Effects of RANKL-Targeted Therapy in Immunity and Cancer.

The role of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK system is well characterized within bone, where RANKL/RANK signaling mediates osteoclastogenesis and bone resorption. However, this system has also been shown to influence biologic processes beyond the skeletal system, including in the immune system and in cancer. RANKL/RANK signaling is important in lymph-node development, lymphocyte differentiation, dendritic cell survival, T-cell activation, and tolerance induction. The RANKL/RANK axis may also have direct, osteoclast-independent effects on tumor cells. Indeed, activity of the RANKL/RANK pathway in cancer cells has been correlated with tumor progression and advanced disease. Denosumab, a fully human monoclonal antibody against RANKL, inhibits osteoclastogenesis and is widely used not just for the treatment of osteoporosis, but for the prevention of skeletal-related events from bone metastases in solid malignancies such as breast and prostate cancer. The potential effects of denosumab on the immune system have been largely ignored. Nevertheless, with the emergence of immunotherapies for cancer, denosumab may impact the effectiveness of these therapies, especially if they are given in combination. In this article, we review the role of RANKL/RANK in bone, immunity, and cancer. Examining the potential effects of routine treatment with denosumab beyond the bone represents an important area of investigation

Fragmentation Mechanisms of Oxofatty Acids Via High-Energy Collisional Activation

AbstractUpon high-energy collisional activation, oxofatty-acid ions undergo fragmentations to produce a unique pattern of product ions by which the position of the ketone is revealed. The reactions occurring in the vicinity of the ketone, which are the subject of this article, produce a spectral pattern that is not symmetrical. Although cleavages of α, β, and γ C–C bonds occur on the side proximal to the charge site, giving α, β, and γ ions, respectively, there is only a γ′ ion formed on the side distal to the charge site. The resulting lack of symmetry seemingly contradicts the concept that the reactions are independent of the charge (i.e., that they are charge remote). To eliminate any interaction between the charge and the reaction site, oxofatty acids were linked to glycyrrhetic acid, a steroid with a rigid polycyclic system. The fragmentation pattern remains the same, indicating that the effect does not depend on charge but rather on the ketone. Isotopic labeling and MS/MS/MS studies confirm that the fragmentations of C–C bonds in the vicinity of the ketone are complex, charge-remote processes. Formation of [M − H − H2O]− and [M − H − CO2]− anions and the ion that is formed by homolytic cleavage of the β bond at the side distal to the charge, however, are charge directed

Tensor-product representations for string-net condensed states

We show that general string-net condensed states have a natural representation in terms of tensor product states (TPS) . These TPS's are built from local tensors. They can describe both states with short-range entanglement (such as the symmetry breaking states) and states with long-range entanglement (such as string-net condensed states with topological/quantum order). The tensor product representation provides a kind of 'mean-field' description for topologically ordered states and could be a powerful way to study quantum phase transitions between such states. As an attempt in this direction, we show that the constructed TPS's are fixed-points under a certain wave-function renormalization group transformation for quantum states.Comment: 11 pages. RevTeX

Strength distribution of repeatedly broken chains

We determine the probability distribution of the breaking strength for chains of N links, which have been produced by repeatedly breaking a very long chain.Comment: 4 pages, 1 figur

Structural determination of oxofatty acids by charge-remote fragmentations

A strategy is described to locate the carbonyl position in oxofatty acids by utilizing charge-remote fragmentations of various molecular ions that are desorbed by fast atom bombardment (FAB). Oxofatty acids were cationized with alkali metal ions (Li+, Na+, K+, Rb+, and Cs+) to form [M+2Met − H]+ or alkaline earth metal ions (Mg2+, Ca2+, Sr2+ or Ba2+) to form [M+Met−H]+ in the gas phase. The cationized acids undergo charge-remote fragmentations upon high-energy activation, giving a product-ion pattern that has a gap corresponding to the oxo position and bordered by two high-intensity peaks. One of the peaks corresponds to an ion that is formed by the cleavage of the C-C bond β to the oxo position and proximal to the charge (β ion), whereas the other is formed from the cleavage of the C-C bond γ to the oxo position and distal to the charge (γ′ ion). The oxo position is easily determined by identifying the gap and the β and γ′ ions. Furthermore, there are two competing patterns of fragments in a CAD spectrum of an oxofatty acid or ester [M+Li]+ ion. These arise because Li+ attaches to either the oxo or the carboxylic end, as was confirmed by ab initio molecular orbital calculations. The results demonstrate that control of the fragmentation can be guided by an understanding of metal-ion affinities. Collisional activation of the anionic carboxylates gives results that are similar to those for positive ions, showing that the process is not related to the charge status. Collisional activation of [M+H]+ ions does not give structural information because the charge migrates, leading to charge-mediated fragmentations