mental states; judged that persons' thoughts in these depictions were subjective in the sense of person-specific (and hence 2 people can have different thoughts about the same state of affairs); and judged that thought-bubble thoughts (a) were representational in the sense of depicting or showing some other state of affairs,(b) were mental and thus showed intangible, private, internal thoughts unlike real pictures or photographs, and (c) can be false, that is, can depict a person's misrepresentation of some state of affairs. We discuss the implications of these findings for young children's understanding of thoughts and thought bubbles, for their learning and comprehension of pictorial conventions, and for the use of thought bubbles to assess children's early understanding of mind.

The main side-effects of BCG vaccination by scarification in 511 patients with malignant melanoma since 1974 have been fatigue and exhaustion, swelling of the lymph-nodes, influenza-like symptoms, nausea and dizziness. Only in 8 patients were the side-effects more severe, requiring the cessation of treatment in some of them. One patient developed granulomatous hepatitis, another experienced a reactivation of pulmonary tuberculosis. Allergic reactions occurred in two patients. A further patient developed recurrent erysipelas in the draining areas of the scarification. In two patients we observed continuous severe joint troubles, which were not due to metastatic disease. The eighth patient developed keloids at the vaccination sites on the upper arms. One third of the patients had no side-effects. Altogether vaccinations were tolerated well by most of the patients. Nearly all of them were able to work normally.