Early-stage non-small cell lung cancer (NSCLC) can be cured by surgical resection, but a substantial fraction of patients ultimately dies due to distant metastasis. In this study, we used subtractive hybridization to identify gene expression differences in stage I NSCLC tumors that either did or did not metastasize in the course of disease. Individual clones (n ¼ 225) were sequenced and quantitative RT-PCR verified overexpression in metastasizing samples. Several of the identified genes (eIF4A1, thymosin b4 and a novel transcript named MALAT-1) were demonstrated to be significantly associated with metastasis in NSCLC patients (n ¼ 70). The genes' association with metastasis was stage-and histology specific. The Kaplan-Meier analyses identified MALAT-1 and thymosin b4 as prognostic parameters for patient survival in stage I NSCLC. The novel MALAT-1 transcript is a noncoding RNA of more than 8000 nt expressed from chromosome 11q13. It is highly expressed in lung, pancreas and other healthy organs as well as in NSCLC. MALAT-1 expressed sequences are conserved across several species indicating its potentially important function. Taken together, these data contribute to the identification of early-stage NSCLC patients that are at high risk to develop metastasis. The identification of MALAT-1 emphasizes the potential role of noncoding RNAs in human cancer.

Background Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin — an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation — to standard chemotherapy would prolong overall survival in this population. Methods We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. Results A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P = 0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P = 0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. Conclusions The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261.)

FLT3 length mutation (FLT3-LM) is a molecular marker potentially useful for the characterization of acute myeloid leukemia (AML). To evaluate the distribution of FLT3-LM within biologic subgroups, we screened 1003 patients with AML at diagnosis for this mutation. FLT3-LM was found in 234 (23.5%) of all patients and thus is the most frequent mutation in AML described so far. Of all positive patients, 165 (70.5%) revealed a normal karyotype. Of the 69 patients with chromosome aberrations, 24 (34.8%) had a t(15;17). The mutation was rare in AML with t(8;21), inv(16) 11q23 rearrangements, and complex karyotypes. FLT3-LM was not distributed equally within different FrenchAmerican-British (FAB) subtypes and was correlated with a high peripheral blood count in FAB M1, M2, and M4 (P < .0001). In addition, the median age of patients with the mutation was lower (54.9 vs 57.6 years; P ‫؍‬ .043), and, at a ratio of 1.36:1 (P ‫؍‬ .023), the mutation was more frequent in females than in males. Within the AMLCG study, FLT3-LM was of intermediate prognostic significance. The complete remission rate of 70.3% in patients with FLT3-LM was similar to that (

Ubiquitination has long been recognised as a key determinator of protein fate by tagging proteins for proteasomal degradation. Most recently, the ability of conjugated ubiquitin chains to confer selectivity to autophagy was demonstrated. Although autophagy was first believed to be a bulk, non-selective 'self-eating' degradative process, the molecular mechanisms of selectivity are now starting to emerge. With the discovery of autophagy receptors -which bind both ubiquitinated substrates and autophagy specific light chain 3 (LC3) modifier on the inner sheath of autophagosomes -a new pathway of selective autophagy is being unravelled. In this review, we focus on the special role of ubiquitin signals and selective autophagy receptors in sorting a variety of autophagic cargos. FactsThe ubiquitin-proteasomal system (UPS) and the ubiquitinlike system (UBL) have functional similarity. Ubiquitination is frequently a prerequisite for substrate recognition and determines selectivity in autophagy in higher eukaryotes. Crosstalk between ubiquitination and autophagy is provided by autophagic adaptor proteins (or autophagy receptors), which bind both ubiquitin and autophagyspecific UBL modifiers (LC3 (light chain 3)/GABARAP (gamma-aminobutyric acid receptor-associated protein)). To date, seven autophagy receptors have been identified, which specifically regulate the selective autophagosomal degradation of large protein aggregates, mitochondria and bacterial pathogens. Open QuestionsWhat are the spatio-temporal mechanisms governing the dynamics of selective autophagosomal degradation? Are there regulatory feedback loops, whereby autophagy activity affects ubiquitination?What are the molecular basics that regulate selective autophagy under certain conditions? Are there germline or somatic mutations in key autophagy regulators that are causative for disease? What is the interplay between selective autophagy pathways and macroautophagy during starvation?Ubiquitin, a small protein consisting of 76 amino acids, is found in all tissues of eukaryotic organisms. With only three aminoacid differences between mammals, yeast and plants, ubiquitin displays a remarkable evolutionary conservation.