Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) ß5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.

Affective differentiation in breast cancer patients.

Fifty-three breast cancer patients completed an Internet-based diary measuring daily negative affect and positive affect and daily negative and positive events for seven consecutive evenings shortly after surgery. The authors used Hierarchical Linear Modeling (Raudenbush and Bryk in Hierarchical linear models: applications and data analysis methods. Sage, Thousand Oaks, CA, 2002) to examine moderators of affective differentiation, or the daily relationship between the patients' negative affect and positive affect. Strong affective differentiation is characterized by the relative independence of negative and positive affect. There were no significant Level 1 (within-subject) moderators of affective differentiation. However, at Level 2 (between-subject), as predicted, increased age was associated with stronger affective differentiation, as was greater use of planning to cope with breast cancer. Also as predicted, increased anxiety and greater use of behavioral disengagement and denial coping were associated with weaker affective differentiation. The results suggest the value of the affective differentiation construct, and a daily diary methodology, for research on the daily lives of breast cancer patients.

Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes.

OBJECTIVE: Few data are available regarding the long-term psychological impact of uninformative BRCA1/2 test results. This study examines change in distress from pretesting to 12-months post-disclosure, with medical, family history, and psychological variables, such as pretesting perceived risk of carrying a deleterious mutation prior to testing and primary and secondary appraisals, as predictors. METHODS: Two hundred and nine women with uninformative BRCA1/2 test results completed questionnaires at pretesting and 1-, 6-, and 12-month post-disclosure, including measures of anxiety and depression, cancer-specific and genetic testing distress. We used a mixed models approach to predict change in post-disclosure distress. RESULTS: Distress declined from pretesting to 1-month post-disclosure, but remained stable thereafter. Primary appraisals predicted all types of distress at 1-month post-disclosure. Primary and secondary appraisals predicted genetic testing distress at 1-month as well as change over time. Receiving a variant of uncertain clinical significance and entering testing with a high expectation for carrying a deleterious mutation predicted genetic testing distress that persisted through the year after testing. CONCLUSIONS: As a whole, women receiving uninformative BRCA1/2 test results are a resilient group. For some women, distress experienced in the month after testing does not dissipate. Variables, such as heightened pretesting perceived risk and cognitive appraisals, predict greater likelihood for sustained distress in this group and could be amenable to intervention.

Seeing the silver lining: potential benefits of trauma exposure in college students.

In the current study we compare college students exposed to a potentially traumatic event (PTE) meeting self-report criteria for Posttraumatic Stress Disorder (PTSD), PTE-exposed students not meeting criteria for PTSD, and non-exposed students on measures of perceived social support, self-esteem, and optimism (i.e., personal resources) and report use of specific coping strategies. Results indicate that the PTE-exposed/probable PTSD group reported fewer personal resources, greater use of avoidance-focused coping, and less use of approach-focused coping than the other two groups. The PTE-exposed/no PTSD group reported greater perceived social support and less use of avoidance-focused coping than the non-exposed group. We discuss the findings' implications for the prevention and treatment of trauma-related psychopathology.

Social constraints on disclosure predict daily well-being in couples coping with early-stage breast cancer.

According to the social-cognitive processing model (Lepore, 2001), social constraints on disclosure can limit an individual's ability to communicate openly with others and consequently have negative effects on psychological adjustment, especially in the context of stressful experiences such as the diagnosis and treatment of cancer. The goal of the present study was to examine the influence of social constraints on daily event sharing, individual well-being, and relationship well-being in couples coping with breast cancer. Forty-five patients recently diagnosed and treated for early stage breast cancer and their spouses reported perceptions of spousal constraints on patient disclosure and completed a 7-day electronic diary. Analyses revealed that patient-reported social constraints, independent of the spouse's report, were linked to reduced patient sharing of both cancer-related and other important daily events. Patient and spouse perceptions of social constraints, independent of their shared consensus, predicted reduced daily individual well-being indexed by self-esteem and negative affect, as well as reduced daily relationship well-being indexed by relationship happiness and intimacy. Moreover, many of the aforementioned effects on daily well-being remained after controlling for global marital quality. Overall, these findings reveal that individual perceptions of social constraints have a negative influence on both patient and spouse daily well-being outcomes.

Daily support in couples coping with early stage breast cancer: maintaining intimacy during adversity.

OBJECTIVE: Recent work has identified intimacy as a potentially important determinant of psychological adjustment in couples coping with cancer. Little work has examined specific social support processes within the context of the everyday life of couples' cancer experience. Specifically, we examined the links between breast cancer patient reports of receiving support from one's spouse/partner (support receipt) and spouse reports of providing support to the patient (support provision) with daily intimacy outcomes. We hypothesized that both patient and spouse would benefit from support receipt and support provision. METHOD: Forty-five women with early stage breast cancer and their spouses independently completed an Internet-based electronic diary assessing support receipt, support provision, and relationship intimacy for seven consecutive evenings shortly after surgery. Study outcomes consisted of daily relationship intimacy reported by each partner. RESULTS: As hypothesized, when controlling for patient report of support receipt, spouse report of support provision was uniquely associated with a significant additional increase in feelings of relationship intimacy for patients. Moreover, the independent effects of support receipt and support provision were also found to be beneficial for nonpatient spouses' daily feelings of intimacy. CONCLUSION: Findings highlight the use of dyadic diary methods and corresponding modeling to uncover the unique benefits of support provision that may sometimes occur outside the awareness of the recipient. Results are discussed in terms of conceptualizing the cancer experience in a shared interpersonal context, whereby patients and their spouses can both benefit from support as they adjust to cancer together.

Effects of cognitive therapy for depression on daily stress-related variables.

This study used a daily diary design to evaluate depressed patients' changes on daily stress-related variables during cognitive therapy (CT). Patients completed daily diaries on two week-long occasions: after the intake interview and again after the sixth session of CT. Patients also completed a measure of depressive symptoms before every treatment session. After six sessions of CT, patients reported a significant reduction in: (a) depressive symptoms; (b) daily sad affect (SA); (c) daily negative thoughts associated with the day's most stressful event; and (d) SA reactivity to daily stressors. In addition, patients reported a significant increase in: (e) daily positive affect (PA); and (f) SA reactivity to daily negative thoughts. The results suggest that CT has its intended effects on the daily lives of depressed adults, and highlight the value of a daily diary methodology for research on CT.

Negative affective spillover from daily events predicts early response to cognitive therapy for depression.

This study evaluated the predictive role of depressed outpatients' (N = 62) affective reactivity to daily stressors in their rates of improvement in cognitive therapy (CT). For 1 week before treatment, patients completed nightly electronic diaries that assessed daily stressors and negative affect (NA). The authors used multilevel modeling to compute each patient's within-day relationship between daily stressors and daily NA (within-day reactivity), as well as the relationship between daily stressors and next-day NA (next-day reactivity; affective spillover). In growth model analyses, the authors evaluated the predictive role of patients' NA reactivity in their early (Sessions 1-4) and late (Sessions 5-12) response to CT. Within-day NA reactivity did not predict early or late response to CT. However, next-day reactivity predicted early response to CT, such that patients who had greater NA spillover in response to negative events had a slower rate of symptom change during the first 4 sessions. Affective spillover did not influence later response to CT. The findings suggest that depressed patients who have difficulty bouncing back the next day from their NA reactions to a relative increase in daily negative events will respond less quickly to the early sessions of CT.

Daily affective reactivity as a prospective predictor of depressive symptoms.

Daily affective reactivity refers to the within-subject relationship between daily stress and daily mood. Most stress researchers have conceptualized daily affective reactivity as a dependent variable to be predicted by individual difference variables such as personality and psychopathology. In contrast, in our recent research, we have conceptualized daily affective reactivity as an independent variable that can predict depressive symptoms. In this article, we summarize three studies that relied on a daily process methodology and multilevel modeling to assess affective reactivity in the context of daily stressful events. Two of the studies (Cohen, Butler, Gunthert, & Beck, 2005; Gunthert, Cohen, Butler, & Beck, 2005) sampled adult outpatients in cognitive therapy and evaluated the predictive role of daily affective reactivity in treatment outcome (depression reduction). A third study (O'Neill, Cohen, Tolpin, & Gunthert, 2004) evaluated the predictive role of college students' daily affective reactivity in the development of depressive symptoms. We consider the strengths and weaknesses of a daily process methodology for research on depression in both clinical and nonclinical samples.

Borderline personality features and instability of daily negative affect and self-esteem.

We used a daily process design and multilevel modeling to examine the role of borderline personality features in the day-to-day stability of college students' negative affect and self-esteem and their reactivity to interpersonal stressors. At the end of each day for two weeks, students completed a checklist of daily stressors and measures of state affect and self-esteem. We predicted that high scores on a measure of borderline features would be related to more daily interpersonal stressors, greater negative affective and self-esteem reactivity to these stressors, and less day-to-day carryover of negative mood and self-esteem. The first and third hypotheses were supported, but not the second. The findings demonstrate the utility of a daily process methodology and multilevel modeling to study the day-to-day functioning of individuals with borderline features.

In vitro drug interactions of cytochrome p450: an evaluation of fluorogenic to conventional substrates.

Clinically observed drug interactions with cytochrome p450 (p450) enzymes have increased the need to assess drug interactions of new chemical entities early in the discovery process. To meet this need, fluorogenic substrates have been commercialized. However, only limited evaluations of their utility and comparisons to drug probes have been reported. This study examines the correlation between IC50 values obtained with fluorogenic and conventional drug probes for structurally diverse inhibitors of the five major human p450 isoforms. In general, correlations are weak, with significant numbers of compounds being missed as inhibitors by either probe. For p450s 1A2, 2C9, and 2C19, correlation coefficients were above 0.6 with slopes that ranged from 1.5 to 4.2. However, for p450s 1A2 and 2C9, about 20% of compounds were not included because an IC50 value could not be determined with one of the two probes. CYP 2C19 had the highest correlation (correlation coefficient 0.84), with a slope of 2.0 and less than 5% of compounds excluded. CYP 2D6 showed a good correlation for IC50 values less than 10 microM. However, at higher IC50 values, a high degree of scatter was observed. CYP 3A4 had the weakest correlation, and a large number of compounds were excluded with the fluorogenic probe. Overall, the study shows the care needed when selecting fluorogenic probes and the caution needed when results with fluorogenic probes are used to drive structure-activity relationships with respect to drug interactions.