Citations

The chromosomal translocation t (11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1–driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1–expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G 1 –S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2’s antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1–expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1–expressing tumors.

Abstract Immune responses against cancer rely upon leukocyte trafficking patterns that are coordinated by chemokines. CCR5, the receptor for chemotactic chemokines MIP1alpha, MIP1beta, and RANTES (CCL3, CCL4, CCL5), exerts major regulatory effects on CD4+- and CD8+ T cell-mediated immunity. Although CCR5 and its ligands participate in the response to various pathogens, its relevance to tumoral immune control has been debated. Here, we report that CCR5 has a specific, ligand-dependent role in optimizing antitumor responses. In adoptive transfer studies, efficient tumor rejection required CCR5 expression by both CD4+ and CD8+ T cells. CCR5 activation in CD4+ cells resulted in CD40L upregulation, leading to full maturation of antigen-presenting cells and enhanced CD8+ T-cell crosspriming and tumor infiltration. CCR5 reduced chemical-induced fibrosarcoma incidence and growth, but did not affect the onset or progression of spontaneous breast cancers in tolerogenic Tg(MMTV-neu) mice. However, CCR5 was required for TLR9-mediated reactivation of antineu responses in these mice. Our results indicate that CCR5 boosts T-cell responses to tumors by modulating helper-dependent CD8+ T-cell activation. Cancer Res; 71(16); 5455–66. ©2011 AACR.

Abstract Mind body therapies appear to reduce morbidity and mortality in patients with cardiovascular diseases, but there is limited understanding of the mechanisms that mediate this effect. Vascular endothelial dysfunction is a central feature of atherogenesis that is adversely impacted by mental stress. We conducted a systematic review and meta-analysis of the effect of mind body therapies on peripheral endothelial function in patients with and without established cardiovascular disease. The search included Medline, Cochrane Library, Scopus and Embase to identify studies up to November 2009. Eligible studies were randomized controlled trials that compared the effects of mind body therapies and placebo on endothelial function. Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. Three eligible trials enrolled a total of 258 patients. Sixty one (24 percent) were women and 53 percent had established cardiovascular disease. The trials had good methodological quality. Meta-analysis using random-effects model showed a non significant improvement of endothelial function by mind body therapies (standardized mean difference 0.15; 95% CI, -0.36 to 0.67, P=0.56). The analysis was underpowered due to small sample size. Circumstantial evidence indicates that mind body therapies may have a therapeutic benefit on endothelial dysfunction, however, the aggregate data from the three small randomized trials to date do not support this hypothesis. This biologically plausible effect requires additional investigation in adequately powered studies.

Background and Purpose —During focal cerebral ischemia, the ischemic penumbra or border-zone regions of moderate cortical blood flow reductions have a heterogeneous development of intracellular cortical acidosis. This experiment tested the hypotheses that (1) this acidosis is secondary to glucose utilization and (2) this intracellular acidosis leads to recruitment of potentially salvageable tissue into infarction. Methods —Brain pH i , regional cortical blood flow, and NADH redox state were measured by in vivo fluorescent imaging, and infarct volume was assessed by triphenyltetrazolium chloride histology. Thirty fasted rabbits divided into 6 groups of 5 each were subjected to 4 hours of permanent focal ischemia in the presence of hypoglycemia (≈2.8 mmol/L), moderate hyperglycemia (≈11 mmol/L), and severe hyperglycemia (>28 mmol/L) under either normoxia or moderate hypoxia (Pa o 2 ≈50 mm Hg). Results —Preischemic hyperglycemia led to a more pronounced intracellular acidosis and retardation of NADH regeneration than in the hypoglycemia groups under both normoxia and moderate hypoxia in the ischemic penumbra. For example, 4 hours after ischemia, brain pH i in the severe hyperglycemia/normoxia group measured 6.46, compared with 6.84 in the hypoglycemia/normoxia group ( P <0.01), and NADH fluorescence measured 173% compared with 114%. Infarct volume in the severe hyperglycemia/normoxia group measured 35.1±6.9% of total hemispheric volume, compared with 13.5±4.2% in the hypoglycemia/normoxia group ( P <0.01). Conclusions —Hyperglycemia significantly worsened both cortical intracellular brain acidosis and mitochondrial function in the ischemic penumbra. This supports the hypothesis that the evolution of acidosis in the ischemic penumbra is related to glucose utilization. Furthermore, the observation that hypoglycemia significantly decreased infarct size supports the postulate that cortical acidosis leads to recruitment of ischemic penumbra into infarction.

Abstract Activation of the Sonic hedgehog (Shh) pathway and increased expression of Gli1 play an important role in proliferation and transformation of granule cell progenitors (GCP) in the developing cerebellum. Medulloblastomas arising from cerebellar GCPs are frequently driven by Shh pathway–activating mutations; however, molecular mechanisms of Shh pathway dysregulation and transformation of neural progenitors remain poorly defined. We report that the transcription factor and oncogene Snail1 (Sna1) is directly induced by Shh pathway activity in GCPs, murine medulloblastomas, and human medulloblastoma cells. Enforced expression of Sna1 was sufficient to induce GCPs and medulloblastoma cell proliferation in the absence of Shh/Gli1 exposure. In addition, enforced expression of Sna1 increased transformation of medulloblastoma cells in vitro and in vivo. Analysis of potential Sna1 targets in neural cells revealed a novel Sna1 target, N-Myc, a transcription factor known to play a role in Shh-mediated GCP proliferation and medulloblastoma formation. We found that Sna1 directly induced transcription of N-Myc in human medulloblastoma cells and that depletion of N-Myc ablated the Sna1-induced proliferation and transformation. Taken together, these results provide further insight into the mechanism of Shh-induced transformation of neural progenitor cells and suggest that induction of Sna1 may serve to amplify the oncogenic potential of Shh pathway activation through N-Myc induction. Cancer Res; 71(15); 5336–45. ©2011 AACR.

Neurally derived tachykinins such as substance P (SP) play a key role in modulating airway contractility (especially with inflammation). Separately, the neurotrophin brain-derived neurotrophic factor (BDNF; potentially derived from nerves as well as airway smooth muscle; ASM) and its tropomyosin-related kinase receptor, TrkB, are involved in enhanced airway contractility. In this study, we hypothesized that neurokinins and neurotrophins are linked in enhancing intracellular Ca2+ concentration ([Ca2+]i) regulation in ASM. In rat ASM cells, 24 h exposure to 10 nM SP significantly increased BDNF and TrkB expression ( P < 0.05). Furthermore, [Ca2+]i responses to 1 μM ACh as well as BDNF (30 min) effects on [Ca2+]i regulation were enhanced by prior SP exposure, largely via increased Ca2+ influx ( P < 0.05). The enhancing effect of SP on BDNF signaling was blunted by the neurokinin-2 receptor antagonist MEN-10376 (1 μM, P < 0.05) to a greater extent than the neurokinin-1 receptor antagonist RP-67580 (5 nM). Chelation of extracellular BDNF (chimeric TrkB-Fc; 1 μg/ml), as well as tyrosine kinase inhibition (100 nM K252a), substantially blunted SP effects ( P < 0.05). Overnight (24 h) exposure of ASM cells to 50% oxygen increased BDNF and TrkB expression and potentiated both SP- and BDNF-induced enhancement of [Ca2+]i ( P < 0.05). These results suggest a novel interaction between SP and BDNF in regulating agonist-induced [Ca2+]i regulation in ASM. The autocrine mechanism we present here represents a new area in the development of bronchoconstrictive reflex response and airway hyperreactive disorders.

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all‐cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

Our aim was to determine the pattern of expression of MUC1 mucin cytoplasmic tail (MUC1 CT) in breast carcinoma. A total of 98 invasive breast adenocarcinoma tumor samples were assayed by immunohistochemical (IHC) analysis. The pattern of reaction was classified as membrane, cytoplasmic, or mixed. Subcellular fractions were prepared after SDS-PAGE and Western blotting. The antibodies employed were anti-MUC1 CT (CT2 monoclonal antibody, MAb) and C595 MAb against the extracellular MUC1 core protein. With the CT2 MAb, IHC showed a high percentage of positive staining in 93% of specimens, with membrane staining the most common pattern observed. C595 MAb was reactive in 73% of specimens. Similar percentages of membrane and cytoplasmic staining were found, mainly in a mixed pattern. Western blotting showed different bands. With the CT2 MAb, the membrane fraction showed the most intense reaction; a strong band of reaction was detected at approximately <30 kD. With the C595 MAb, in most cases a double band at 200 kD was found. In breast epithelium, the pattern of MUC1 CT expression may constitute an indicator of MUC1 production because it does not depend on glycosylation. The pattern and extension of MUC1 CT positivity do not vary according to the histopathological subtype of the tumor.