Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of patients with very different five-year overall survival rates (70% versus 12%). The model also effectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention.     

PI4P and Rab inputs collaborate in myosin-V-dependent transport of secretory compartments in yeast

Cell polarity involves transport of specific membranes and macromolecules at the right time to the right place. In budding yeast, secretory vesicles are transported by the myosin-V Myo2p to sites of cell growth. We show that phosphatidylinositol 4-phosphate (PI4P) is present in late secretory compartments and is critical for their association with, and transport by, Myo2p. Further, the trans-Golgi network Rab Ypt31/32p and secretory vesicle Rab Sec4p each bind directly, but distinctly, to Myo2p, and these interactions are also required for secretory compartment transport. Enhancing the interaction of Myo2p with PI4P bypasses the requirement for interaction with Ypt31/32p and Sec4p. Together with additional genetic data, the results indicate that Rab proteins and PI4P collaborate in the association of secretory compartments with Myo2p. Thus, we show that a coincidence detection mechanism coordinates inputs from PI4P and the appropriate Rab for secretory compartment transport.     

Design and synthesis of novel antibacterial agents with inhibitory activity against DNA polymerase III

4-Substituted 2-amino-6-(anilino)pyrimidines have been found to be selective inhibitors of DNA polymerase III, a replicative enzyme known to be essential in the DNA synthesis of Gram-positive bacteria. Among the analogues, 18 displayed an IC(50) of 10 microM against DNA polymerase III from Staphylococcus aureus.     

Climate–growth relationships of the dominant tree species from semi-arid savanna woodland in Ethiopia

Long-term climate–growth relationships, were examined in tree rings of four co-occurring tree species from semi-arid Acacia savanna woodlands in Ethiopia. The main purpose of the study was to prove the presence of annual tree rings, evaluate the relationship between radial growth and climate parameters, and evaluate the association of El Niño and drought years in Ethiopia. The results showed that all species studied form distinct growth boundaries, though differences in distinctiveness were revealed among the species. Tree rings of the evergreen Balanites aegyptiaca were separated by vessels surrounding a thin parenchyma band and the growth boundary of the deciduous acacias was characterized by thin parenchyma bands. The mean annual diameter increment ranged from 3.6 to 5.0 mm. Acacia senegal and Acacia seyal showed more enhanced growth than Acacia tortilis and B. aegyptiaca. High positive correlations were found between the tree-ring width chronologies and precipitation data, and all species showed similar response to external climate forcing, which supports the formation of one tree-ring per year. Strong declines in tree-ring width correlated remarkably well with past El Niño Southern Oscillation (ENSO) events and drought/famine periods in Ethiopia. Spectral analysis of the master tree-ring chronology indicated occurrences of periodic drought events, which fall within the spectral peak equivalent to 2–8 years. Our results proved the strong linkage between tree-ring chronologies and climate, which sheds light on the potential of dendrochronological studies developing in Ethiopia. The outcome of this study has important implications for paleoclimatic reconstructions and in restoration of degraded lands.