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.

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.

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.