Molecular Signature in HCV-Positive Lymphomas

Hepatitis C virus (HCV) is a positive, single-stranded RNA virus, which has been associated to different subtypes of B-cell non-Hodgkin lymphoma (B-NHL). Cumulative evidence suggests an HCV-related antigen driven process in the B-NHL development. The underlying molecular signature associated to HCV-related B-NHL has to date remained obscure. In this review, we discuss the recent developments in this field with a special mention to different sets of genes whose expression is associated with BCR coupled to Blys signaling which in turn was found to be linked to B-cell maturation stages and NF-κb transcription factor. Even if recent progress on HCV-B-NHL signature has been made, the precise relationship between HCV and lymphoma development and phenotype signature remain to be clarified

Antibody Vh Repertoire Differences between Resolving and Chronically Evolving Hepatitis C Virus Infections

Despite the production of neutralizing antibodies to hepatitis C virus (HCV), many patients fail to clear the virus and instead develop chronic infection and long-term complications. To understand how HCV infection perturbs the antibody repertoire and to identify molecular features of antibody genes associated with either viral clearance or chronic infection, we sequenced the V(D)J region of naïve and memory B cells of 6 persons who spontaneously resolved an HCV infection (SR), 9 patients with a newly diagnosed chronically evolving infection (CE), and 7 healthy donors. In both naïve and memory B cells, the frequency of use of particular antibody gene subfamilies and segments varied among the three clinical groups, especially between SR and CE. Compared to CE, SR antibody genes used fewer VH, D and JH gene segments in naïve B cells and fewer VH segments in memory B cells. SR and CE groups significantly differed in the frequency of use of 7 gene segments in naïve B cell clones and 3 gene segments in memory clones. The nucleotide mutation rates were similar among groups, but the pattern of replacement and silent mutations in memory B cell clones indicated greater antigen selection in SR than CE. Greater clonal evolution of SR than CE memory B cells was revealed by analysis of phylogenetic trees and CDR3 lengths. Pauciclonality of the peripheral memory B cell population is a distinguishing feature of persons who spontaneously resolved an HCV infection. This finding, previously considered characteristic only of patients with HCV-associated lymphoproliferative disorders, suggests that the B cell clones potentially involved in clearance of the virus may also be those susceptible to abnormal expansion

“Gli aspetti innovativi dell’informativa finanziaria nelle “entità” del settore pubblico: gli IPSAS 5, 15, 18, 19 e 21”

Per il citato lavoro, che rappresenta un contributo alla ricerca della Scuola Superiore della Pubblica Amministrazione “Principi e metodi di contabilità economico-patrimoniale per lo Stato e le Pubbliche Amministrazioni nel quadro teorico ed operativo internazionale” (coordinatore Prof. L. Anselmi, anni 2007/2008), sono stati assolti gli obblighi di pubblicazione direttamente dall’autore, ai sensi della Legge 15.4.2006 n. 106 e del D.P.R. 03.05.2006, n. 252

Identification of new major histocompatibility complex‐A, ‐B, ‐C alleles in chimpanzees (Pan troglodytes)

Two new Patr-A, five new Patr-B and three new Patr-C alleles from Pan troglodytes are described

Description of two new major histocompatibility complex (MHC) class II DRB1 [Pan troglodytes (Patr)-DRB1] alleles

Sequence-based typing strategy is used to identify polymorphism of Patr-DRB1. Two new Patr-DRB1 are described

Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families

Common mutations in immunoglobulin VK3 light chain sequences from B-cells of HCV-related disorders

It has been proposed that persistent HCV infection drives the proliferation of B cells through an antigen-selective stimulation, mediated by B-cell receptor (BCR) involvement that preferentially includes a IgL Vk-3 chain. The aim of this study is to characterize IgL Vk rearrangements from different setting of HCV-related disorders to investigate if there is a preferential subset of BCR repertoire among 5 clinical groups. 26 HCV+ve patients (HBV-ve; HIV-ve) were studied: 2 MC, 12 NHL without clinical manifestation of MC, 6 HCV spontaneously resolved (SR), 6 HCV chronic infected (CE). Six blood donors (BD) were used as controls. VK3 gene region was amplified using VK3 specific and a mixture of JK primers. In the present study VK3-20, VK3-15 and VK3-11 subfamilies were the most represented (>90% of total clones). IGKV3-15 gene was over represented in both NHL and MC groups (67%) vs CE+SR+BD (22%, p<0.001). IGKV3-20 gene was the most represented gene in BD and IGKV3-11 in CE, SR. An higher mutation frequency was detected both in BD (media of mutations 2,62%) and NHL (2,41%) with respect to CE (2,04%), MC (1,75%) and SR (1,55%) groups. The higher and the lower levels of R mutations were detected in SR, respectively in FR1 region (1,52%) and in the CDR2 (0,06%). Both in FR1 and FR2, the R:S ratio of SR was the highest (35%), in CDR2 was the lowest (1,5%). In FR3 and in CDR1 the R:S ratio was similar between groups, while in CDR2 BD had the highest value (10,5%). Multiple alignments of amino acid sequences obtained (472 clones) were carried to produce a consensus sequence Data highlighted that FR2 and CDR2 VK3-regions were conserved in all the 5 groups. FR1, CDR1 and CDR3 were commonly shared by CE, SR and BD. FR3 distinguish SR from these other groups in the in the first residue (Thr vs Asn). MC and NHL shared a consensus sequence among them that was more similar to VK3-15 chain mainly in the hypervariable CDR3 (Asn93), FR1 (Val13) and FR3 (Thr54, Glu71; Gln80 and Ser81) regions. In addition, Asn residue in pos32 in MC and in pos33 in NHL, distinguishes MC from NHL in CDR1. A 3D structural modelling is now in course to evaluate the potential impact on antibody-HCV antigen interactions (Leukemia, 2006). In conclusion we described common mutations in HCV-related lymphoproliferative diseases that should be useful to corroborate the molecular insights of HCV outcomes and to better define targets for potential anti-idiotype therapeutic approaches

Use of Metabolomics as a Complementary Omic Approach to Implement Risk Criteria for First-Degree Relatives of Gastric Cancer Patients

A positive family history is a strong and consistently reported risk factor for gastric cancer (GC). So far, it has been demonstrated that serum pepsinogens (PGs), and gastrin 17 (G17) are useful for screening individuals at elevated risk to develop atrophic gastritis but they are suboptimal biomarkers to screen individuals for GC. The main purpose of this study was to investigate serum metabolomic profiles to find additional biomarkers that could be integrated with serum PGs and G17 to improve the diagnosis of GC and the selection of first-degree relatives (FDR) at higher risk of GC development. Serum metabolomic profiles included 188 serum metabolites, covering amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexoses. Serum metabolomic profiles were performed with tandem mass spectrometry using the Biocrates AbsoluteIDQ p180 kit. The initial cohort (training set) consisted of n = 49 GC patients and n = 37 FDR. Differential metabolomic signatures among the two groups were investigated by univariate and multivariate partial least square differential analysis. The most significant metabolites were further selected and validated in an independent group of n = 22 GC patients and n = 17 FDR (validation set). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic power and the optimal cut-off for each of the discriminant markers. Multivariate analysis was applied to associate the selected serum metabolites, PGs, G17 and risk factors such as age, gender and Helicobacter pylori (H. pylori) infection with the GC and FDR has been performed and an integrative risk prediction algorithm was developed. In the training set, 40 metabolites mainly belonging to phospholipids and acylcarnitines classes were differentially expressed between GC and FDR. Out of these 40 metabolites, 9 were further confirmed in the validation set. Compared with FDR, GC patients were characterized by lower levels of hydroxylated sphingomyelins (SM(OH)22:1, SM(OH)22:2, SM(OH)24:1) and phosphatidylcholines (PC ae 40:1, PC ae 42:2, PC ae 42:3) and by higher levels of acylcarnitines derivatives (C2, C16, C18:1). The specificity and sensitivity of the integrative risk prediction analysis of metabolites for GC was 73.47% and 83.78% respectively with an area under the curve of the ROC curve of 0.811 that improves to 0.90 when metabolites were integrated with the serum PGs. The predictive risk algorithm composed of the C16, SM(OH)22:1 and PG-II serum levels according to the age of individuals, could be used to stratify FDR at high risk of GC development, and then this can be addressed with diagnostic gastroscopy

A new mutation of the CDH1 gene in a patient with an aggressive signet-ring cell carcinoma of the stomach

Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs E-cadherin to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment