Childrens Hospital Boston Boston

Boston, MA, United States

Childrens Hospital Boston Boston

Boston, MA, United States
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Mccandless S.E.,Case Western Reserve University | Yanovski J.A.,National Health Research Institute | Miller J.,University of Florida | Fu C.,Vanderbilt University | And 19 more authors.
Diabetes, Obesity and Metabolism | Year: 2017

Aims: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. Materials and Methods: Participants with PWS (12-65years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8mg beloranib or 2.4mg beloranib injection for 26weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. Results: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n=34); 1.8mg beloranib (n=36); or 2.4mg beloranib (n=37). Improvement (reduction) in HQ-CT total score was greater in the 1.8mg (mean difference -6.3, 95% CI -9.6 to -3.0; P =.0003) and 2.4mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P =.0001) vs placebo. Compared with placebo, weight change was greater with 1.8mg (mean difference-8.2%, 95% CI -10.8 to -5.6; P <.0001) and 2.4mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P <.0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. Conclusions: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity. © 2017 John Wiley & Sons Ltd.


PubMed | Childrens Hospital Boston Boston
Type: | Journal: Frontiers in human neuroscience | Year: 2010

The default mode network (DMN) refers to regional brain activity that is greater during rest periods than during attention-demanding tasks; many studies have reported DMN alterations in patient populations. It has also been shown that the DMN is suppressed by scanner background noise (SBN), which is the noise produced by functional magnetic resonance imaging (fMRI). However, it is unclear whether different approaches to rest in the noisy MR environment can alter the DMN and constitute a confound in studies investigating the DMN in particular patient populations (e.g., individuals with schizophrenia, Alzheimers disease). We examined 27 healthy adult volunteers who completed an fMRI experiment with three different instructions for rest: (1) relax and be still, (2) attend to SBN, or (3) ignore SBN. Region of interest analyses were performed to determine the influence of rest period instructions on core regions of the DMN and DMN regions previously reported to be altered in patients with or at risk for Alzheimers disease or schizophrenia. The dorsal medial prefrontal cortex (dmPFC) exhibited greater activity when specific resting instructions were given (i.e., attend to or ignore SBN) compared to when non-specific resting instructions were given. Condition-related differences in connectivity were also observed between regions of the dmPFC and inferior parietal/posterior superior temporal cortex. We conclude that rest period instructions and SBN levels should be carefully considered for fMRI studies on the DMN, especially studies on clinical populations and groups that may have different approaches to rest, such as first-time research participants and children.


PubMed | Childrens Hospital Boston Boston
Type: | Journal: Frontiers in molecular neuroscience | Year: 2012

Trauma in the adult mammalian central nervous system leads to irreversible structural and functional impairment due to failed regeneration attempts. In contrast, neurons in the peripheral nervous system exhibit a greater regenerative ability. It has been proposed that an orchestrated sequence of transcriptional events controlling the expression of specific sets of genes may be the underlying basis of an early cell-autonomous regenerative response. Understanding whether transcriptional fine tuning, in parallel with strategies aimed at counteracting extrinsic impediments promotes axon re-growth following central nervous system injuries represents an exciting challenge for future studies. Transcriptional pathways controlling axon regeneration are presented and discussed in this review.


PubMed | Childrens Hospital Boston Boston
Type: | Journal: Frontiers in immunology | Year: 2012

In this review, we discuss how changes in the intragraft microenvironment serve to promote or sustain the development of chronic allograft rejection. We propose two key elements within the microenvironment that contribute to the rejection process. The first is endothelial cell proliferation and angiogenesis that serve to create abnormal microvascular blood flow patterns as well as local tissue hypoxia, and precedes endothelial-to-mesenchymal transition. The second is the overexpression of local cytokines and growth factors that serve to sustain inflammation and, in turn, function to promote a leukocyte-induced angiogenesis reaction. Central to both events is overexpression of vascular endothelial growth factor (VEGF), which is both pro-inflammatory and pro-angiogenic, and thus drives progression of the chronic rejection microenvironment. In our discussion, we focus on how inflammation results in angiogenesis and how leukocyte-induced angiogenesis is pathological. We also discuss how VEGF is a master control factor that fosters the development of the chronic rejection microenvironment. Overall, this review provides insight into the intragraft microenvironment as an important paradigm for future direction in the field.

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