| 1. |
- Agathangelidis, Andreas, et al.
(författare)
-
Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia : a molecular classification with implications for targeted therapies
- 2012
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:19, s. 4467-4475
-
Tidskriftsartikel (refereegranskat)abstract
- Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
|
|
| 2. |
- Goma, Eduard, et al.
(författare)
-
Insomnia in the Access (or How to Curb Access Network Related Energy Consumption)
- 2011
-
Ingår i: Proceedings of the ACM SIGCOMM 2011 Conference on Applications, Technologies, Architectures, and Protocols for Computer Communications. - New York, New York, USA : Association for Computing Machinery (ACM). - 9781450307970 ; , s. -349
-
Konferensbidrag (refereegranskat)abstract
- Access networks include modems, home gateways, and DSL Access Multiplexers (DSLAMs), and are responsible for 70-80% of total network-based energy consumption. In this paper, we take an in-depth look at the problem of greening access networks, identify root problems, and propose practical solutions for their user- and ISP-parts. On the user side, the combination of continuous light traffic and lack of alternative paths condemns gateways to being powered most of the time despite having Sleep-on-Idle (SoI) capabilities. To address this, we introduce Broadband Hitch-Hiking (BH2), that takes advantage of the overlap of wireless networks to aggregate user traffic in as few gateways as possible. In current urban settings BH2 can power off 65-90% of gateways. Powering off gateways permits the remaining ones to synchronize at higher speeds due to reduced crosstalk from having fewer active lines. Our tests reveal speedup up to 25%. On the ISP side, we propose introducing simple inexpensive switches at the distribution frame for batching active lines to a subset of cards letting the remaining ones sleep. Overall, our results show an 80% energy savings margin in access networks. The combination of BH2 and switching gets close to this margin, saving 66% on average.
|
|
| 3. |
- Hadzidimitriou, Anastasia, et al.
(författare)
-
Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia
- 2009
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 113:2, s. 403-411
-
Tidskriftsartikel (refereegranskat)abstract
- We analyzed somatic hypermutation (SHM) patterns and secondary rearrangements involving the immunoglobulin (IG) light chain (LC) gene loci in 725 patients with chronic lymphocytic leukemia (CLL). Important differences regarding mutational load and targeting were identified in groups of sequences defined by IGKV/IGLV gene usage and/or K/LCDR3 features. Recurrent amino acid (AA) changes in the IGKV/IGLV sequences were observed in subsets of CLL cases with stereotyped B-cell receptors (BCRs), especially those expressing IGHV3-21/IGLV3-21 and IGHV4-34/IGKV2-30 BCRs. Comparison with CLL LC sequences carrying heterogeneous K/LCDR3s or non-CLL LC sequences revealed that distinct amino acid changes appear to be "CLL-biased." Finally, a significant proportion of CLL cases with monotypic LC expression were found to carry multiple potentially functional LC rearrangements, alluding to active, (auto) antigen-driven receptor editing. In conclusion, SHM targeting in CLL LCs is just as precise and, likely, functionally driven as in heavy chains. Secondary LC gene rearrangements and subset-biased mutations in CLL LC genes are strong indications that LCs are crucial in shaping the specificity of leukemic BCRs, in association with defined heavy chains. Therefore, CLL is characterized not only by stereotyped HCDR3 and heavy chains but, rather, by stereotyped BCRs involving both chains, which generate distinctive antigen-binding grooves.
|
|
| 4. |
- Murray, Fiona, et al.
(författare)
-
Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia : implications for the role of antigen selection in leukemogenesis
- 2008
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:3, s. 1524-1533
-
Tidskriftsartikel (refereegranskat)abstract
- Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, "stereotyped" amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are un-derrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).
|
|
