Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer.

Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.

The use of health related quality of life measurement in cardiovascular and pulmonary physical therapy practice: an exploratory study.

BACKGROUND: The American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) recommends health related quality of life (HRQL) measurement with all cardiovascular and pulmonary patients. The current pattern of use of HRQL measurement among cardiovascular and pulmonary physical therapists is unknown. OBJECTIVE: The purpose of this study was to evaluate the pattern of use of HRQL measurement among cardiovascular and pulmonary physical therapists. DESIGN: The study used a semi-structured interview format within the context of 3 focus groups. METHODS: Eleven physical therapists participated in this study and all were members of the Cardiovascular and Pulmonary Section of the American Physical Therapy Association (APTA). Participants participated in a conference call and were provided a question tree to guide discussion. RESULTS: Several primary themes emerged, including decreased knowledge, barriers, and poor indicators of patient status. In addition, several subthemes developed including lack of familiarity, lack of use, administrative and cost limitations, inappropriateness of tool for patient population, correlation between function and quality of life, and suggestions for future outcome measures. CONCLUSIONS: A lack of familiarity and use of HRQL measurement and barriers to their use were established. In addition, ideas for future research on HRQL measurements with specific patient populations in physical therapy practice were defined.

Feeding muscles scale differently from swimming muscles in sunfish (Centrarchidae).

The physiological properties of vertebrate skeletal muscle typically show a scaling pattern of slower contractile properties with size. In fishes, the myotomal or swimming muscle reportedly follows this pattern, showing slower muscle activation, relaxation and maximum shortening velocity (V(max)) with an increase in body size. We asked if the muscles involved in suction feeding by fishes would follow the same pattern. We hypothesized that feeding muscles in fishes that feed on evasive prey are under selection to maintain high power output and therefore would not show slower contractile properties with size. To test this, we compared contractile properties in feeding muscles (epaxial and sternohyoideus) and swimming muscle (myotomal) for two members of the family Centrarchidae (sunfish): the bluegill (Lepomis macrochirus) and the largemouth bass (Micropterus salmoides). Consistent with our predictions, the V(max) of myotomal muscle in both species slowed with size, while the epaxials showed no significant change in V(max) with size. In the sternohyoideus, V(max) slowed with size in the bluegill but increased with size in the bass. The results indicate that scaling patterns of contractile properties appear to be more closely tied to muscle function (i.e. locomotion versus feeding) than overall patterns of size.