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Loss of major histocompatibility complex class II (MHC II) expression is associated with poor patient outcome in diffuse large B-cell lymphoma (DLBCL). As MHC II molecules are lost with plasmacytic differentiation in normal cells, we asked whether MHC II loss in DLBCL is associated with an altered differentiation state. We used gene expression profiling, quantum dots, and immunohistochemistry to study the relationship between MHC II and plasma cell markers in DLBCL and plasmablastic lymphoma (PBL). Results demonstrate that MHC II(−) DLBCL immunophenotypically overlap with PBL and demonstrate an inverse correlation between MHC II and plasma cell markers MUM1, PRDM1/Blimp1, and XBP1s. In addition, MHC II expression is significantly higher in germinal center-DLBCL than activated B cell-DLBCL. A minor subset of cases with an unusual pattern of mislocalized punctate MHC II staining and intermediate levels of mRNA is also described. Finally, we show that PBL is negative for MHC II. The results imply a spectrum of MHC II expression that is more frequently diminished in tumors derived from B cells at the later stages of differentiation (with complete loss in PBL). Our observations provide a possible unifying concept that may contribute to the poor outcome reported in all MHC II(−) B-cell tumors.

BACKGROUND The PI3K/AKT/mTOR pathway is central to prostate cancer progression. A preliminary investigation of immuno-histochemical expression of mammalian target of rapamycin (mTOR) pathway markers was undertaken to identify patterns of expression in prostate tissue. METHODS Immunohistochemistry was performed on a custom-made prostate tissue array. Mean long scores and variability of long scores for each marker were recorded for normal lumenal cells, prostate intraepithelial neoplasia (PIN), and cancer. RESULTS Expression of PTEN decreased and mTOR signaling pathway markers increased in PIN and in cancer as compared to normal cells in the majority of samples. Overexpression of 4E-BP1 and p-4E-BP1 was observed in PIN and cancer. However, in cancer, the overexpression of 4E-BP1 was significantly higher than with any other marker. DISCUSSION Results suggest that 4E-BP1 overexpression is strongly associated with prostate cancer, especially when combined with PTEN and mTOR expression data. Hierarchical clustering analysis utilizing PTEN, mTOR, and 4E-BP1 separated normal from cancer cell populations in most cases. Prostate © 2006 Wiley-Liss, Inc.

White spot syndrome virus (WSSV), Taura syndrome virus (TSV), Yellow head virus (YHV), and Infectious hypodermal and hematopoietic necrosis virus (IHHNV) have caused significant economic losses of farmed penaeid shrimp worldwide. Because the presence of large numbers of seabirds at shrimp grow-out ponds may be related to disease transmission, we hypothesized that these birds may be capable of carrying infectious viral particles in their feces from affected ponds to nearby unaffected ponds, and perhaps even to nearby farms. Because of the difficulties posed by working with wild fowl in a laboratory setting, a surrogate model, employing domestic white leghorn chickens (Gallus domesticus), was developed to compare with the detection and infectivity results from captive laughing gulls (Larus atricilla). Using standard histology, PCR/RT-PCR and infectivity challenges, this study demonstrated that IHHNV and TSV remained infectious for up to 1 day following passage through both chickens and seagulls, while no viable WSSV or YHV were found following passage through the gut of either bird species. This study demonstrated that wild seabirds may serve as mechanical vectors of TSV and IHHNV by passing infectious particles to aquatic environments in their feces, and that chickens may be used as a surrogate laboratory model for seabirds in such viral infectivity tests.

While the acquisition of invasiveness is a critical step in early stage breast carcinomas (DCIS), no established molecular markers reliably identify tumor progression. The metastasis gene osteopontin is subject to alternative splicing, which yields 3 messages, osteopontin-a, osteopontin-b and osteopontin-c. Osteopontin-c is selectively expressed in invasive, but not in noninvasive, breast tumor cell lines, and it effectively supports anchorage independence. We evaluated osteopontin-c as a biomarker. The RNA message for osteopontin-c was present in 16 of 20 breast cancers (80%), but was undetectable in 22 normal specimens obtained from reduction mammoplasty. In contrast, osteopontin-a RNA was expressed at various levels in all 20 breast cancers, 11 tumor-surrounding tissues and 21 normal samples. The splice variant osteopontin-b was present at barely detectable levels in 18 of 20 cancers and in 6 of 22 normal breasts. By immunohistochemistry, 66 of 69 normal breasts were negative, while 3 showed low level staining. Among the breast cancers, 43 of 56 cores (77%) stained positive for osteopontin-c. When correlated with tumor grade, the staining for osteopontin-c increased from grade 1 to grade 3. In a total of 178 breast specimens analyzed, osteopontin-c was present in 78% of cancers, 36% of surrounding tissues and 0% of normal tissues. Furthermore, osteopontin-c detects a higher fraction of breast cancers than estrogen receptor (ER), progesterone receptor or HER2. In conjunction, osteopontin-c, ER and HER2 reliably predict grade 2-3 breast cancer. Hence, osteopontin-c is a diagnostic and prognostic marker that may have value in a diagnostic panel together with conventional breast cancer markers.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma diagnosed in the U.S. It displays marked heterogeneity, biologically and clinically, with patients demonstrating a wide range of responses to therapy. Major histocompatibility class II (MHCII) molecules are involved in antigen presentation and are vital to the immune system. Decreased MHCII expression is one of the normal changes seen as B-cells differentiate into mature, antibody-secreting plasma cells. This decrease occurs in concert with changes in other proteins and transcription factors which define the phenotype of a B- or plasma cell. Loss of MHCII expression in DLBCL patients is associated with extremely poor prognosis. In this study, we asked whether MHCII loss in DLBCL was associated with a more differentiated phenotype. We hypothesized that malignant cells from MHCII(-) DLBCL cases would be closer to the plasma cell end of the differentiation spectrum than MHCII(+) cases. We previously used a 40-case tissue microarray to demonstrate that although MHCII(-) DLBCL cases did not present a fully plasma cell differentiated phenotype, protein expression of the late B-cell marker, MUM1/IRF4, was inversely associated with MHCII, suggesting that MHCII loss may be associated with cases further along the differentiation continuum (Wilkinson, AACR 2009). Here, we built upon this work using immunohistochemistry (IHC) to score expression of a panel of B- and plasma cell markers. These included B-cell transcription factors Oct2, Bob 1, Pax5 and mature B-cell surface marker CD20 as well as plasma cell markers XBP1, BLIMP1, and CD138. IHC results were semi-quantitatively assessed by scoring both frequency and intensity of staining. The results were compared to MHCII expression as previously determined with gene expression profiling and IHC. Using this routine IHC assessment, the presence of plasma cell markers XBP1, BLIMP1, or CD138 did not correlate with low or absent expression of MHCII, while the B-cell markers were present in most cases. Thus, no clear evidence of a more differentiated phenotype was observed in MHCII(-) DLBCL. These findings could result from lack of association between loss of MHCII expression and plasma cell differentiation or the limitations of the methodology used. To further investigate this question, we have developed protocols with QdotsR (Life Technologies) to more accurately quantify expression of the plasma cell-associated proteins relative to MHCII. By using nanocrystals with narrow emission spectra coupled to monoclonal antibodies, multiple colors can be visualized and specifically measured in each cell. This technique may yield more accurate, quantitative data regarding protein expression of plasma cell markers and MHCII. The results of these studies should lead to a better understanding of MHCII expression in DLBCL with possible implications for therapeutic targeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1769.