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Cognitive Remediation in Schizophrenia
Cognitive deficits in schizophrenia are pervasive, severe, and largely independent of the positive and negative symptoms of the illness. These deficits are increasingly considered to be core features of schizophrenia with evidence that the extent of cognitive impairment is the most salient predictor of daily functioning. Unfortunately, current schizophrenia treatment has been limited in addressing the cognitive deficits of the illness. Alterations in neuroplasticity are hypothesized to underpin these cognitive deficits, though preserved neuroplasticity may offer an avenue towards cognitive remediation. Key neuroplastic principles to consider in designing remediation interventions include ensuring sufficient intensity and duration of remediation programs, "bottom-up" training that proceeds from simple to complex cognitive processes, and individual tailoring of remediation regimens. We discuss several cognitive remediation programs, including cognitive enhancement therapy, which embrace these principles to target neurocognitive and social cognitive improvements and which havebeen demonstrated to be effective in schizophrenia. Future directions in cognitive remediation research include potential synergy with pharmacologic treatment, non-invasive stimulation techniques, and psychosocial interventions, identification of patient characteristics that predict outcome with cognitive remediation, and increasing the access to these interventions in front-line settings
Human IgG1 antibodies suppress angiogenesis in a target-independent manner
Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies