The cytotoxic protein can induce autophagocytosis in addition to apoptosis in MCF-7 human breast cancer cells.

Phagocytic clearance of dying cells is found in many phagocytes. It has been shown that dying cells can be phagocytosed by other phagocytic cells through autophagic or apoptotic cellular death. To date, whether cancer cells have such phagocytic activity has not been studied. In this study, our data shows that RC-RNase can trigger cell death in human breast cancer MCF-7 cells through the apoptotic pathway. Interestingly, when treated with cytotoxic protein, the remaining MCF-7 cells can phagocytose the dying MCF-7 cells via autophagocytic activity, demonstrated directly by real-time image observation and electron microscopy analysis. To sum up, this study demonstrates for the first time that RC-RNase can trigger apoptosis and autophagocytosis in MCF-7 cancer cells.

Immunotherapy for SV40 T/t antigen-induced breast cancer by recombinant adeno-associated virus serotype 2 carrying interleukin-15 in mice.

Human interleukin-15 (hIL15) exerts anticancer effects through the activities of lymphokine-activated killer (LAK) cells. However, its short half-life hinders its clinical application. Recombinant adeno-associated virus serotype 2 (rAAV2) is used for hIL15 gene transfer vectors, because of its low immunogenicity and long-term gene expression in human clinical trials. SV40 T/t antigens are related with many human epithelial cancers and are generally found in human breast cancer. In order to demonstrate the anticancer effects of hIL15 on SV40 T/t antigen-induced breast cancer, rAAV2-hIL15 was constructed and an SV40 T/t antigen-induced transgenic mouse breast cancer model was established. Our study showed that rAAV2-hIL15 could express the hIL15 protein with anticancer bioactivity. In addition, rAAV2-hIL15 could activate the cytotoxic activity of LAK cells in vivo. Furthermore, the rAAV2-hIL15 successfully delayed cancer growth and eventually led to cancer cell death in SV40 T/t antigen-induced breast cancer transgenic mice. In summary, our study indicates that rAAV2-hIL15 may be applied for cancer immunotherapy of SV40 T/t antigen-induced breast cancer.

Neurobiology of decision making in depressed adolescents: a functional magnetic resonance imaging study.

OBJECTIVE: Despite evidence that impaired reward- and risk-related behavior during adolescence can have potentially serious short- and long-term consequences, few studies have investigated the impact of depression on reward-related selection in adolescents. This study examined the relationship between reward-related behavior and prefrontal activations in depressed and healthy adolescents during a decision-making task. METHOD: A total of 22 adolescents with no personal or family history of psychiatric illness and 22 adolescents with major depressive disorder were administered a monetary, two-option decision-making task, the Wheel of Fortune, using a functional magnetic resonance imaging protocol. The analysis was focused on the selection phase, i.e., the first phase of the decision-making process, which typically includes two more phases, the anticipation of outcome and the feedback. RESULTS: Similar prefrontal regions were activated in healthy and depressed adolescents during reward-related selection. However, in a contrast involving the selection of high-risk (low-probability/high-magnitude reward) versus equal-risk (50% chance of reward) options, healthy adolescents showed greater activation than patients in the right lateral orbitofrontal cortex (OFC), whereas participants with depression showed greater activation than healthy subjects in the left dorsal OFC and right caudal anterior cingulate cortex. In addition, healthy adolescents, but not participants with depression, showed a negative correlation between high-risk behavior and neuronal activation in prespecified prefrontal regions. CONCLUSIONS: These results suggest subtle changes in the neural responses to reward selection in depressed adolescents. These findings should be replicated in larger samples, and the association of these neuronal changes with treatment response and prognosis should be examined.

Relationship between adolescent risk preferences on a laboratory task and behavioral measures of risk-taking.

PURPOSE: The goal of the study was to assess individual differences among adolescents regarding risk-taking behavior in the laboratory. The second aim was to evaluate whether the laboratory-based risk-taking behavior is associated with other behavioral and psychological measures associated with risk-taking behavior. METHODS: A total of 82 adolescents with no personal history of psychiatric disorder completed a computerized decision-making task, the Wheel of Fortune. On the basis of the choices made between clearly defined probabilities and real monetary outcomes, this task assesses risk preferences when participants are confronted with potential rewards and losses. The participants also completed a variety of behavioral and psychological measures associated with risk-taking behavior. RESULTS: Performance on the task varied on the basis of probability and anticipated outcomes. In the winning sub-task, participants selected low-probability-high-magnitude reward (high-risk choice) less frequently than high-probability-low-magnitude reward (low-risk choice). In the losing sub-task, participants selected low-probability-high-magnitude loss more often than high-probability-low-magnitude loss. On average, the selection of probabilistic rewards was optimal and similar to performance in adults. There were, however, individual differences in performance, and one-third of the adolescents made high-risk choice more frequently than low-risk choice while selecting a reward. After controlling for sociodemographic and psychological variables, high-risk choice on the winning task predicted "real-world" risk-taking behavior and substance-related problems. CONCLUSIONS: These findings highlight individual differences in risk-taking behavior. Regarding validity of the Wheel of Fortune task, the preliminary data suggest that it might be a valuable laboratory tool for studying behavioral and neurobiological processes associated with risk-taking behavior in adolescents.

Neurobiology of decision-making in adolescents.

The study examined the relationship between risk-taking behavior during selection of monetary rewards and activations in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), brain regions that are associated with decision-making. Thirty-three adolescents with no personal or family history of any psychiatric illness were administered the Wheel of Fortune (WOF) task using a functional magnetic resonance imaging protocol. The WOF is a computerized two-choice, probabilistic monetary reward task. Selection of a reward, particularly a low-probability/high-magnitude reward choice, induced greater activations in dorsal ACC, ventrolateral OFC and mPFC than the control condition. Although similar findings have been reported by earlier studies, the results from this study were not impacted by reaction times and expected values and persisted even after controlling for sociodemographic factors. Post hoc analysis revealed greater activation of ACC and mPFC in response to selection of rewards of larger magnitude than those of smaller magnitude when the probability of reward was maintained constant. Adolescents with greater frequency of high-risk behavior (defined as low-probability/high-magnitude reward choice) had lower activation of ACC, OFC and mPFC than those who engaged in this behavior less frequently. These findings suggest individual differences in prefrontal cortical function with regards to decision-making process in adolescents.

Hippocampal changes associated with early-life adversity and vulnerability to depression.

BACKGROUND: Smaller hippocampal volume has been reported in some adult and pediatric studies of unipolar major depressive disorder. It is not clear whether the smaller hippocampal volume precedes or is a consequence of the illness. Early-life adversity is associated with both smaller hippocampal volume and increased vulnerability to depressive disorder. Hippocampal changes may mediate the relationship between early-life adversity and depressive illness in a subset of patients. However, there are no reports of longitudinal clinical studies that have examined this issue. METHODS: Thirty adolescents with unipolar major depressive disorder, 22 adolescent volunteers with no personal history of a psychiatric illness including depression but who were at high risk for developing depression by virtue of parental depression (high-risk group), and 35 adolescent volunteers with no personal or family history of a psychiatric disorder (control subjects) underwent volumetric magnetic resonance imaging studies. Information was also gathered on early and recent adverse experiences with standard interviews. The participants were followed for up to 5 years to assess the onset and clinical course of depression. RESULTS: Depressed and high-risk groups had significantly smaller left and right hippocampal volumes than control subjects. Higher levels of early-life adversity were associated with smaller hippocampal volumes. Smaller hippocampal volume partially mediated the effect of early-life adversity on depression during longitudinal follow-up. CONCLUSIONS: Smaller hippocampal volume in adolescents at high risk for depression suggests that it may be a vulnerability marker for the illness. Early-life adversity may interact with genetic vulnerability to induce hippocampal changes, potentially increasing the risk for depressive disorder.

Characteristics, correlates, and outcomes of childhood and adolescent depressive disorders.

Depressive illness beginning early in life can have serious developmental and functional consequences. Therefore, understanding the disorder during this developmental stage is critical for determining its etiology and course, as well as for developing effective intervention strategies. This paper summarizes current knowledge regarding the etiology, phenomenology, correlates, natural course, and consequences of unipolar depression in children and adolescents. Using adult depression as a framework, the unique aspects of childhood and adolescence are considered in order to better understand depression within a developmental context. The data suggest that the clinical presentation, correlates, and natural course of depression are remarkably similar across the lifespan. There are, however, important developmental differences. Specifically, the familial and psychological context in which depression develops in youngsters is associated with variability in the frequency and nature of depressive symptoms and comorbid conditions among children and adolescents. Maturational differences have also been identified in the neurobiological correlates of depression. These developmental differences may be associated with the observed variability in clinical response to treatment and longitudinal course. Characterization of the developmental differences will be helpful in developing more specific and effective interventions for youngsters, thereby allowing them to reach their full potential as adults.

Do atypical antipsychotics effectively treat co-occurring bipolar disorder and stimulant dependence? A randomized, double-blind trial.

OBJECTIVES: The primary objective was to compare the efficacy and tolerability of quetiapine and risperidone in the treatment of mood symptoms, drug cravings, and drug use in outpatients with concurrent DSM-IV-defined bipolar I or II disorder and cocaine or methamphetamine dependence. METHOD: Men and women of all ethnic origins, 20 to 50 years of age, were eligible to participate. Persons were excluded if they were inpatients, met DSM-IV criteria for substance-induced mood disorder, had any other substance dependence, were euthymic or suicidal, had any life-threatening illnesses, or were currently receiving antipsychotic medications. Duration of the trial was 20 weeks. Study participants attended weekly visits and were evaluated for mood symptoms, drug cravings, drug use, and medication side effects. Treatment outcomes were analyzed using linear mixed models. Fixed-effects terms for medication group, study week, and group-by-study-week were included in the models. The study was conducted between October 2002 and November 2006. RESULTS: Of 124 consenting outpatients, an evaluable sample of 80 patients who attended baseline and at least 1 follow-up study visit was formed. The mean +/- SD exit dose for quetiapine was 303.6 +/- 151.9 mg/day and 3.1 +/- 1.2 mg/day for risperidone. Both quetiapine (N = 42) and risperidone (N = 38) significantly improved manic and depressive symptoms and reduced drug cravings (p < .0005) compared to baseline. Decreased drug cravings were related to less frequent drug use (p = .03). The 2 medications did not significantly differ in their effects on mood symptoms, drug craving, or drug use. CONCLUSIONS: Relative to baseline mood and drug-craving status, both quetiapine and risperidone were associated with manic, mixed, and depressive symptom improvement and reduced drug cravings. Both medications were well tolerated. The interpretation of these results is limited by the absence of a placebo control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00227123.

Effects of early and recent adverse experiences on adrenal response to psychosocial stress in depressed adolescents.

BACKGROUND: As observed in depressed adults, there is considerable variability in the degree and direction of hypothalamic-pituitary-adrenal (HPA) dysfunction in depressed adolescents. The variability in HPA findings may be attributed to experiential factors. METHODS: A modified version of a standard psychosocial stressor used in adults, the Trier Social Stress Test (TSST), was administered to 30 adolescents with major depressive disorder and 25 healthy adolescent volunteers. Cortisol concentrations were measured in saliva samples collected before and after the stressor. Information was also gathered on early and recent adverse experiences with standard interviews. RESULTS: Participants from both groups had increased cortisol secretion in response to TSST. Compared with control subjects, depressed subjects showed more elevated and prolonged cortisol secretion in response to TSST. The combination of early-life adversity and high levels of chronic stress during adolescence was the most powerful predictor of enhanced adrenal response to the TSST. CONCLUSIONS: These results support previous findings on the role of experiential factors on HPA response to stress and in the development of mood disorders. Dissection of the heterogeneous pathophysiology of adolescent depression will assist in developing more specific interventions for different subgroups of patients.

Neurobiological and psychosocial processes associated with depressive and substance-related disorders in adolescents.

Adolescents are at heightened risk for the development of both depressive and substance-related disorders. These two disorders frequently co-occur in adolescents and are associated with significant morbidity and mortality. Given the substantial economic and psychosocial burden associated with the comorbid condition, the identification of causal mechanisms associated with their co-occurrence is of great public health importance. Although there is significant understanding of the environmental and neurobiological factors involved in depression and addictive disorders considered separately, the mechanisms underlying the comorbid illness have not been investigated carefully. The purpose of this review is to summarize the extant literature on genetic, environmental and neurobiological processes involved in the etiology of depressive and substance-related disorders in adolescents and adults. It is important to note that the data on common neurobiological systems that link addictive and depressive disorders are primarily from research with adult animals and humans. Given the ongoing maturation of these systems throughout adolescence and early adult life, it is not clear how these neurobiological processes influence the development and progression of both disorders. A better understanding of the pathophysiological mechanisms leading to the onset and course of these disorders during adolescence will be helpful in developing more effective preventive and treatment strategies not only for this population but also for adult patients with early-onset illness.