Citations

AbstractVEGF induces vascular permeability (VP) in ischemic diseases and cancer, leading to many pathophysiological consequences. The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood and in vivo models that easily facilitate real-time, genetic studies of VP do not exist. In the present study, we report a heat-inducible VEGF transgenic zebrafish (Danio rerio) model through which VP can be monitored in real time. Using this approach with morpholino-mediated gene knock-down and knockout mice, we describe a novel role of phospholipase Cβ3 as a negative regulator of VEGF-mediated VP by regulating intracellular Ca2+ release. Our results suggest an important effect of PLCβ3 on VP and provide a new model with which to identify genetic regulators of VP crucial to several disease processes.

OBJECTIVE: To develop guidelines for management and treatment of maladaptive aggression in the areas of family engagement, assessment and diagnosis, and initial management, appropriate for use by primary care clinicians and mental health providers. Maladaptive aggression in youth is increasingly treated with psychotropic medications, particularly second-generation antipsychotic agents. Multiple treatment modalities are available, but guidance for clinicians’ assessment and treatment strategies has been inadequately developed. To address this need, the Center for Education and Research on Mental Health Therapeutics and the REACH Institute convened a steering group of national experts to develop evidence-based treatment recommendations for maladaptive aggression in youth. METHODS: Evidence was assembled and evaluated in a multistep process that included a systematic review of published literature; a survey of experts on recommended treatment practices; a consensus conference that brought together clinical experts along with researchers, policy makers, and family advocates; and subsequent review and discussion by the steering committee of successive drafts of the recommendations. The Center for Education and Research on Mental Health Therapeutics Treatment of Maladaptive Aggression in Youth (T-MAY) guidelines reflect a synthesis of the available evidence, based on this multistep process. RESULTS: The current article describes 9 recommendations for family engagement, assessment, and diagnosis as key prerequisites for treatment selection and initiation. CONCLUSIONS: Recognizing the family and social context in which aggressive symptoms arise, and understanding the underlying psychiatric conditions that may be associated with aggression, are essential to treatment planning.

OBJECTIVE: To develop guidelines for management and treatment of maladaptive aggression in youth in the areas of psychosocial interventions, medication treatments, and side-effect management. METHODS: Evidence was assembled and evaluated in a multistep process, including systematic reviews of published literature; an expert survey of recommended practices; a consensus conference of researchers, policymakers, clinicians, and family advocates; and review by the steering committee of successive drafts of the recommendations. The Center for Education and Research on Mental Health Therapeutics Treatment of Maladaptive Aggression in Youth guidelines reflect a synthesis of the available evidence, based on this multistep process. RESULTS: This article describes the content, rationale, and evidence for 11 recommendations. Key treatment principles include considering psychosocial interventions, such as evidence-based parent and child skills training as the first line of treatment; targeting the underlying disorder first following evidence-based guidelines; considering individual psychosocial and medical factors, including cardiovascular risk in the selection of agents if medication treatment (ideally with the best evidence base) is initiated; avoiding the use of multiple psychotropic medications simultaneously; and careful monitoring of treatment response, by using structured rating scales, as well as close medical monitoring for side effects, including metabolic changes. CONCLUSIONS: Treatment of children with maladaptive aggression is a “moving target” requiring ongoing assimilation of new evidence as it emerges. Based on the existing evidence, the Treatment of Maladaptive Aggression in Youth guidelines provide a framework for management of maladaptive aggression in youth, appropriate for use by primary care clinicians and mental health providers.

AbstractThe POEMS syndrome (polyradiculoneuropathy, organomegaly, multiple endocrinopathies, monoclonal protein, skin changes) is a rare disease associated with a plasma cell dyscrasia. Patients with disseminated POEMS can be treated with high-dose therapy and autologous stem cell transplantation (ASCT). While clinical improvement is nearly universal in these patients, the long-term outcomes after transplantation are unclear. We therefore assessed the long-term clinical outcomes of 59 POEMS patients treated with ASCT at our institution. With a median follow-up of 45 months, 14 patients have progressed with a progression-free survival of 98% and 75% at 1 and 5 years, respectively. Factors associated with progression have included an IgG-λ monoclonal component (hazard ratio [HR] 7.5; 95% confidence interval [CI], 2.3-28.3; P = .0008), fluorodeoxyglucose-avid lesions on baseline positron emission tomography (HR 6.4; 95% CI, 1.2-120; P = .03), lack of complete hematologic response (HR 5.4; 95% CI, 1.8-16.7; P = .003), and patients aged 50 years or younger at transplantation (HR 4.4; 95% CI, 1.3-20; P = .01). The most common progression events have been radiologic followed by rising VEGF. Symptomatic progression has been rare. Most patients could be salvaged with immunomodulatory drugs or radiation. The 5-year survival is 94%. Herein, we describe a system of monitoring response and progression among patients with POEMS after ASCT.

AbstractPurpose: The TNF receptor superfamily member CD27 is best known for its important role in T-cell immunity but is also recognized as a cell-surface marker on a number of B- and T-cell malignancies. In this article, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27.Experimental Design: The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro. Severe combined immunodeficient (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct antitumor effects. A pilot study of 1F5 was conducted in non-human primates to assess toxicity.Results: 1F5 binds with high affinity and specificity to human and macaque CD27 and competes with ligand binding. 1F5 activates T cells only in combination with T-cell receptor stimulation and does not induce proliferation of primary CD27-expressing tumor cells. 1F5 significantly enhanced the survival of SCID mice bearing Raji or Daudi tumors, which may be mediated through direct effector mechanisms such as antibody-dependent cellular cytotoxicity. Importantly, administration of up to 10 mg/kg of 1F5 to cynomolgus monkeys was well tolerated without evidence of significant toxicity or depletion of circulating lymphocytes.Conclusions: Collectively, the data suggest that the human mAb 1F5, which has recently entered clinical development under the name CDX-1127, may provide direct antitumor activity against CD27-expressing lymphoma or leukemia, independent of its potential to enhance immunity through its agonistic properties. Clin Cancer Res; 18(14); 3812–21. ©2012 AACR.