Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.

It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.

Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery.

OBJECTIVE: This was an evaluation of the cost-effectiveness of oral dabigatran etexilate compared with subcutaneous low-molecular-weight heparin (enoxaparin) for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR) and total hip replacement (THR) surgery from the perspective of the UK National Health Service. METHODS: Dabigatran etexilate (220 mg once daily) was compared with enoxaparin (40 mg once daily) in patients undergoing TKR (duration of prophylaxis, 6-10 days) and THR (duration of prophylaxis, 28-35 days). The 10-week acute postsurgical phase was modeled using a decision tree. A Markov process (1-year cycle length) was used to model long-term events (recurrent VTE, postthrombotic syndrome, and consequences of intracranial hemorrhage) for patients' remaining lifetimes. Relative risks for VTE and bleeding events were derived from 2 Phase III studies that compared dabigatran etexilate with enoxaparin 40 mg once daily. The probabilities of long-term events were estimated using data from published longitudinal studies. RESULTS: Rates of VTE and bleeding events did not differ significantly between dabigatran etexilate and enoxaparin. Dabigatran etexilate was less costly than enoxaparin in TKR and substantially less costly in THR, primarily due to differences in administration costs. The cost of prophylaxis for THR patients, including drugs and administration costs, was estimated at pound 137 for dabigatran etexilate and pound 237 for enoxaparin ( pound 7 for nursing time during the hospital stay, pound 91 for nurse home visits for administration after hospital discharge, and an additional pound 2 in drug costs). At a willingness-to-pay threshold of pound 20,000 per quality-adjusted life-year, the probability of cost-effectiveness for dabigatran etexilate was 75% in TKR and 97% in THR. These results were robust across a range of sensitivity analyses. CONCLUSION: From the perspective of the UK National Health Service, thromboprophylaxis with dabigatran etexilate was cost-saving compared with enoxaparin 40 mg once daily, with comparable efficacy and safety profiles.

Four and a half LIM protein 1 binds myosin-binding protein C and regulates myosin filament formation and sarcomere assembly.

Four and a half LIM protein 1 (FHL1/SLIM1) is highly expressed in skeletal and cardiac muscle; however, the function of FHL1 remains unknown. Yeast two-hybrid screening identified slow type skeletal myosin-binding protein C as an FHL1 binding partner. Myosin-binding protein C is the major myosin-associated protein in striated muscle that enhances the lateral association and stabilization of myosin thick filaments and regulates actomyosin interactions. The interaction between FHL1 and myosin-binding protein C was confirmed using co-immunoprecipitation of recombinant and endogenous proteins. Recombinant FHL2 and FHL3 also bound myosin-binding protein C. FHL1 impaired co-sedimentation of myosin-binding protein C with reconstituted myosin filaments, suggesting FHL1 may compete with myosin for binding to myosin-binding protein C. In intact skeletal muscle and isolated myofibrils, FHL1 localized to the I-band, M-line, and sarcolemma, co-localizing with myosin-binding protein C at the sarcolemma in intact skeletal muscle. Furthermore, in isolated myofibrils FHL1 staining at the M-line appeared to extend partially into the C-zone of the A-band, where it co-localized with myosin-binding protein C. Overexpression of FHL1 in differentiating C2C12 cells induced "sac-like" myotube formation (myosac), associated with impaired Z-line and myosin thick filament assembly. This phenotype was rescued by co-expression of myosin-binding protein C. FHL1 knockdown using RNAi resulted in impaired myosin thick filament formation associated with reduced incorporation of myosin-binding protein C into the sarcomere. This study identified FHL1 as a novel regulator of myosin-binding protein C activity and indicates a role for FHL1 in sarcomere assembly.