The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (DeltaPsi(m)) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-X(L), whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.

The significance and the informative value of risk and protective factor combinations, e.g., for selective ultrasound surveys, are limited. Early universal ultrasound screening using the Graf method is advised to timely detect hip immaturity and pathologies and to provide the optimal approach for mature or immature but appropriate for age and pathologic hips. What is Known: • Ultrasound screening is essential for diagnosis and treatment of DDH in time while the weighting and correlation of protective factors and perinatal risk and their role for the ultrasound screening protocol still give rise to debate. What is New: • The effects of single risk and protective factors for DDH do not cumulate or counteract, resulting in a limited value of a selective screening protocol based on risk and protective factors. • A universal screening protocol using the Graf ultrasound method is recommended.

Benzenesulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone were prepared and found to inhibit microtubule formation by an in vitro tubulin polymerization assay. Several analogues showed potent cytotoxic activity in an assay based on K562 leukemia cells with IC50 values of <100 nM. The methylamino analogue 14i was the most active compound in this assay (14i, IC50 K562: 0.05 muM). Antiproliferative activities of selected compounds were additionally evaluated against a panel of 12 tumor cell lines, including multi-drug-resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that KB/HeLa cells treated with selected compounds were arrested in the G2/M phases of the cell cycle. In competition experiments, these compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values lower than that of colchicine. The results demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.