Citations

Abstract The t(14;19)(q32;q13) involving the IGH@ and BCL3 loci is an infrequent cytogenetic abnormality detected in B-cell malignancies. We describe the clinicopathologic, cytogenetic, and molecular genetic characteristics of 14 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with t(14;19)(q32;q13). All patients (10 men and 4 women) had lymphocytosis; 10 had lymphadenopathy. Blood and bone marrow lymphocytes were predominantly small, but cytologically and immunophenotypically atypical. In all cases, t(14;19) was found in the neoplastic stem line; it was the sole abnormality in 4. Ten cases showed additional cytogenetic abnormalities, including trisomy 12 in 9 and complex karyotypes in 7. Fluorescence in situ hybridization demonstrated IGH@/BCL3 fusion gene in all cases. In all cases, the IGHV genes were unmutated, but only 7 expressed ZAP70. Seven cases preferentially used IGHV4-39. Our results indicate that t(14;19)(q32;q13) identifies a subset of CLL/SLL with distinctive clinicopathologic and genetic features. Furthermore, t(14;19) may represent an early, possibly primary, genetic event.

Abstract Vitamin A metabolite retinoic acid (RA) regulates life-sustaining differentiation processes and metabolic homeostasis. The aldehyde dehydrogenase-1 (Aldh1) family of enzymes (Aldh1a1, a2, and a3) catalyzes RA production from retinaldehyde and thereby controls concentrations of this transcriptionally active metabolite. The hierarchy of Aldh1 functions in adipose tissue has not been elucidated. We hypothesized that Aldh1 enzymes produce endogenous RA and regulate adipogenesis and fat formation in a fat depot-specific manner. We demonstrate that adipogenesis in vitro is accompanied by RA production generated primarily by Aldh1a1. In Aldh1a1-deficient adipocytes, adipogenesis is impaired compared with wild-type adipocytes due to markedly reduced expression of PPARγ regulated through zinc-finger protein 423 (ZFP423)-dependent mechanisms. These effects were recovered to some extent either by RA stimulation or overexpression of any of the Aldh1 enzymes in Aldh1a1−/− cells arguing that Aldh1a1 plays a dominant role in autocrine RA production. In vivo studies in C57/BL6 and Aldh1a1−/− mice on a regular diet revealed that multiple Aldh1 enzymes regulate differences in the formation of sc and visceral fat. In Aldh1a1−/− mice, visceral fat essentially lacked all Aldh1 expression. This loss of RA-producing enzymes was accompanied by 70% decreased expression of ZFP423, PPARγ, and Fabp4 in visceral fat of Aldh1a1−/−vs. wild-type mice and by the predominant loss of visceral fat. Subcutaneous fat of Aldh1a1−/− mice expressed Aldh1a3 for RA production that was sufficient to maintain expression of ZFP423 and PPARγ and sc fat mass. Our data suggest a paradigm for regulation of fat depots through the concerted action of Aldh1 enzymes that establish RA-dependent tandem regulation of transcription factors ZFP423 and PPARγ in a depot-specific manner.

Caveolae are specialized membrane microdomains expressing the scaffolding protein caveolin-1. We recently demonstrated the presence of caveolae in human airway smooth muscle (ASM) and the contribution of caveolin-1 to intracellular calcium ([Ca2+]i) regulation. In the present study, we tested the hypothesis that caveolin-1 regulates ASM contractility. We examined the role of caveolins in force regulation of porcine ASM under control conditions as well as TNF-α-induced airway inflammation. In porcine ASM strips, exposure to 10 mM methyl-β-cyclodextrin (CD) or 5 μM of the caveolin-1 specific scaffolding domain inhibitor peptide (CSD) resulted in time-dependent decrease in force responses to 1 μM ACh. Overnight exposure to the cytokine TNF-α (50 ng/ml) accelerated and increased caveolin-1 expression and enhanced force responses to ACh. Suppression of caveolin-1 with small interfering RNA mimicked the effects of CD or CSD. Regarding mechanisms by which caveolae contribute to contractile changes, inhibition of MAP kinase with 10 μM PD98059 did not alter control or TNF-α-induced increases in force responses to ACh. However, inhibiting RhoA with 100 μM fasudil or 10 μM Y27632 resulted in significant decreases in force responses, with lesser effects in TNF-α exposed samples. Furthermore, Ca2+sensitivity for force generation was substantially reduced by fasudil or Y27632, an effect even more enhanced in the absence of caveolin-1 signaling. Overall, these results indicate that caveolin-1 is a critical player in enhanced ASM contractility with airway inflammation.

A 15-gene expression signature predicts whether a patient with diffuse large B cell lymphoma will respond to dacetuzumab, a therapeutic antibody.

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom ( p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg ( p < .001) and nominally significant for 100 mg and 10 mg ( p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

Percutaneous transluminal renal stenting (PTRS) does not consistently improve renal function in patients with atherosclerotic renovascular disease, but the mechanisms underlying irreversible kidney injury have not been fully elucidated. We hypothesized that renal dysfunction after PTRS is linked to ongoing renal microvascular (MV) remodeling. Pigs were studied after 10 wk of atherosclerosis and renal artery stenosis (ARAS), ARAS treated with PTRS 4 wk earlier, and normal controls ( n = 10 each). Renal blood flow (RBF) and glomerular filtration rate (GFR) were studied using multidetector computer tomography. Renal microvascular architecture (micro-CT), angiogenic activity, oxidative stress, and fibrosis were evaluated ex vivo. Four weeks after PTRS, blood pressure was normalized. However, GFR and RBF remained similarly decreased in untreated ARAS and ARAS+PTRS ( P < 0.05 vs. normal). MV rarefaction was unaltered after revascularization, and the spatial density of outer cortical microvessels correlated with residual GFR. Interstitial fibrosis and altered expression of proangiogenic and profibrotic factors persisted after PTRS. Tubulointerstitial injury in ARAS persisted 4 wk after mechanically successful PTRS, and vessel loss correlated with residual renal dysfunction. MV loss and fibrosis in swine ARAS might account for persistent renal dysfunction after PTRS and underscore the need to assess renal parenchymal disease before revascularization.

Abstract 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 LB-186.

Abstract Heregulin internalization to the nucleus is mediated via binding to Nucleolin Lin Yang, and Ruth Lupu. Department of Laboratory Medicine and Pathology, Mayo Clinic Foundation, Rochester, Minnesota 55902 Heregulin (HRG) is known as a soluble secreted growth factor of EGF-like family, which binds and activates HER3 and HER4 and transactivates HER2 and HER1 receptors. It has been shown that HRG translocates to the nucleus in triple negative breast cancer cells that express high level of HRG. The mechanism by which HRG translocates to the nucleus is still unknown. We have recently uncovered that Nucleolin binds to Heregulin and allows HRG to translocate to the nucleus. Mass spectrometry analysis revealed that multifunctional protein Nucleolin is a major HRG-associated protein. Using co-immunoprecipitation we confirmed HRG interacts with Nucleolin in both endogenous and ectopic levels. Then, we made deleted mutants of HRG to map the Nucleolin binding domain on HRG and we found that Nucleolin binds to HRG on its N-terminus which contains a putative nuclear localization signal (NLS). Remarkably, in these cells we found a striking peri-nuclear accumulation when Nucleolin was knocked down. These results show for the first time that HRG translocate to the nucleus mediated by Nucleolin binding in breast cancer cells. Importantly, the nuclear function of HRG remains as a positive regulator of chemosensitization. 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 271.

Abstract Epidemiologic studies suggest that breast cancer risk factor associations vary by tumor marker expression; however, individual studies have had limited power to address this question. We pooled data from up to 35,568 invasive breast cancer cases from 34 studies participating in the Breast Cancer Association Consortium (BCAC) to evaluate associations between established risk factors (age at menarche, nulliparity, age at first full time birth [AFFTB], body mass index [BMI] and family history) and breast cancer subtypes, defined by immunohistochemical expression of ER, PR, HER2, and basal markers (CK5/6 or CK5, EGFR). We used polychotomous logistic regression to evaluate relationships between risk factors and tumor subtypes in case-only analyses and to estimate case-control odds ratios and 95% confidence intervals for the associations between risk factors and specific tumor subtypes in 11 population-based studies including up to 12,841 cases and 17,032 controls. In case-only analyses, we found that reproductive risk factors were more common in hormone receptor positive tumors: early age at menarche was most strongly related to PR status (34.6% vs. 32.4% of women with age at menarche ≤12 years among PR+ and PR- cases, respectively, P= 0.001); whereas nulliparity, and late AFFTB in parous women were most strongly related to ER status (15.3% vs. 13.6% nulliparous women, 17.1% vs. 15.2% women with late AFFTB [≥30 years], among ER+ and ER- cases, respectively, P=2.6×10−6 for nulliparity and P=2.0×10−7 for late AFFTB). Nulliparity and late AFFTB were less common among triple negative (TN) tumors overall and among TN tumors expressing basal markers. Elevated BMI in women aged 50 years or younger was more common in ER-&PR- than ER+&PR+ tumors (17.0% vs 13.6% women with BMI ≥30, respectively, P=1.3×10−7), whereas above age 50 years, elevated BMI was more common in ER+&PR+ than ER+&PR- tumors (20.9% vs 16.7% women with BMI ≥30, respectively, P=2.8×10−8 comparing BMI ≥30 to BMI &lt;25). In case-control analyses, early age at menarche was associated with increased risk of PR+ tumors; nulliparity and late AFFTB were most strongly associated with increased risk of (ER+ or PR+)&HER2- tumors, and did not increase the risk of TN tumors. Having a family history of breast cancer increased the risk of all tumor subtypes, although the association was strongest for TN tumors expressing basal markers. Our data provide convincing evidence for etiological heterogeneity with respect to breast cancer risk factors stratified by ER and PR status. Stratification by additional markers provides additional insights about etiologic differences in breast cancer risk. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 870.