An age-based, RNA expression paradigm for survival biomarker identification for pediatric neuroblastoma and acute lymphoblastic leukemia

Abstract Background Pediatric cancer survival rates overall have been improving, but neuroblastoma (NBL) and acute lymphoblastic leukemia (ALL), two of the more prevalent pediatric cancers, remain particularly challenging. One issue not yet fully addressed is distinctions attributable to age of diagnosis. Methods In this report, we verified a survival difference based on diagnostic age for both pediatric NBL and pediatric ALL datasets, with younger patients surviving longer for both diseases. We identified several gene expression markers that correlated with age, along a continuum, and then used a series of age-independent survival metrics to filter these initial correlations. Results For pediatric NBL, we identified 2 genes that are expressed at a higher level in lower surviving patients with an older diagnostic age; and 4 genes that are expressed at a higher level in longer surviving patients with a younger diagnostic age. For pediatric ALL, we identified 3 genes expressed at a higher level in lower surviving patients with an older diagnostic age; and 17 genes expressed at a higher level in longer surviving patients with a younger diagnostic age. Conclusions This process implicated pan-chromosome effects for chromosomes 11 and 17 in NBL; and for the X chromosome in ALL

A scoring system for the electrostatic complementarities of T-cell receptors and cancer-mutant amino acids: multi-cancer analyses of associated survival rates.

The anti-tumor immune response is considered to be due to the T-cell receptor (TCR) binding to tumor antigens, which can be either wild-type, early stem cell proteins, presumably foreign to a developed immune system; or mutant peptides, foreign to the immune system because of a mutant amino acid (aa) or otherwise somatically altered aa sequence. Recently, very large numbers of TCR complementarity-determining region-3 (CDR3) aa sequences obtained from tumor specimens have become available. We developed a novel algorithm for assessing the complementarity of tumor mutant peptides and TCR CDR3s, based on the retrieval of TCR CDR3 aa sequences from both tumor specimen and patient blood exomes and by using an automated process of assessing CDR3 and mutant aa electrical charges. Results indicated many instances where high electrostatic complementarity was associated with a higher survival rate. In particular, our approach led to the identification of specific genes contributing significantly to the complementary, TCR CDR3-mutant aa. These results suggest a novel approach to tumor immunoscoring and may lead to the identification of high-priority neo-antigen, peptide vaccines; or to the identification of ex vivo stimulants of tumor-infiltrating lymphocytes

A scoring system for the electrostatic complementarities of T‐cell receptors and cancer‐mutant amino acids: multi‐cancer analyses of associated survival rates

The anti-tumor immune response is considered to be due to the T-cell receptor (TCR) binding to tumor antigens, which can be either wild-type, early stem cell proteins, presumably foreign to a developed immune system; or mutant peptides, foreign to the immune system because of a mutant amino acid (aa) or otherwise somatically altered aa sequence. Recently, very large numbers of TCR complementarity-determining region-3 (CDR3) aa sequences obtained from tumor specimens have become available. We developed a novel algorithm for assessing the complementarity of tumor mutant peptides and TCR CDR3s, based on the retrieval of TCR CDR3 aa sequences from both tumor specimen and patient blood exomes and by using an automated process of assessing CDR3 and mutant aa electrical charges. Results indicated many instances where high electrostatic complementarity was associated with a higher survival rate. In particular, our approach led to the identification of specific genes contributing significantly to the complementary, TCR CDR3-mutant aa. These results suggest a novel approach to tumor immunoscoring and may lead to the identification of high-priority neo-antigen, peptide vaccines; or to the identification of ex vivo stimulants of tumor-infiltrating lymphocytes

Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37

Despite the essential functions of Hsp90, little is known about the mechanism that controls substrate entry into its chaperone cycle. We show that the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find that it participates in the selective recruitment of only client kinases. Cdc37 recognizes kinase specificity determinants in both clients and nonclients and acts as a general kinase scanning factor. Kinase sorting within the client-to-nonclient continuum relies on the ability of Cdc37 to challenge the conformational stability of clients by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms stable complexes through a multidomain cochaperone interface. The interaction with nonclients is not accompanied by conformational changes of the substrate and results in substrate dissociation. Collectively, Cdc37 performs a quality control of protein kinases, where induced conformational instability acts as a flag for Hsp90 dependence and stable cochaperone association

Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37

Despite the essential functions of Hsp90, little is known about the mechanism that controls substrate entry into its chaperone cycle. We show that the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find that it participates in the selective recruitment of only client kinases. Cdc37 recognizes kinase specificity determinants in both clients and nonclients and acts as a general kinase scanning factor. Kinase sorting within the client-to-nonclient continuum relies on the ability of Cdc37 to challenge the conformational stability of clients by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms stable complexes through a multidomain cochaperone interface. The interaction with nonclients is not accompanied by conformational changes of the substrate and results in substrate dissociation. Collectively, Cdc37 performs a quality control of protein kinases, where induced conformational instability acts as a flag for Hsp90 dependence and stable cochaperone association

Chemical Complementarity Between Immune Receptor CDR3s and IDH1 Mutants Correlates with Increased Survival for Lower Grade Glioma

Focusing on highly specific aspects of the immune response is likely to answer a number of basic questions, and in some cases even resolve basic contradictions, in cancer immunology. For example, there are many cases, where chronic inflammation is associated with cancer development, and many other cases where an immune response represents an anticancer process. In this study, using bioinformatics algorithms, we examined the chemical relationships between the amino acid sequences of the complementarity-determining region-3 (CDR3) represented by immune receptors associated with lower grade glioma and isocitrate dehydrogenase-1 (IDH1) mutants. In particular, we developed a chemical complementarity scoring approach to classify tumors based on the complementarity of CDR3s and mutant IDH1 amino acids, relying on net charge per residue and hydropathy parameters. There was a strong correlation between the increased survival in low-grade glioma (LGG) and complementarity of IDH1 mutants to the CDR3 domain of the T-cell receptor beta chain (TRB). Similar results were obtained for TRB CDR3s and NRAS mutants in melanoma. Furthermore, the clear connection between increased survival rates and immune receptor-IDH1 mutant complementarities may also, partially, explain the better LGG prognosis for patients with IDH1 mutants

Predicted signalase cleavage sites.

<p>Predicted signalase cleavage sites.</p

Glycosylation sites of Australian orthobunyavirus M-segment polyprotein sequences.

<p>Predicted N-glycosylation sites are indicated along the M-segment sequence by their recognition sequence and aa position. MAPV, Mapputta virus; TRUV, Trubanaman virus; BUCV, Buffalo Creek virus; MURBV, Murrumbidgee virus; GGV, Gan Gan virus; SASHV, Salt Ash virus; MPKV, Maprik virus.</p

Phylogenetic relationship of Australian Mapputta group and K10441 isolates to other selected orthobunyaviruses.

<p>Deduced amino acid sequences of the S- (N ORF; panel <b>A</b>), M- (Gn, NSm,Gc polyprotein ORF; panel <b>B</b>), and L-segment (RdRp-ORF; panel <b>C</b>) were aligned and trees reconstructed with the Neighbor-Joining method applying a Poisson substitution model as implemented in MEGA 6. Bootstrap values resulting from 1000 pseudoreplicates are indicated at the respective nodes; scale bars indicate the number of substitutions per site, and GenBank accession number and isolate name (where known) are given next to the virus name. MAPV, Mapputta virus; MPKV, Maprik virus; TRUV, Trubanaman virus; GGV, Gan Gan virus.</p

Characterized Australian orthobunyaviruses.

<p>Characterized Australian orthobunyaviruses.</p