(ICH) is the most devastating adverse event in patients receiving oral anticoagulation. There is only sparse evidence regarding ICH related to the use of non-vitamin K antagonist oral anticoagulant (NOAC) agents. OBJECTIVE To evaluate the early clinical and radiological course, acute management, and outcome of ICH related to NOAC use. DESIGN, SETTING, AND PARTICIPANTS Prospective investigator-initiated, multicenter observational study. All diagnostic and treatment decisions, including administration of hemostatic factors (eg, prothrombin complex concentrate), were left to the discretion of the treating physicians. The setting was 38 stroke units across Germany (February 1, 2012, to December 31, 2014). The study included 61 consecutive patients with nontraumatic NOAC-associated ICH, of whom 45 (74%) qualified for the hematoma expansion analysis. MAIN OUTCOMES AND MEASURES Hematoma expansion, intraventricular hemorrhage, and reversal of anticoagulation during the acute phase. Recorded were the 3-month functional outcome, factors associated with an unfavorable outcome (modified Rankin Scale score, 3-6), any new intraventricular extension or an increase in the modified Graeb score by at least 2 points, and the frequency of substantial hematoma expansion (defined as relative [Ն33%] or absolute [Ն6-mL] volume increase). RESULTS In total, 41% (25 of 61) of patients with NOAC-associated ICH were female, and the mean (SD) patient age was 76.1 (11.6) years. At admission, the median National Institutes of Health Stroke Scale score was 10 (interquartile range, 4-18). The mean (SD) baseline hematoma volume was 23.7 (31.3) mL. In patients with sequential imaging for the hematoma expansion analysis, substantial hematoma expansion occurred in 38% (17 of 45). New or increased intraventricular hemorrhage was observed in 18% (8 of 45). Overall mortality was 28% (17 of 60 [follow-up data were missing in 1 patient]) at 3 months, and 65% (28 of 43) of survivors had an unfavorable outcome (modified Rankin Scale score, 3-6). Overall, 57% (35 of 61) of the patients received prothrombin complex concentrate, with no statistically significant effect on the frequency of substantial hematoma expansion (43% [12 of 28] for prothrombin complex concentrate vs 29% [5 of 17] for no prothrombin complex concentrate, P = .53), or on the occurrence of an unfavorable outcome (modified Rankin Scale score, 3-6) (odds ratio, 1.20; 95% CI, 0.37-3.87; P = .76). CONCLUSIONS AND RELEVANCE Non-vitamin K antagonist oral anticoagulant-associated ICH has a high mortality and an unfavorable outcome, and hematoma expansion is frequent. Larger-scale prospective studies are needed to determine whether the early administration of specific antidotes can improve the poor prognosis of NOAC-associated ICH.

We demonstrate in this paper that CDK4 which is a G1 phase speci®c cell cycle regulator and catalytic subunit of D-type cyclins has oncogenic activity similar to Dtype cyclins themselves and is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo ®broblasts. Surprisingly, using two di erent mutants we show that CDK4's ability to bind to p16 INK4a and not its kinase activity is important for its transforming potential. In addition, p16 INK4a but not a mutant form that is found in human tumours can completely abrogate focus formation by CDK4 suggesting that CDK4 can malignantly transform cells by sequestering p16 INK4a or other CKIs. We demonstrate that both cyclin D1 and CDK4 functionally depend on active Myc to exert their potential as oncogenes and vice versa that the transforming ability of Myc requires functional cyclin D/CDK complexes. Moreover, we ®nd that p16 INK4a and the Rb related protein p107 which releases Myc after phosphorylation by cyclin D1/CDK4 e ciently block Myc's activity as a transcriptional transactivator and as an oncogene. We conclude that both p16 INK4a and cyclin D/CDK4 complexes are upstream regulators of Myc and directly govern Myc function in transcriptional transactivation and transformation via the pocket protein p107.

The non-steroidal anti-in¯ammatory drug sulindac is used in cancer prevention and therapy, but the molecular aspects of its anti-tumor eect remain unresolved. In vivo the prodrug sulindac, is converted into the metabolite sulindac sul®de. We found that sulindac sul®de strongly inhibits Ras induced malignant transformation and Ras/ Raf dependent transactivation. Sulindac sul®de decreases the Ras induced activation of its main eector, the cRaf-1 kinase. In vitro sulindac sul®de directly binds to the Ras gene product p21ras in a non-covalent manner. Moreover, we can show that sulindac sul®de inhibits the interaction of p21ras with the p21ras binding domain of the Raf protein. In addition, sulindac sul®de can impair the nucleotide exchange on p21ras by CDC25 as well as the acceleration of the p21ras GTPase reaction by p120GAP. Due to its action at the most critical site in Ras signaling we propose sulindac sul®de as a lead compound in the search for novel anti-cancer drugs which directly inhibit Ras mediated cell proliferation and malignant transformation.