ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas. The mutation is associated with loss of protein expression as assessed by immunohistochemistry. In this study, we evaluated ARID1A immunoreactivity in a wide variety of carcinomas in order to determine the prevalence of ARID1A inactivation in carcinomas; mutational analysis of ARID1A was performed in selected cases. Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors. Uterine low-grade endometrioid carcinomas demonstrated a relatively high frequency of loss of ARID1A expression, as 15 (26%) of 58 cases were negative. The other tumor that had a relatively high frequency loss of ARID1A expression was gastric carcinoma (11%). Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinoma, none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. All mutations in endometrioid carcinomas were nonsense or insertion/ deletion mutations and tumors with ARID1A mutations demonstrated complete loss or clonal loss of ARID1A expression. In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high frequency of loss of expression and mutation of ARID1A.

The effector functions of CD8+ T cells are influenced by tissue inflammatory microenvironments. IL-33, a member of the IL-1 family, acts as a danger signal after its release during cell necrosis. The IL-33/ST2 axis has been implicated in various Th2 responses. Its role in CD8+ T cell-mediated immune response is, however, not known. Here we find that type 1 cytotoxic T (Tc1) cells cultured in vitro unexpectedly express high levels of the IL-33 receptor ST2. Interestingly, the expression of ST2 in Tc1 cells is dependent on T-bet, a master Th1/Tc1 transcription factor. In addition, IL-33 enhances TCR-triggered IFN-γ production. IL-33 together with IL-12 can stimulate IFN-γ production in Tc1 cells. Moreover, IL-33 synergizes with IL-12 to promote CD8+ T cell effector function. The synergistic effect of IL-33 and IL-12 is partly mediated by Gadd45b. Together, these in vitro data establish a novel role of IL-33 in promoting effector type 1 adaptive immune responses.

Presenilin-1 (PS1) and presenilin 2 (PS2) are proposed to be transmembrane aspartyl proteases that cleave amyloid precursor protein and Notch. PS1-and PS2-mediated activities were individually characterized using blastocyst-derived (BD) cells and membranes from PS1 ؉/؊ -PS2 ؊/؊ and PS1 PS2؉/؉ mice, respectively. The relative amounts of PS1 and PS2 in the various BD cells were determined from the intensities of the anti-PS1 and anti-PS2 immunoblot signals by comparison with standard curves using radiolabeled PS1 and PS2 standards produced by in vitro transcription and translation. Cellular membranes from wild type, PS1, and PS1 PS2؊/؊ BD cells generated the A␤40 and A␤42 products from the C100FLAG substrate. PS1-associated ␥-secretase displays considerably higher specific activity than PS2-associated ␥-secretase. Moreover, the PS1 PS2؊/؊ BD cells and corresponding membranes exhibited much higher ␥-secretase activity as compared with other BD cells and membranes. The PS1-mediated ␥-secretase activity correlated better with the amount of PS1 that is modifiable by a photoactivated active sitedirected ␥-secretase inhibitor rather than total PS1; hence, only a small portion (<14%) of the PS1 in wild-type membranes appears to be engaged in an active ␥-secretase complex. This finding suggests that PS1 may serve other biological functions in addition to that associated with its ␥-secretase activity. Furthermore, the PS1 ␥-secretase complex and the PS2 ␥-secretase complex activities can be discriminated on the basis of their susceptibility to inhibition by a potent ␥-secretase inhibitor. The distinct yet overlapping enzymatic properties of the PS1 ␥-secretase complex and the PS2 ␥-secretase complex imply that these two putative aspartyl class proteases may contribute to different biological processes.

Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/08/16/jimmunol.100074

Introduction. The purpose of this review is to compare and contrast the values, purpose, processes, and outcomes of human-centered design (HCD) and community-based participatory research (CBPR) approaches to address public health issues and to provide recommendations for how HCD can be incorporated into CBPR partnerships and projects. Review Process. By consulting published literature, source materials, and experts on both approaches, a team of researchers completed a three-phased process of synthesizing key similarities and differences between HCD and CBPR and generating recommendations for ways to integrate HCD strategies in CBPR projects. Results. There are five HCD strategies that can be readily incorporated into CBPR projects to improve outcomes: (1) form transdisciplinary teams, (2) center empathy, (3) recruit and work with “extreme users,” (4) rapidly prototype, and (5) create tangible products or services. Conclusions. Integrating HCD in CBPR projects may lead to solutions that potentially have greater reach, are more readily adopted, are more effective, and add innovation to public health services, products, and policies.