A fundamental yet poorly understood aspect of gene regulation in eukaryotic organisms is the mechanisms that control allelic exclusion and mutually exclusive gene expression. In the malaria parasite Plasmodium falciparum, this process regulates expression of the var gene family-a large, hypervariable repertoire of genes that are responsible for the ability of the parasite to evade the host immune system and for pathogenesis of the disease. A central problem in understanding this process concerns the mechanisms that limit expression to a single gene at a time. Here, we describe results that provide information on the mechanisms that control silencing and single gene expression and differentiate between several models that have recently been proposed. The results provide the first evidence, to our knowledge, supporting the existence of a postulated var-specific, subnuclear expression site and also reinforce the conclusion that var gene regulation is based on cooperative interactions between the two promoters of each var gene. Keywords: malaria; antigenic variation; allelic exclusion; silencing; transcription EMBO reports (2007) 8, 959-965.

Objectives Patients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. Materials and Methods We reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. Results Of 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. Conclusion The main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

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