Oncotarget
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Renal ischemia-reperfusion (rI/R) could cause remote acute lung injury (ALI) and combination of these two organ injuries can remarkably increase the mortality. This study aims to determine whether dexmedetomidine, an α2-adrenoreceptor agonist sedative, can ameliorate pulmonary microvascular hyper-permeability following rI/R injury and explore the underlying mechanisms. In vivo, C57BL/6J mice received dexmedetomidine (25µg/kg, i.p.) in the absence or presence of α2-adrenergic antagonist atipamezole (250µg/kg, i.p.) or focal adhesion kinase (FAK) inhibitor (30mg/kg, i.p.) before bilateral renal pedicle clamping for 45 minutes followed by 24 hours reperfusion. ⋯ In vitro, the permeability of PMVECs monolayer following exposure to serum from rI/R mice was increased significantly, and decreased by dexmedetomidine. Dexmedetomidine increased phospho-tyrosine397FAK in a time- and dose-dependent manner, which was correlated with the changes in trans-endothelial permeability. Our data indicated that dexmedetomidine is able to ameliorate remote pulmonary microvascular hyper-permeability induced by rI/R, at least in part, via FAK modulation.
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While the molecular chaperone heat shock protein 90 (HSP90) is involved in a multitude of physiological and pathological processes, its role relating to pulmonary arterial hypertension (PAH) remains unclear. In the present study, we investigated the effect in which HSP90 improves pulmonary arteriole remodeling, and explored the therapeutic utility of targeting HSP90 as therapeutic drug for PAH. By Elisa and immunohistochemistry, HSP90 was found to be increased in both plasma and membrane walls of pulmonary arterioles from PAH patients. ⋯ The inflammatory response attributed to PH could be attenuated by 17-AAG through reduction of NF-κB signaling. Moreover, 17-AAG was found to suppress PDGF-stimulated proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through induction of cell cycle arrest in the G1 phase. In conclusion, HSP90 inhibitor 17-AAG could improve pulmonary arteriole remodeling via inhibiting the excessive proliferation of PASMCs, and inhibition of HSP90 may represent a therapeutic avenue for the treatment of PAH.
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Osteosarcoma is an aggressive bone cancer that has a high propensity for metastasis to the lungs. Patients with metastatic disease face a very poor prognosis. Therefore, novel therapeutics, efficiently suppressing the metastatic process, are urgently needed. ⋯ Cilengitide induced a decline in cell viability, blocked the cell cycle in the G1 phase and caused anoikis by activation of the Hippo pathway. In a xenograft orthotopic mouse model cilengitide minimally affected intratibial primary tumor growth but, importantly, suppressed pulmonary metastasis. The data demonstrate that targeting αvβ3 and αvβ5 integrins in osteosarcoma should be considered as a novel therapeutic option for patients with metastatic disease.
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Because the need of clinical prognostic evaluation by specific metastatic organ, we aim to analyze the prognostic factors in lung cancer patients with M1b disease with Surveillance Epidemiology and End-Results database (SEER). This retrospective study evaluated lung cancer patients of adenocarcinoma (AD), squamous cell carcinoma (SQCC), and small cell lung cancer (SCLC) selected from SEER. We provided the prognostic correlates of overall survival (OS) and lung cancer-specific survival (LCSS) in this population. 23,679 eligible patients were included. ⋯ In conclusion, we estimated multiple survival outcomes by histology of primary tumor and sites of metastasis. Liver metastasis is found to be the worst prognostic factor for AD and SCLC patients with distant metastasis. More in-depth research is warranted to identify patients who are prone to develop distance metastasis, especially to liver.
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Review
DMET™ (Drug Metabolism Enzymes and Transporters): a pharmacogenomic platform for precision medicine.
In the era of personalized medicine, high-throughput technologies have allowed the investigation of genetic variations underlying the inter-individual variability in drug pharmacokinetics/pharmacodynamics. Several studies have recently moved from a candidate gene-based pharmacogenetic approach to genome-wide pharmacogenomic analyses to identify biomarkers for selection of patient-tailored therapies. In this aim, the identification of genetic variants affecting the individual drug metabolism is relevant for the definition of more active and less toxic treatments. This review focuses on the potentiality, reliability and limitations of the DMET™ (Drug Metabolism Enzymes and Transporters) Plus as pharmacogenomic drug metabolism multi-gene panel platform for selecting biomarkers in the final aim to optimize drugs use and characterize the individual genetic background.