J. Rubenstein

Bio: J. Rubenstein is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Gene expression profiling & B cell. The author has an hindex of 1, co-authored 1 publications receiving 135 citations.

Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell

Abstract: To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.

Age, gender, and racial differences in incidence and survival in primary CNS lymphoma

Abstract: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma that accounts for ∼4% of newly diagnosed central nervous system (CNS) tumours. The objective of this study was to analyse the epidemiology, incidence, and outcome of these rare tumours. Primary brain and CNS lymphoma cases were identified from the Surveillance, Epidemiology, and End Results (SEER) research data sets for the years 1980–2008 for analysis of trends in incidence and survival. SEER*Stat v. 7.0.4 software was used to analyse the data. The overall incidence rate of PCNSL was 0.47 per 100 000 person-years. The incidence was significantly higher in males compared with females, blacks aged 0–49 years at diagnosis compared with whites, and whites aged 50 years and older at diagnosis compared with blacks. After a significant decline in incidence between 1995 and 1999, incidence rates rose slightly; those aged 75+ years at diagnosis had the most dramatic increase in incidence rates over time. Five-year survival rates were significantly higher in whites compared with blacks aged 0–49 years at diagnosis, but was primarily driven by white women aged 0–49 years. There is an increase in incidence of PCNSL in the elderly, and elderly blacks have lower incidence compared with white population. Survival remains poor and is negatively dominated by factors associated with HIV infection and advanced age.

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Abstract: Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design:We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single nucleotide polymorphism (SNPa) arrays (n=29) and whole-exome sequencing (n=4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by real time quantitative polymerase chain reaction and Sanger sequencing respectively. Molecular results were correlated with prognosis. Results:All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. SNPa analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus); (ii) 6q loss; (iii) CDKN2A homozygous deletions; (iv) 12q12-q22; (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (p=0.006 and p=0.01), and CDKN2A homozygous deletion (p=0.02 and p=0.01) were significantly associated with shorter progression free survival and overall survival. Conclusions:Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NFkB signaling pathway, that may be promising targets for future therapeutic strategies.

Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder

Abstract: Schizophrenia and bipolar disorder share a number of common features, both symptomatically and biologically. Abnormalities in the neuroimmune and the stress-signaling pathways have been previously identified in brains of individuals with both diseases. However, the possible relationship between abnormalities in stress and neuroimmune signaling within the cortex of people with psychotic illness has not been defined. To test the hypothesis that combined alterations in brain stress responsiveness and neuroimmune/inflammatory status are characteristic of some individuals suffering from major mental illness, we examined gene expression in the Stanley Array Cohort of 35 controls, 35 individuals with schizophrenia and 34 individuals with bipolar disorder. We used levels of 8 inflammatory-related transcripts, of which SERPINA3 was significantly elevated in individuals with schizophrenia (F(2,88)=4.137, P<0.05), and 12 glucocorticoid receptor signaling (stress) pathway transcripts previously examined, to identify two clusters of individuals: a high inflammation/stress group (n=32) and a low (n=68) inflammation/stress group. The high inflammation/stress group has a significantly greater number of individuals with schizophrenia (n=15), and a trend toward having more bipolar disorder individuals (n=11), when compared with controls (n=6). Using these subgroups, we tested which microarray-assessed transcriptional changes may be associated with high inflammatory/stress groups using ingenuity analysis and found that an extended network of gene expression changes involving immune, growth factors, inhibitory signaling and cell death factors also distinguished these groups. Our work demonstrates that some of the heterogeneity in schizophrenia and bipolar disorder may be partially explained by inflammation/stress interactions, and that this biological subtype cuts across Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined categories.

Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma

Abstract: Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL.