Clinical impact of pharmacogenetic risk variants in a large chinese cohort.

Incorporating pharmacogenetics into clinical practice promises to improve therapeutic outcomes by optimizing drug selection and dosage based on genetic factors affecting drug response. A key advantage of PGx-guided therapy is to decrease the likelihood of adverse events. To evaluate the clinical impact of PGx risk variants, we performed a retrospective study using genetic and clinical data from the largest Han Chinese cohort, comprising 486,956 individuals, assembled by the Taiwan Precision Medicine Initiative. We found that nearly all participants carried at least one genetic variant that could affect drug response, with many carrying multiple risk variants. Here we show the detailed analyses of four gene-drug pairs, azathioprine (NUDT15/TPMT), clopidogrel (CYP2C19), statins (ABCG2/CYP2C9/SLCO1B1), and NSAIDs (CYP2C9), for which sufficient data exists for statistical power. While the results validate previous findings that PGx risk variants are significantly associated with drug-related adverse events or ineffectiveness, the excess risk of adverse events or lack of efficacy is small compared to that found in those without the PGx risk variants, and most patients with PGx variants do not suffer from adverse events. Our results point to the complexity of implementing PGx in clinical practice and the need for integrative approaches to optimize precision medicine

A Novel Peptide Enhances Therapeutic Efficacy of Liposomal Anti-Cancer Drugs in Mice Models of Human Lung Cancer

Lung cancer is the leading cause of cancer-related mortality worldwide. The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues. In this study, we isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC) cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells. Both the targeting phage and the synthetic peptide recognized the surgical specimens of NSCLC with a positive rate of 75% (27 of 36 specimens). In severe combined immunodeficiency (SCID) mice bearing NSCLC xenografts, the targeting phage specifically bound to tumor masses. The tumor homing ability of the targeting phage was inhibited by the cognate synthetic peptide, but not by a control or a WTY-mutated peptide. When the targeting peptide was coupled to liposomes carrying doxorubicin or vinorelbine, the therapeutic index of the chemotherapeutic agents and the survival rates of mice with human lung cancer xenografts markedly increased. Furthermore, the targeting liposomes increased drug accumulation in tumor tissues by 5.7-fold compared with free drugs and enhanced cancer cell apoptosis resulting from a higher concentration of bioavailable doxorubicin. The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy

Epstein–Barr Virus: New Research in Epithelial Carcinoma

Epstein-Barr virus (EBV) can not be detected in untransformed squamous metaplastic epithelia of nasophparynx, but can be detected as an episomal form in certain nasopharyngeal carcinoma (NPC) biopsy specimens and cell lines. In the latter only a subpopulation of NPC cells contains EBV DNA. It appears only in the early passages, but disappears in all lines after 30 passages. EBV can not infect NPC cells and other transformed epithelial cells directly, but can only infect the transformed epithelial cells if the latter express IgA receptor (IgAR) through IgAR mediated endocytosis. EBVinfected (EBV+) NPC cells show clonal terminal repeats of EBV DNA. EBV enhances the proliferation rate, invasion activity and the expressions of some growth factors and their receptors, the cytokines, invasion and metastasis-related genes in vitro. Untransformed squamous metaplastic epithelia of nasopharynx do not express EBV receptor or IgAR. The IgAR expression and EBV infection in severe dysplastic epithelia and carcinoma in situ of nasopharynx are unusual. But about 70 to 80% of tumor cells in each EBV+ NPC case are infected by EBV. The EBV+ NPC cells in the biopsy specimens have a geographical distribution with areas of clonal expansion and some EBV+ lymphocytic infiltration. Each biopsy specimen contains 4 types of NPC cells: tumor cells do not express IgAR and not contain EBV DNA; tumor cells express strong IgAR and contain EBV or not; tumor cells express very weak or no IgAR but contain EBV DNA. The EBV+ xenografts in the SCID mice grow faster and bigger than the EBVgrafts. The EBV+ tumor mass also has a clonal terminal repeats of EBV DNA sequence. In the EBV- NPC xenograft, a fraction of the cells expresses moderate EGFR protein. However, in EBV+ xenograft, some tumor cells contain both EBV signal and strong EGFR protein expression, but other fraction of those tumor cells only contain EBV signal without EGFR protein. The same phenomenon has also presented in the double localization of EBV signal and MDM2 protein. The EBV latent membrane protein (LMP-1) in the NPC cells can not regulated the host gene expression which is not expressed in the host cells, but can indirectly regulated certain host gene expression which are expressed in the host cells. The major function of EBV in infected NPC cells is to enhance tumor cell progression but less likely to play a role as an initiator or promoter in NPC pathogenesis