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Seismic retrofitting is the most effective way to reduce casualties from earthquakes. Yet, seismic retrofitting of vulnerable residential structures faces many impediments. As no single policy measure can overcome these obstacles, seismic retrofitting requires that multiple policy measures be applied in tandem and therefore policy packages are necessary. As seismic threats are spread over multiple locales, differing in their characteristics, no single policy package is likely to fit all settings. Indeed, efforts to promote seismic retrofitting in California, New Zealand and Israel show high variability in success across different locales. Our study builds upon previous work which outlined three potential policy packages for seismic retrofitting, led by market forces, local government and central government respectively. In this study we advance an asymmetric decentralization approach to match the most appropriate policy package to local conditions. We combine this with seismic vulnerability assessment to prioritize the national allocation of retrofitting funds. The approach is applied to the Israeli case, a country that is prone to infrequent large earthquakes and in which there is a large, substandard housing stock. [ABSTRACT FROM AUTHOR]

Abstract: Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances. [Copyright &y& Elsevier]

Abstract: The development of targeting approaches to selectively release chemotherapeutic drugs into malignant tissue is a major challenge in anticancer therapy. We have synthesized an N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer–drug conjugate with an AB3 self-immolative dendritic linker. HPMA copolymers are known to accumulate selectively in tumors. The water-soluble polymer–drug conjugate was designed to release a triple payload of the hydrophobic drug paclitaxel as a result of cleavage by the endogenous enzyme cathepsin B. The polymer–drug conjugate exhibited enhanced cytotoxicity on murine prostate adenocarcinoma (TRAMP C2) cells in comparison to a classic monomeric drug–polymer conjugate. [Copyright &y& Elsevier]

KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit. [Display omitted] • CRAF depletion inhibits tumor growth but not ERK signaling in KRAS mutant cells • CRAF kinase domain dimerization and not kinase activity is essential for tumorigenesis • Quantitative proteomics reveal increased levels of CRAF:ARAF versus CRAF:BRAF dimers • ARAF dimers promote ERK signaling upon CRAF loss, leading to cell-cycle arrest Venkatanarayan et al. demonstrate that the CRAF kinase domain and not kinase activity is essential for KRAS -driven tumorigenesis. Quantitative proteomics identify increased levels of CRAF:ARAF dimers in KRAS mutant cells. CRAF loss or dimer disruption results in dysregulated ERK activation and cell-cycle arrest. [ABSTRACT FROM AUTHOR]

Abstract: Self-immolative dendritic prodrugs, activated through a single catalytic reaction by a specific enzyme, could offer significant advantages in inhibition of tumor growth relative to monomeric prodrug, especially if the targeted or secreted enzyme exists at relatively low levels in the malignant tissue. We have designed and synthesized new AB3 self-immolative dendritic prodrug system that releases three active drugs by a single cleavage of the enzyme penicillin-G-amidase. The cleavage signal is transferred from the dendron focal point to its periphery through fast elimination reactions and the design leads to three-fold signal amplification. In cell-growth inhibition assays, the elimination-based AB3 self-immolative dendritic prodrug was significantly more effective than a cyclization-based AB3 dendritic prodrug. [Copyright &y& Elsevier]