ABSTRACT
Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.
Subject(s)
Connective Tissue Growth Factor/antagonists & inhibitors , Connective Tissue Growth Factor/genetics , Melanoma/drug therapy , Melanoma/genetics , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Line, Tumor , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Hypoxia/genetics , Hypoxia-Inducible Factor 1/genetics , Matrix Metalloproteinase 9/genetics , Melanoma/pathology , Mice , Mice, SCIDABSTRACT
BACKGROUND: From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. METHOD: We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. RESULTS: Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07). CONCLUSIONS: Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.
Subject(s)
Anxiety Disorders/diagnosis , Anxiety Disorders/epidemiology , Learning Disabilities/diagnosis , Learning Disabilities/epidemiology , Mood Disorders/diagnosis , Mood Disorders/epidemiology , Reversal Learning/physiology , Adolescent , Child , Female , Humans , Male , Probability , Severity of Illness IndexABSTRACT
This fMRI study investigates neural activity associated with the interfering effects of emotional distracters. While in the scanner, participants made simple motor responses to target stimuli that were preceded and followed by positive, negative, or neutral images. Despite instructions to disregard the pictorial images, participants were slower to respond in the presence of positive or negative relative to neutral distracters, and significantly slower for negative relative to positive distracters. Enhanced activity in the amygdala and visual cortex was evident during trials that included positive and negative distracters. In contrast, increased activity in inferior frontal gyrus (BA 47) was only observed during trials that involved negative distracters. Connectivity analysis showed that activity in right amygdala correlated with activity in cingulate gyrus, posterior cingulate, middle temporal cortex, and was negatively correlated with activity in lateral superior frontal gyrus, middle frontal/orbital gyrus, and parietal cortex. The pattern of neural activity observed was interpreted within the framework of current cognitive models of attention. During a task demonstrating behavioural interference in the context of emotional distracters, increased activity in neural regions implicated in emotional processing (the amygdala) was associated with reduced activity in regions thought to be involved in exerting attentional control over task-relevant sensory representations (a frontoparietal network).
