Cancer immunotherapy drives implementation science in oncology.

Cancer immunotherapy has come a long way. The hope that immunological approaches may help cancer patients has sparked many initiatives in research and development (R&D). For many years, progress was modest and disappointments were frequent. Today, the increasing scientific and medical knowledge has established a solid basis for improvements. Considerable clinical success was first achieved for patients with hematological cancers. More recently, immunotherapy has entered center stage in the development of novel therapies against solid cancers. Together with R&D in angiogenesis, the field of immunology has fundamentally extended the scientific scope, which has evolved from a cancer-cell-centered view to a comprehensive and integrated vision of tumor biology. Current R&D is focused on a large array of possible disease mechanisms, driven by cancer cells, and amplified by tumor stroma, inflammatory and immunological actors, blood and lymph vessels, and the "macroenvironment," i.e. systemic mechanisms of the host, particularly of the haematopoietic system. Contrasting to this large spectrum of pathophysiological events promoting tumor growth, only a small number of biological mechanisms, namely of the immune system, have the potential to counteract tumor growth. They are of prime interest because therapeutic enhancement may result in clinical benefit for patients. This special issue is dedicated to immunotherapeutics against cancer, with particular emphasis on vaccination and combination therapies, providing updates and extended insight in this booming field.

Diagnostic Performances of 18F-FDG Positron Emission Tomography in Large Vessels Vasculitis: Meta-analysis

Toperform a meta-analysis of FDG-PET performances in the diagnosis of largevessels vasculitis (Giant Cell Arteritis (GCA) associated or not withPolymyalgia Rheumatica(PMR), Takayasu). Materials and methods : The MEDLINE,Cochrane Library, Embase were searched for relevant original articlesdescribing FDG-PET for vasculitis assessment, using MesH terms ("GiantCell Arteritis or Vasculitis" AND "PET"). Criteria for inclusionwere:(1)FDG-PET for diagnosis of vasculitis(2)American College of Rheumatologycriteria as reference standard(3)control group. After data extraction, analyseswere performed using a random-effects model. Results : Of 184 citations(database search and references screening),70 articles were reviewed of which12 eligible studies were extracted (sensitivity range from 32% to 97%). 7studies fulfilled all inclusion criteria. Owing to overlapping population, 1study was excluded. Statistical heterogeneity justified the random-effectsmodel. Pooled 6 studies analysis(116 vasculitis,224 controls) showed a 81%sensitivity (95%CI:70-89%);a 89% specificity (95%CI:77-95%);a 85%PPV(95%CI:63-95%); a 90% NPV(95%CI:79-95%);a 7.1 positive LR(95%CI:3.4-14.9); a0.2 negative LR(95%CI:0.14-0.35) and 90.1 DOR(95%CI: 18.6-437). Conclusion :FDG-PET has good diagnostic performances in the detection of large vesselsvasculitis. Its promising role could be extended to follow up patients undertreatment, but further studies are needed to confirm this possibility.

AssociationViewer: a scalable and integrated software tool for visualization of large-scale variation data in genomic context.

SUMMARY: We present a tool designed for visualization of large-scale genetic and genomic data exemplified by results from genome-wide association studies. This software provides an integrated framework to facilitate the interpretation of SNP association studies in genomic context. Gene annotations can be retrieved from Ensembl, linkage disequilibrium data downloaded from HapMap and custom data imported in BED or WIG format. AssociationViewer integrates functionalities that enable the aggregation or intersection of data tracks. It implements an efficient cache system and allows the display of several, very large-scale genomic datasets. AVAILABILITY: The Java code for AssociationViewer is distributed under the GNU General Public Licence and has been tested on Microsoft Windows XP, MacOSX and GNU/Linux operating systems. It is available from the SourceForge repository. This also includes Java webstart, documentation and example datafiles.

Large TCR diversity of virus-specific CD8 T cells provides the mechanistic basis for massive TCR renewal after antigen exposure.

Ex vivo analysis of virus-specific CD8 T cell populations by anchored PCR has shown that the CD8 TCR repertoire was less oligoclonal (seven to nine clonotypes per individual epitope) than previously thought. In the current study, TCR diversity was investigated by assessing both the overall TCR β-chain variable regions usage as well as the CDR3 regions in ex vivo-isolated CMV- and EBV-specific CD8 T cells from 27 healthy donors. The average number of clonotypes specific to most single viral epitopes comprised between 14 and 77. Changes in the CD8 TCR repertoire were also longitudinally assessed under conditions of HIV-1 chronic infection (i.e., in patients with suppressed virus replication and after treatment interruption and Ag re-exposure). The results showed that a large renewal (≤80%) of the TRB repertoire occurred after Ag re-exposure and was eventually associated with an increased T cell recognition functional avidity. These results demonstrate that the global CD8 TCR repertoire is much more diverse (≤9-fold) than previously estimated and provide the mechanistic basis for supporting massive repertoire renewal during chronic virus infection and Ag re-exposure.

Creating large and accurate mosaics of the mid-atlantic ridge

We present an approach for creating image mosaics using navigation data consisting on 3D position estimates provided by sensors such as LBL available in deep water surveys. A central issue with acoustic 3D positioning is that the accuracy is far too low compositing the images within reasonable accuracy

Integrated Analysis of High-Resolution Gene Expression and Copy Number Profiling Identified Biallelic Deletion of CDKN2A/2B Tumor Suppressor Locus As the Most Frequent and Unique Genomic Abnormality in Diffuse Large B-Cell Lymphoma (DLBCL) with Strong Prognostic Value in Both GCB and ABC Subtypes and Not Overcome by a Dose-Intensive Immunochemotherapy Regimen Plus Rituximab. Results of a Prospective GELA Clinical Trial Program

Background and aim of the study: Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods: Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results: A total of 1363 recurrent (defined by a penetrance > 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL...), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1...) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR < 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value < 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32-61] respectively vs. 74% [66-82] for patients in germline configuration; 4y OS = 53% [39-72] vs 83% [76-90]). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1-3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4-4.1], p = 0.001) and GCB status (HR = 1.3 [0.8-2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29-63] vs. 66% [55-78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28-84] vs. 83% [74-92], p=0.003), and in GCB (4y PFS = 50% [27-93] vs. 81% [73-90], p=0.02), or ABC/unclassified (5y PFS = 42% [28-61] vs. 67% [55-82] p = 0.009) molecular subtypes (Figure 1). Conclusion: We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches.

The effects of physiologically plausible connectivity structure on local and global dynamics in large scale brain models.

Functionally relevant large scale brain dynamics operates within the framework imposed by anatomical connectivity and time delays due to finite transmission speeds. To gain insight on the reliability and comparability of large scale brain network simulations, we investigate the effects of variations in the anatomical connectivity. Two different sets of detailed global connectivity structures are explored, the first extracted from the CoCoMac database and rescaled to the spatial extent of the human brain, the second derived from white-matter tractography applied to diffusion spectrum imaging (DSI) for a human subject. We use the combination of graph theoretical measures of the connection matrices and numerical simulations to explicate the importance of both connectivity strength and delays in shaping dynamic behaviour. Our results demonstrate that the brain dynamics derived from the CoCoMac database are more complex and biologically more realistic than the one based on the DSI database. We propose that the reason for this difference is the absence of directed weights in the DSI connectivity matrix.

VLA multifrequency observations of RSCVn binaries

We present multiepoch Very Large Array (VLA) observations at 1.4 GHz, 4.9 GHz, 8.5 GHz and 14.9 GHz for a sample of eight RS CVn binary systems. Circular polarization measurements of these systems are also reported. Most of the fluxes observed are consistent with incoherent emission from mildly relativistic electrons. Several systems show an increase of the degree of circular polarization with increasing frequency in the optically thin regime, in conflict with predictions by gyrosynchrotron models. We observed a reversal in the sense of circular polarization with increasing frequency in three non-eclipsing systems: EI Eri, DM Uma and HD 8358. We find clear evidence for coherent plasma emission at 1.4 GHz in the quiescent spectrum of HD 8358 during the helicity reversal. The degrees of polarization of the other two systems could also be accounted for by a coherent emission process. The observations of ER Vul revealed two U-shaped flux spectra at the highest frequencies. The U-shape of the spectra may be accounted for by an optically thin gyrosynchrotron source for the low frequency part whereas the high frequency part is dominated by a thermal emission component.

The Coordinated Radio and Infrared Survey for High-Mass Star Formation (The CORNISH Survey). I. Survey Design

We describe the motivation, design, and implementation of the CORNISH survey, an arcsecondresolution radio continuum survey of the inner galactic plane at 5 GHz using the Very Large Array (VLA). It is a blind survey coordinated with the northern SpitzerGLIMPSE I region covering 10°

Faint arc-minute extended radio emission around Cygnus X-3

Aims.We revisit the vicinity of the microquasar Cygnus X-3 at radio wavelengths. We aim to improve our previous search for possible associated extended radio features/hot spots in the position angle of the Cygnus X-3 relativistic jets focusing on shorter angular scales than previously explored. Methods.Our work is mostly based on analyzing modern survey and archive radio data, mainly including observations carried out with the Very Large Array and the Ryle Telescopes. We also used deep near-infrared images that we obtained in 2005. Results.We present new radio maps of the Cygnus X-3 field computed after combining multi-configuration Very Large Array archive data at 6 cm and different observing runs at 2 cm with the Ryle Telescope. These are probably among the deepest radio images of Cygnus X-3 reported to date at cm wavelengths. Both interferometers reveal an extended radio feature within a few arc-minutes of the microquasar position, thus making our detection more credible. Moreover, this extended emission is possibly non-thermal, although this point still needs confirmation. Its physical connection with the microquasar is tentatively considered under different physical scenarios. We also report on the serendipitous discovery of a likely Fanaroff-Riley type II radio galaxy only away from Cygnus X-3.

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury.

BACKGROUND: After peripheral nerve injury, spontaneous ectopic activity arising from the peripheral axons plays an important role in inducing central sensitization and neuropathic pain. Recent evidence indicates that activation of spinal cord microglia also contributes to the development of neuropathic pain. In particular, activation of p38 mitogen-activated protein kinase (MAPK) in spinal microglia is required for the development of mechanical allodynia. However, activity-dependent activation of microglia after nerve injury has not been fully addressed. To determine whether spontaneous activity from C- or A-fibers is required for microglial activation, we used resiniferatoxin (RTX) to block the conduction of transient receptor potential vanilloid subtype 1 (TRPV1) positive fibers (mostly C- and Adelta-fibers) and bupivacaine microspheres to block all fibers of the sciatic nerve in rats before spared nerve injury (SNI), and observed spinal microglial changes 2 days later. RESULTS: SNI induced robust mechanical allodynia and p38 activation in spinal microglia. SNI also induced marked cell proliferation in the spinal cord, and all the proliferating cells (BrdU+) were microglia (Iba1+). Bupivacaine induced a complete sensory and motor blockade and also significantly inhibited p38 activation and microglial proliferation in the spinal cord. In contrast, and although it produced an efficient nociceptive block, RTX failed to inhibit p38 activation and microglial proliferation in the spinal cord. CONCLUSION: (1) Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers) is not enough to prevent nerve injury-induced spinal microglial activation. (2) Peripheral input from large myelinated fibers is important for microglial activation. (3) Microglial activation is associated with mechanical allodynia.

Diffuse large B-cell lymphoma of Waldeyer's ring has distinct clinicopathologic features: a GELA study.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.

Large calcite and bulk-rock volume loss in metacarbonate xenoliths from the Qu,rigut massif (French Pyrenees)

Chemical mass transfer was quantified in a metacarbonate xenolith enclosed within the granodiorite of the Qu,rigut massif (Pyrenees, France). Mass balance calculations suggest a strong decrease of CaO, SrO and CO(2) contents (up to -90%), correlated with a decrease of modal calcite content as the contact is approached. Most other chemical elements behave immobile during metasomatism. They are therefore passively enriched. Only a small increase of SiO(2), Al(2)O(3) and Fe(2)O(3) contents occurs in the immediate vicinity of the contact. Hence, in this study, skarn formation is characterized by the lack of large chemical element influx from the granitoid protolith. A large decrease of the initial carbonate volume (up to -86%) resulted from a combination of decarbonation reactions and loss of CaO and CO(2). The resulting volume change has potentially important consequences for the interpretation of stable isotope profiles: the isotope alteration could have occured over greater distances than those observed today.