The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.

We show that the so-called 'positive inside' rule, i.e. the observation that positively charged amino acids tend to be more prevalent in cytoplasmic than in extra-cytoplasmic segments in transmembrane proteins [von Heijne, G. (1986) EMBO J. 5, 3021-30271, seems to hold for all polar segments in multi-spanning eukaryotic membrane proteins irrespective of their position in the sequence and hence can be used in conjunction with hydrophobicity analysis to predict their transmembrane topology. Further, as suggested by others, we confirm that the net charge difference across the first transmembrane segment correlates well with its orientation [Hartmann, E., Rapoport, T. A. and Lodish, H. F. (1989) Proc. Natl Acad. Sci. USA 86, 5786-57901, and that the overall amino-acid composition of long polar segments can also be used to predict their cytoplasmic or extra-cytoplasmic location [Nakashima, H. and Nishikawa, K. (1992 We present an approach to the topology prediction problem for eukaryotic membrane proteins based on a combination of these methods.Integral membrane proteins seem to come in two basic varieties: the helical bundle proteins with membrane domains built from a bundle of hydrophobic transmembrane a helices [l, 21, and the P-barrel proteins which form large, anti-parallel / 3 barrels with a hydrophobic outer surface facing the lipids [3, 41. In both cases, the requirement that a continuous outer apolar surface must be formed has necessitated a structurally rather well-defined solution. This greatly facilitates the task of predicting structure from sequence, and the secondary structure of both types of protein can now be fairly well predicted [4, 51. For the helical bundle proteins, two easily identified features of the nascent chain seem to be the major structural determinants: the long, apolar stretches that form the transmembrane a helices and the biased distribution of arginines and lysines in the polar regions exposed on either side of the membrane, the 'positive inside' rule [6, 71. In fact, we have recently shown that transmembrane segments in bacterial inner-membrane proteins can be predicted with very high confidence if this charge bias is taken into account [5].The possibility of similarly improving the prediction of transmembrane helices in eukaryotic membrane proteins has not been explored so far. A priori, there are a number of reason why a charge-bias analysis of the kind shown to work well for prokaryotic proteins may be less informative in this case: in contrast to the situation in prokaryotes, the initial insertion of eukaryotic proteins into the membrane of the endoplasmic reticulum is thought to be largely co-translational, suggesting that only the most N-terminal apolar segment(s) will determine the final topology; the (Arg+Lys) bias between cytoplasmic and extra-cytoplasmic (lumenal) segments is less extreme than in prokaryotes [7] ; it appears that the net charge difference (including negatively charged Asp and Glu residues) across the first transmembrane segment, rather than the differe...

A very large cis-regulatory region of approximately 300 kb is responsible for the complex patterns of expression of the three homeotic genes of the bithorax complex Ubx, abd-A and Abd-B. This region can be subdivided in nine parasegment-specific regulatory subunits. Recent genetic and molecular analysis has revealed the existence of two novel cis-regulatory elements Mcp and Fab-7. Mcp is located between iab-4 and iab-5, the parasegment-specific regulatory subunits which direct Abd-B in parasegments 9 and 10. Similarly, Fab-7 is located between iab-6 and iab-7, the parasegment 11 and 12-specific regulatory units. Mcp and Fab-7 appear to function as domain boundaries that separate adjacent cis-regulatory units. We report the analysis of two new Mcp mutant deletions (McpH27 and McpB116) that allow us to localize sequences essential for boundary function to a approximately 0.4 kb DNA segment. These essential sequences closely coincide to a approximately 0.3 kb nuclease hypersensitive region in chromatin. We also show that sequences contributing to the Fab-7 boundary appear to be spread over a larger stretch of DNA, but like Mcp have an unusual chromatin structure.

The three homeotic genes of the bithorax complex (BX-C), Ubx, abd-A and Abd-B control the identity of the posterior thorax and all abdominal segments. Large segment-specific cis-regulatory regions control the expression of Ubx, abd-A or Abd-B in each of the segments. These segment-specific cis-regulatory regions span the whole 300 kb of the BX-C and are arranged on the chromosome in the same order as the segments they specify. Experiments with lacZ reporter constructs revealed the existence of several types of regulatory elements in each of the cis-regulatory regions. These include initiation elements, maintenance elements, cell type-or tissue-specific enhancers, chromatin insulators and the promoter targeting sequence. In this paper, we extend the analysis of regulatory elements within the BX-C by describing a series of internal deficiencies that affect the Abd-B regulatory region. Many of the elements uncovered by these deficiencies are further verified in transgenic reporter assays. Our results highlight four key features of the iab-5, iab-6 and iab-7 cis-regulatory region of Abd-B. First, the whole Abd-B region is modular by nature and can be divided into discrete functional domains. Second, each domain seems to control specifically the level of Abd-B expression in only one parasegment. Third, each domain is itself modular and made up of a similar set of definable regulatory elements. And finally, the activity of each domain is absolutely dependent on the presence of an initiator element.