Analysis of the copy number profiles of several tumor samples from the same patient reveals the successive steps in tumorigenesis

We present a computational method, TuMult, for reconstructing the sequence of copy number changes driving carcinogenesis, based on the analysis of several tumor samples from the same patient. We demonstrate the reliability of the method with simulated data, and describe applications to three different cancers, showing that TuMult is a valuable tool for the establishment of clonal relationships between tumor samples and the identification of chromosome aberrations occurring at crucial steps in cancer progression

Inclusive 2H(3He,t) reaction at 2 GeV

The inclusive 2H(3He,t) reaction has been studied at 2 GeV for energy transfers up to 500 MeV and scattering angles from 0.25 up to 4 degrees. Data are well reproduced by a model based on a coupled-channel approach for describing the NN and N Delta systems. The effect of final state interaction is important in the low energy part of the spectra. In the delta region, the cross-section is very sensitive to the effects of Delta-N interaction and Delta N - NN process. The latter has also a large influence well below the pion threshold. The calculation underestimates the experimental cross-section between the quasi-elastic and the delta peaks; this is possibly due to projectile excitation or purely mesonic exchange currents.Comment: 9 pages, 9 figures, accepted for publication in EPJ

Reaction ⁶Li(p, Δ⁺⁺)⁶He At 1.04 GeV And The Δ−N Interaction

The reaction ⁶Li(p, Δ⁺⁺)⁶He has been studied at 1.04 GeV for transferred momenta ranging from 0.11 to 0.35 (GeV/c)2. An exponential decrease of the cross section is observed. A Glauber-type calculation is presented. The possibility of extracting information on σ(ΔN) and α(ΔN) is discussed

A comprehensive modular map of molecular interactions in RB/E2F pathway

We present, here, a detailed and curated map of molecular interactions taking place in the regulation of the cell cycle by the retinoblastoma protein (RB/RB1). Deregulations and/or mutations in this pathway are observed in most human cancers. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner 3.5 software and converted into BioPAX 2.0 pathway description format. In the current state the map contains 78 proteins, 176 genes, 99 protein complexes, 208 distinct chemical species and 165 chemical reactions. Overall, the map recapitulates biological facts from approximately 350 publications annotated in the diagram. The network contains more details about RB/E2F interaction network than existing large-scale pathway databases. Structural analysis of the interaction network revealed a modular organization of the network, which was used to elaborate a more summarized, higher-level representation of RB/E2F network. The simplification of complex networks opens the road for creating realistic computational models of this regulatory pathway

Low E-cadherin expression in bladder cancer at the transcriptional and protein level provides prognostic information

We studied E-cadherin down-regulation at the protein level in frozen sections of 111 bladder tumours and 13 normal bladder specimens by means of immunohistochemistry, and at the mRNA level by semi-quantitative RT-PCR in 40 of the same tumours. Results indicate that E-cadherin expression detected by immunohistochemistry correlated with both stage and grade (P< 0.0001 and P< 0.001, respectively). Analysis of recurrence, progression and survival over a mean period of 36 months after surgery in the entire cohort showed that abnormal E-cadherin immunoreactivity correlated strongly with poor outcome (log-rank test: P = 0.001, P = 0.0001 and P = 0.0003, respectively). In multistep logistic regression analysis, only E-cadherin status and stage had significant additional prognostic value (P = 0.008 and OR = 0.2;P = 0.03 and OR = 3.6, respectively). Survival estimates derived from RT-PCR transcript quantification differed significantly for low and high expression (log-rank test: P = 0.0006). These results suggest that the alteration occurs at the transcriptional level and support the clinical and biological relevance of cell adhesion molecules in bladder cancer. © 2000 Cancer Research Campaig

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na$^{+}$]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na$^{+}$]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na$^{+}$] on FGF23 production. Here, we show that an elevated [Na$^{+}$] (+20 mM) suppressed FGF23 formation, whereas low [Na$^{+}$] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na$^{+}$], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na$^{+}$]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na$^{+}$] is a critical regulator of FGF23 synthesis

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis

Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation. Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs. Results: CD8+BTLA? TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA? T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR