A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.     

Risk factors for the development of acute lung injury in patients with infectious pneumonia

ABSTRACT: INTRODUCTION: Although pneumonia has been identified as the single most common risk factor for acute lung injury (ALI), we have a limited knowledge as to why ALI develops in some patients with pneumonia and not in others. The objective of this study was to determine frequency, risk factors, and outcome of ALI in patients with infectious pneumonia. METHODS: A retrospective cohort study of adult patients with microbiologically positive pneumonia, hospitalized at two Mayo Clinic Rochester hospitals between January 1, 2005, and December 31, 2007. In a subsequent nested case-control analysis, we evaluated the differences in prehospital and intrahospital exposures between patients with and without ALI/acute respiratory distress syndrome (ARDS) matched by specific pathogen, isolation site, gender, and closest age in a 1:1 manner. RESULTS: The study included 596 patients; 365 (61.2%) were men. The median age was 65 (IQR, 53 to 75) years. In total, 171 patients (28.7%) were diagnosed with ALI. The occurrence of ALI was less frequent in bacterial (n = 99 of 412, 24%) compared with viral (n = 19 of 55, 35%), fungal (n = 39 of 95, 41%), and mixed isolates pneumonias (n = 14 of 34, 41%; P = 0.002). After adjusting for baseline severity of illness and comorbidities, patients in whom ALI developed had a markedly increased risk of hospital death (ORadj 9.7; 95% CI, 6.0 to 15.9). In a nested case-control study, presence of shock (OR, 8.9; 95% CI, 2.8 to 45.9), inappropriate initial antimicrobial treatment (OR, 3.2; 95% CI, 1.3 to 8.5), and transfusions (OR, 4.8; 95% CI, 1.5 to 19.6) independently predicted ALI development. CONCLUSIONS: The development of ALI among patients hospitalized with infectious pneumonia varied among pulmonary pathogens and was associated with increased mortality. Inappropriate initial antimicrobial treatment and transfusion predict the development of ALI independent of pathogen.     

Review: Modelling placental amino acid transfer − From transporters to placental function

Amino acid transfer to the fetus is dependent on several different factors. While these factors can be understood in isolation, it is still not possible to predict the function of the system as a whole. In order to do this an integrated approach is required which incorporates the interactions between the different determinants of amino acid transfer. Computational modelling of amino acid transfer in the term human placenta provides a mechanism by which this integrated approach can be delivered. Such a model would be invaluable for understanding amino acid transfer in both normal and pathological pregnancies.In order to develop a computational model it is necessary to determine all the biological factors which are important contributors to net amino acid transfer and the ways in which they interact. For instance, how different classes of amino acid transporter must interact to transfer amino acids across the placenta. Mathematically, the kinetics of each type of transporter can be represented by separate equations that describe their transfer rate as a non-linear function of amino acid concentrations. These equations can then be combined in the model to predict the overall system behaviour. Testing these predictions experimentally will demonstrate the strengths and weaknesses of the model, which can then be refined with increasing complexity and retested in an iterative fashion.In this way we hope to develop a functional computational model which will allow exploration of the factors that determine amino acid transfer across the placenta. This model may also allow the development of strategies to optimise placental transfer in pathologies associated with impaired amino acid transfer such as fetal growth restriction.     

Transgenic Overexpression of Gremlin Results in Developmental Defects in Enamel and Dentin in Mice

Bone morphogenetic proteins (BMPs) and BMP antagonists play a crucial role in the regulation of tooth development. One of the BMP extracellular antagonists, gremlin, is a highly conserved 20.7-kDa glycoprotein. Previously, researchers reported that transgenic mice overexpressing gremlin under the control of the osteocalcin promoter (gremlin OE) exhibit a skeletal phenotype and tooth fragility. To further define the tooth phenotype, teeth and surrounding supporting tissues, obtained from gremlin OE at ages of 4 weeks, 2 months, and 4 months, were examined. The histological results demonstrate that gremlin OE exhibit an enlarged pulp chamber with ectopic calcification and thinner dentin and enamel compared with wild-type control. In vitro studies using murine pulp cells revealed that gremlin inhibited BMP-4 mediated induction of Dspp. These data provide evidence that balanced interactions between BMP agonists/antagonists are required for proper development of teeth and surrounding tissues. It is clear that these interactions require further investigation to better define the mechanisms controlling tooth root formation (pulp, dentin, cementum, and surrounding tissue) to provide the information needed to successfully regenerate these tissues.     

Effects of Communities That Care on the Adoption and Implementation Fidelity of Evidence-Based Prevention Programs in Communities: Results from a Randomized Controlled Trial

This paper describes findings from the Community Youth Development Study (CYDS), a randomized controlled trial of the Communities That Care (CTC) prevention system, on the adoption and implementation fidelity of science-based prevention programming in 24 communities. Data were collected using the Community Resource Documentation (CRD), which entailed a multi-tiered sampling process and phone and web-based surveys with directors of community-based agencies and coalitions, school principals, service providers, and teachers. Four years after the initiation of the CTC prevention system, the results indicated increased use of tested, effective prevention programs in the 12 CTC intervention communities compared to the 12 control communities, and significant differences favoring the intervention communities in the numbers of children and families participating in these programs. Few significant differences were found regarding implementation quality; respondents from both intervention and control communities reported high rates of implementation fidelity across the services provided.