Objective The principal objective of this investigation was to identify novel cytokine associations with body mass index and Type 2 diabetes. Methods Cytokines were profiled from African American women with obesity who donated plasma to the Komen Tissue Bank. Multiplex bead arrays of analytes were used to quantify 88 cytokines and chemokines in association with clinical diagnoses of metabolic health. Regression models were generated after elimination of outliers. Results Among women with obesity, Type 2 diabetes was associated with breast adipocyte hypertrophy and with six plasma analytes, including four chemokines: chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 16 (CCL16), chemokine (C-X-C motif) ligand 1 (GRO-1) and chemokine (C-X-C motif) ligand 16 (CXCL16); and two growth factors: interleukin-2 and epidermal growth factor. In addition, three analytes were associated with obesity independently of diabetes: interleukin-4, soluble CD40 ligand and chemokine (C-C motif) ligand 3 (CCL3). Conclusions Profiling of inflammatory cytokines combined with measures of body mass index may produce a more personalized risk assessment for obesity-associated disease in African American women.

The size distribution of adipocytes in fat tissue provides important information about metabolic status and overall health of patients. Histological measurements of biopsied adipose tissue can reveal cardiovascular and/or cancer risks, to complement typical prognosis parameters such as body mass index, hypertension or diabetes. Yet, current methods for adipocyte quantification are problematic and insufficient. Methods such as hand-tracing are tedious and time-consuming, ellipse approximation lacks precision, and fully automated methods have not proven reliable. A semi-automated method fills the gap in goal-directed computational algorithms, specifically for high-throughput adipocyte quantification. Here, we design and develop a tool, AdipoCyze, which incorporates a novel semi-automated tracing algorithm, along with benchmark methods, and use breast histological images from the Komen for the Cure Foundation to assess utility. Speed and precision of the new approach are superior to conventional methods and accuracy is comparable, suggesting a viable option to quantify adipocytes, while increasing user flexibility. This platform is the first to provide multiple methods of quantification in a single tool. Widespread laboratory and clinical use of this program may enhance productivity and performance, and yield insight into patient metabolism, which may help evaluate risks for breast cancer progression in patients with comorbidities of obesity.

Background: Bromodomain-containing coregulators of transcription have been identified recently as new epigenetic targets to treat a variety of hematologic malignancies, including acute myeloid leukemias. However, the bromodomain mechanisms that couple histone acetylation to transcription in lymphopoiesis, and that govern mature lymphocyte responsiveness to growth signals, are only partly understood. Brd2 is a transcriptional co-regulator that contains dual Bromodomains and an ExtraTerminal domain (defining the BET family) that couples chromatin modification to cell cycle progression. We previously reported the first functional characterization of a BET protein as an effector of mammalian mitogenic signal transduction: Eμ-Brd2 transgenic mice develop an ‘activated B cell’ type of diffuse large B cell lymphoma. There have been no other animal models reported for genetic or lentiviral expression of BET proteins, which hampers testing of novel anticancer drugs such as JQ1 and its derivatives. Methods: Here we use Brd2 lentivirus transduction of hematopoietic stem cells and reconstitution of lethally irradiated recipient mice to examine the function of Brd2 in hematopoiesis in the bone marrow and mitogenesis in the periphery. Results: Three-fold over-expression of Brd2 in hematopoietic stem cells selectively leads to a doubling of the B cell compartment and increases mature B cell mitogenic responsiveness ex vivo. Knockdown of Brd2 by shRNA totally ablates hematopoietic lineages, likely by inhibiting the lineage-committed progenitor expansion through down-regulation of cyclin A, which reinforces results from Eμ-Brd2 transgenic mice. The novel small molecule BET inhibitor JQ1 reduces B cell mitogenesis by about 60% in parallel experiments, but this effect likely extends to other related BET family members and lacks Brd2 specificity. Conclusion/Significance: The Brd2 pathway integrates lymphopoiesis, leukemogenesis and normal mitogenesis. Targeting this pathway with therapeutic drugs may therefore confer multiple, diverse benefits in the treatment of hematologic malignancy, B cell mediated disease and likely inflammation. Citation Format: Anna C. Belkina, Wanda P. Blanton, Frank L. Lombardi, Gerald V. Denis. The double bromodomain protein Brd2 controls B cell expansion and mitogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4730. doi:10.1158/1538-7445.AM2013-4730