Mouse Anti-Human B2M Hybridoma [M479]

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor kappa B pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.

Objective: Little or no evidence is available on the impact of the first peritonitis episode on peritoneal transport characteristics. The objective of this study was to investigate the importance of the very first peritonitis episode and distinguish its effect from the natural course by comparison of peritoneal transport before and after infection. Participants: We analyzed prospectively collected data from 541 incident peritoneal dialysis (PD) patients, aged > 18 years, between 1990 and 2010. Standard Peritoneal Permeability Analyses (SPA) within the year before and within the year after (but not within 30 days) the first peritonitis were compared. In a control group without peritonitis, SPAs within the first and second year of PD were compared. Main outcome measurements: SPA data included the mass transfer area coefficient of creatinine, glucose absorption and peritoneal clearances of beta-2-microglobulin (b2m), albumin, IgG and alpha-2-macroglobulin (a2m). From these clearances, the restriction coefficient to macromolecules (RC) was calculated. Also, parameters of fluid transport were determined: transcapillary ultrafiltration rate (TCUFR), lymphatic absorption (ELAR), and free water transport. Crude and adjusted linear mixed models were used to compare the slopes of peritoneal transport parameters in the peritonitis group to the control group. Adjustments were made for age, sex and diabetes. Results: Of 541 patients, 367 experienced a first peritonitis episode within a median time of 12 months after the start of PD. Of these, 92 peritonitis episodes were preceded and followed by a SPA within one year. Forty-five patients without peritonitis were included in the control group. Logistic reasons (peritonitis group: 48% vs control group: 83%) and switch to hemodialysis (peritonitis group: 22% vs control group: 3%) were the main causes of missing SPA data post-peritonitis and post-control. When comparing the slopes of peritoneal transport parameters in the peritonitis group and the control group, a first peritonitis episode was associated with faster small solute transport (glucose absorption, p = 0.03) and a concomitant lower TCUFR (p = 0.03). In addition, a discreet decrease in macromolecular transport was seen in the peritonitis group: mean difference in post-and pre-peritonitis values: IgG: -8 mu L/min (p = 0.01), a2m: -4 mu L/min (p = 0.02), albumin: -10 mu L/min (p = 0.04). Accordingly, the RC to macromolecules increased after peritonitis: 0.09, p = 0.04. Conclusions: The very first peritonitis episode alters the natural course of peritoneal membrane characteristics. The most likely explanation might be that cured peritoneal infection later causes long-lasting alterations in peritoneal transport state.