Reciprocal feedback between self-concept and goal pursuit in daily life.

OBJECTIVE: We hypothesized that self-knowledge and goal perseverance are mutually reinforcing because of the roles of self-knowledge in directing goal pursuit, and of goal pursuit in structuring the self-concept. METHOD: To test this hypothesis, we used a daily diary design with 97 college-aged participants for 40 days to assess whether daily self-concept clarity and grit predict one another's next-day levels. Data were analyzed using multilevel cross-lagged panel modeling. RESULTS: Results indicated that daily self-concept clarity and grit had positive and symmetric associations with each other across time, while controlling for their respective previous values. Similar crossed results were also found when testing the model using individual daily self-concept clarity and grit items. CONCLUSIONS: The results are the first to indicate the existence of reinforcing feedback loops between self-concept clarity and grit, such that fluctuations in the clarity of self-knowledge are associated with fluctuations in goal resolve, and vice versa. Discussion centers on the implications of these results for the functional link between mind and action and on the study's heuristic value for subsequent research.

Reciprocal Markov Modeling of Feedback Mechanisms Between Emotion and Dietary Choice Using Experience-Sampling Data.

With intensively collected longitudinal data, recent advances in the experience-sampling method (ESM) benefit social science empirical research, but also pose important methodological challenges. As traditional statistical models are not generally well equipped to analyze a system of variables that contain feedback loops, this paper proposes the utility of an extended hidden Markov model to model reciprocal the relationship between momentary emotion and eating behavior. This paper revisited an ESM data set (Lu, Huet, & Dube, 2011) that observed 160 participants' food consumption and momentary emotions 6 times per day in 10 days. Focusing on the analyses on feedback loop between mood and meal-healthiness decision, the proposed reciprocal Markov model (RMM) can accommodate both hidden ("general" emotional states: positive vs. negative state) and observed states (meal: healthier, same or less healthy than usual) without presuming independence between observations and smooth trajectories of mood or behavior changes. The results of RMM analyses illustrated the reciprocal chains of meal consumption and mood as well as the effect of contextual factors that moderate the interrelationship between eating and emotion. A simulation experiment that generated data consistent with the empirical study further demonstrated that the procedure is promising in terms of recovering the parameters.

A Phase I Trial of IGF-1R Inhibitor Cixutumumab and mTOR Inhibitor Temsirolimus in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Despite frequent PTEN (phosphatase and tensin homologue) loss and Akt/mammalian target of rapamycin (mTOR) signaling in prostate cancer, the disease is insensitive to single-agent mTOR inhibition. Insulin-like growth factor-1 receptor inhibition might mitigate the feedback inhibition by Torc1 inhibitors, suppressing downstream Akt activation and, thus, potentiating the antitumor activity of mTOR inhibition. PATIENTS AND METHODS: In the present phase I study, patients with metastatic castration-resistant prostate cancer received 6 mg/kg cixutumumab and 25 mg temsirolimus intravenously each week. The primary objective was safety and tolerability. Temsirolimus was decreased if ≥ 2 dose-limiting toxicities (DLTs) were observed in 6 patients. The correlative analyses included measurement of circulating tumor cells, [18F]-fluoro-2-deoxyglucose positron emission tomography, 16ß-[18F]-fluoro-α-dihydrotestosterone positron emission tomography, and tumor biopsy. RESULTS: A total of 16 patients were enrolled across 3 cohorts (1, -1, -2). Two DLTs (grade 3 oral mucositis) were observed in cohort 1 (temsirolimus, 25 mg), and 1 DLT (grade 3 lipase) in cohort -1 (temsirolimus, 20 mg). The most common adverse events included hyperglycemia (100%; 31% grade 3), oral mucositis (63%; 19% grade 3), and diarrhea (44%; 0 grade 3). Low-grade pneumonitis occurred in 7 of 11 patients (44%; 0 grade 3), prompting the opening of a 3-weekly cohort (temsirolimus, 20 mg/kg), without pneumonitis events. No patient had a >50% decline in prostate-specific antigen from baseline. The best radiographic response was stable disease, with median study duration of 22 weeks (range, 7-63 weeks). CONCLUSIONS: Despite a strong scientific rationale for the combination, temsirolimus plus cixutumumab demonstrated limited antitumor activity and a greater than expected incidence of toxicity, including low-grade pneumonitis and hyperglycemia. Hence, the trial was stopped in favor of alternative androgen receptor/phosphatidylinositol 3-kinase-directed combinatorial therapies.

Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy.

The RAS-RAF-MEK-ERK signaling pathway (MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers. As key elements in this pathway, MEK1/2 play crucial roles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy. Dozens of potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement in clinical outcomes over the past decade. However, the efficacy of these agents is limited, and response rates are variable in a wide range of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from the persistence of MAPK signaling and increased activation of the mutual feedback networks. Both intrinsic and acquired resistance to MEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent. In this review, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examined with a focus on MEK inhibitors. Then, the activation of feedback networks accompanying MEK inhibition is briefly reviewed. Combination strategies that involve the simultaneous inhibition of the original and resistance pathways are highlighted and elaborately described on the basis of the latest research progress. Finally, the obstacles to the development of MEK-related combination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments for individual patients with MAPK-hyperactivated malignancies.

The disrupted basal ganglia and behavioural control: an integrative cross-domain perspective of spontaneous stereotypy.

Spontaneous stereotypic behaviour (SB) is common in many captive animal species, as well as in humans with some severe psychiatric disorders, and is often cited as being related to general basal ganglia dysfunction. Despite this assertion, there is little in the literature examining SB specifically in terms of the basal ganglia mechanics. In this review, we attempt to fill this gap by offering an integrative, cross-domain perspective of SB by linking what we currently understand about the SB phenotype with the ever-growing literature on the anatomy and functionality of the basal ganglia. After outlining current models of SB from different theoretical perspectives, we offer a broad but detailed overview of normally functioning basal ganglia mechanics, and attempt to link this with current neurophysiological evidence related to spontaneous SB. Based on this we present an empirically derived theoretical framework, which proposes that SB is the result of a dysfunctional action selection system that may reflect dysregulation of excitatory (direct) and inhibitory (indirect and hyperdirect) pathways as well as alterations in mechanisms of behavioural switching. This approach also suggests behaviours that specifically become stereotypic may reflect inbuilt low selection threshold behavioural sequences associated with early development and the species-specific ethogram or, low threshold behavioural sequences that are the result of stress-induced dopamine exposure at the time of performance.

A dynamically minimalist cognitive explanation of musical preference: is familiarity everything?

This paper examines the idea that attraction to music is generated at a cognitive level through the formation and activation of networks of interlinked "nodes." Although the networks involved are vast, the basic mechanism for activating the links is relatively simple. Two comprehensive cognitive-behavioral models of musical engagement are examined with the aim of identifying the underlying cognitive mechanisms and processes involved in musical experience. A "dynamical minimalism" approach (after Nowak, 2004) is applied to re-interpret musical engagement (listening, performing, composing, or imagining any of these) and to revise the latest version of the reciprocal-feedback model (RFM) of music processing. Specifically, a single cognitive mechanism of "spreading activation" through previously associated networks is proposed as a pleasurable outcome of musical engagement. This mechanism underlies the dynamic interaction of the various components of the RFM, and can thereby explain the generation of positive affects in the listener's musical experience. This includes determinants of that experience stemming from the characteristics of the individual engaging in the musical activity (whether listener, composer, improviser, or performer), the situation and contexts (e.g., social factors), and the music (e.g., genre, structural features). The theory calls for new directions for future research, two being (1) further investigation of the components of the RFM to better understand musical experience and (2) more rigorous scrutiny of common findings about the salience of familiarity in musical experience and preference.