Role of the Transplant Pharmacist

At the National Cerebral and Cardiovascular Center, Japan, pharmacists have been involved in drug treatment management and patient care as members of multidisciplinary heart transplant teams that include surgeons, physicians, recipient transplant coordinators, and nurses during the waiting period for heart transplantation (HTx), HTx surgery, and post-HTx. During the waiting period, pharmacists play an important role in adjusting the use of antibiotics, anticoagulants, and antiarrhythmics by patients receiving a ventricular assist device (VAD). During HTx surgery and post-HTx, pharmacists advise physicians regarding the individualized medication protocol for immunosuppression and infection prevention to be used for each patient based on the patient’s pre-HTx characteristics as well as gene polymorphisms. They thus contribute to reducing the burden on the physician through the sharing of tasks. Throughout all three phases of HTx, pharmacists repeatedly provide medication and adherence education to the patients and caregivers. It is hoped that an academic society-led training protocol as well as transplant pharmacists will be established in Japan and other developed countries, and that these specialized transplant pharmacists would then provide individualized pharmacotherapy for the use of various antibiotics, anticoagulants, and immunosuppressive agents that have a narrow range of treatment in VAD and HTx patients

Histone acetyltransferase MOZ acts as a co-activator of Nrf2–MafK and induces tumour marker gene expression during hepatocarcinogenesis

HATs (histone acetyltransferases) contribute to the regulation of gene expression, and loss or dysregulation of these activities may link to tumorigenesis. Here, we demonstrate that expression levels of HATs, p300 and CBP [CREB (cAMP-response-element-binding protein)-binding protein] were decreased during chemical hepatocarcinogenesis, whereas expression of MOZ (monocytic leukaemia zinc-finger protein; MYST3) – a member of the MYST [MOZ, Ybf2/Sas3, Sas2 and TIP60 (Tat-interacting protein, 60 kDa)] acetyltransferase family – was induced. Although the MOZ gene frequently is rearranged in leukaemia, we were unable to detect MOZ rearrangement in livers with hyperplastic nodules. We examined the effect of MOZ on hepatocarcinogenic-specific gene expression. GSTP (glutathione S-transferase placental form) is a Phase II detoxification enzyme and a well-known tumour marker that is specifically elevated during hepatocarcinogenesis. GSTP gene activation is regulated mainly by the GPE1 (GSTP enhancer 1) enhancer element, which is recognized by the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2)–MafK heterodimer. We found that MOZ enhances GSTP promoter activity through GPE1 and acts as a co-activator of the Nrf2–MafK heterodimer. Further, exogenous MOZ induced GSTP expression in rat hepatoma H4IIE cells. These results suggest that during early hepatocarcinogenesis, aberrantly expressed MOZ may induce GSTP expression through the Nrf2-mediated pathway

Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G

The human APOBEC3G (A3G) DNA cytosine deaminase restricts and hypermutates DNA-based parasites including HIV-1. The viral infectivity factor (Vif) prevents restriction by triggering A3G degradation. Although the structure of the A3G catalytic domain is known, the structure of the N-terminal Vif-binding domain has proven more elusive. Here, we used evolution- and structure-guided mutagenesis to solubilize the Vif-binding domain of A3G, thus permitting structural determination by NMR spectroscopy. A smaller zinc-coordinating pocket and altered helical packing distinguish the structure from previous catalytic-domain structures and help to explain the reported inactivity of this domain. This soluble A3G N-terminal domain is bound by Vif; this enabled mutagenesis and biochemical experiments, which identified a unique Vif-interacting surface formed by the alpha1-beta1, beta2-alpha2 and beta4-alpha4 loops. This structure sheds new light on the Vif-A3G interaction and provides critical information for future drug development