NKT cells are CD1d-restricted innate-like T cells expressing both T cell receptor and NK cell markers. The major group of NKT cells in both human and mice is the invariant NKT (iNKT) cells and the best-known function of iNKT cells is their potent anti-tumor function in mice. Since its discovery 25 years ago, the prototype ligand of iNKT cells, α-galactosylceramide (α-GalCer) has been used in over 30 anti-tumor clinical trials with mostly suboptimal outcomes. To realize its therapeutic potential, numerous preclinical models have been developed to optimize the scheme and strategies for α-GalCer-based cancer immunotherapies. Nevertheless, since there is no standard protocol for α-GalCer delivery, we reviewed the preclinical studies with a focus on B16 melanoma model in the goal of identifying the best treatment schemes for α-GalCer treatment. We then reviewed the current progress in developing more clinically relevant mouse models for these preclinical studies, most notably the generation of new mouse models with a humanized CD1d/iNKT cell system. With ever-emerging novel iNKT cell ligands, invention of novel α-GalCer delivery strategies and significantly improved preclinical models for optimizing these new strategies, one can be hopeful that the full potential of anti-tumor potential for α-GalCer will be realized in the not too distant future.
We investigated how cytochrome P450 (CYP) 3A5 polymorphism affects pharmacokinetics of tacrolimus and its interaction with diltiazem in Chinese kidney transplant recipients. Sixty-two CYP3A5 expressers and 58 non-expressers were, respectively, randomized to receive diltiazem supplement or not. Their pharmacokinetic profiles were acquired on 14th day, sixth month, and 18th month post-transplant and compared among groups. A dosing equation was fit based on above data with CYP3A5 genotype and diltiazem co-administration as variables. Then, necessary initial doses with or without diltiazem were calculated and used in 11 CYP3A5 expressers, respectively, when another 11 expressers received routine doses as control. Trough concentration was measured on the third-day post-transplant and patients failed to reach target range were presented in percentage. These two parameters were compared among three groups. Patients were followed up until June 2010, kidney function, biopsy-proved acute rejection, and other adverse events were monitored. Results showed that CYP3A5 expressers needed more tacrolimus to reach therapeutic concentration window and were more susceptible to diltiazem-induced concentration increase than CYP3A5 non-expressers. CYP3A5 polymorphism-guided dosing equation helped to determine appropriate initial doses of tacrolimus in individuals. In conclusion, CYP3A5 polymorphism profoundly influences pharmacokinetics of tacrolimus and helps to individualize tacrolimus dose.
Protein complexes are involved in many important processes in living cells. To understand the mechanisms of these processes, it is necessary to solve the 3D structures of the protein complexes. When protein complex structures have not yet been determined by experiment, protein-protein docking tools can be used to computationally model the structures of these complexes. Here, we present a webserver which provides access to LZerD and Multi-LZerD protein docking tools. The protocol provided by the server have performed consistently among the top in the CAPRI blind evaluation. LZerD docks pairs of structures, while Multi-LZerD can dock three or more structures simultaneously. LZerD uses a soft protein surface representation with 3D Zernike descriptors and explores the binding pose space using geometric hashing. Multi-LZerD performs multi-chain docking by combining pairwise solutions by LZerD. Both methods output full-atom docked models of the input proteins. Users can also input distance constraints between interacting or non-interacting residues as well as residues that locate at the interface or far from the interface. The webserver is equipped with a user-friendly panel that visualizes the distribution and structures of binding poses of top scoring models. The LZerD webserver is available at https://lzerd.kiharalab.org.
Proteins are involved in almost all functions in a living cell, and functions of proteins are realized by their tertiary structures. Obtaining a global perspective of the variety and distribution of protein structures lays a foundation for our understanding of the building principle of protein structures. In light of the rapid accumulation of low-resolution structure data from electron tomography and cryo-electron microscopy, here we map and classify three-dimensional (3D) surface shapes of proteins into a similarity space. Surface shapes of proteins were represented with 3D Zernike descriptors, mathematical moment-based invariants, which have previously been demonstrated effective for biomolecular structure similarity search. In addition to single chains of proteins, we have also analyzed the shape space occupied by protein complexes. From the mapping, we have obtained various new insights into the relationship between shapes, main-chain folds, and complex formation. The unique view obtained from shape mapping opens up new ways to understand design principles, functions, and evolution of proteins.
Chinese renal transplant recipients face a high risk of TB because of their immuno-compromised state and epidemiological prevalence of the disease. Therefore, attention should be given to this differential diagnosis in clinical practice. Balancing the benefits and disadvantages of anti-tuberculosis chemotherapy is of importance for this specific population.
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