Porównanie metod inicjalizacji algorytmu EM dla wieloskładnikowych heteroscedastycznych mieszanin rozkładów normalnych

A basic approach to estimation of mixture model parameters is by using expectation maximization (EM) algorithm for maximizing the likelihood function. However, it is essential to provide the algorithm with proper initial conditions, as it is highly dependent on the first estimation (“guess”) of parameters of a mixture. This paper presents several different initial condition estimation methods, which may be used as a first step in the EM parameter estimation procedure. We present comparisons of different initialization methods for heteroscedastic, multi-component Gaussian mixtures.Algorytm EM (ang. expectation-maximization) jest szeroko stosowanym rozwiązaniem problemu estymacji parametrów mieszanin rozkładów prawdopodobieństwa poprzez maksymalizację wiarygodności. Istotne znaczenie dla działania algorytmu mają parametry początkowe, stanowiące pierwsze przybliżenie badanej mieszaniny. Publikacja przybliża kilka metod wyznaczania warunku początkowego dla iteracji algorytmu EM oraz porównuje ich skuteczność dla przypadku heteroscedastycznych, wieloskładnikowych mieszanin rozkładów normalnych

Senescence induction in renal carcinoma cells by Nutlin-3: a potential therapeutic strategy based on MDM2 antagonism.

Although the role of p53 as a tumour suppressor in renal cell carcinoma (RCC) is unclear, our recent analysis suggests that increased wild-type p53 protein expression is associated with poor outcome. A growing body of evidence also suggests that p53 expression and increased co-expression of MDM2 are linked with poor prognosis in RCC. We have therefore examined whether an MDM2 antagonist; Nutlin-3, might rescue/increase p53 expression and induce growth inhibition or apoptosis in RCC cells that retain wild-type p53. We show that inhibition of p53 suppression by MDM2 in RCC cells promotes growth arrest and p53-dependent senescence - phenotypes known to mediate p53 tumour suppression in vivo. We propose that future investigations of therapeutic strategies for RCC should incorporate MDM2 antagonism as part of strategies aimed at rescuing/augmenting p53 tumour suppressor function

Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer.

PURPOSE: The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 is undergoing Phase I evaluation in the UK. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use. EXPERIMENTAL DESIGN: AZD3965 sensitivity was determined for 7 SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 were assessed by western blot. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray from 78 SCLC patients. RESULTS: AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intra-tumor lactate. In the tissue microarray, high MCT1 expression was associated with worse prognosis (p=0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors. CONCLUSIONS: This study provides a rationale to test AZD3965 in SCLC patients. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond