Nuclear magnetic resonance studies of a cisplatin-modified DNA 9-mer

Cisplatin is a platinum-based anti-cancer drug that is used to treat a variety of cancers; although it is best known for its effectiveness in treating testicular cancer. Since its serendipitous discovery and subsequent FDA approval in 1978, 1 cisplatin’s mechanism of action has been widely studied. Cisplatin is able to enter the cell through passive diffusion and hydrolyze to a more active form. It then forms 1,2-intrastrand cross-links, distorting the helical structure of DNA. While the distorted helical structure of DNA may be enough to stop replication and transcription, leading to cell death, other mechanisms have also been proposed.2 The purpose of my research is to further the mechanistic studies of cisplatin-modified DNA by using a DNA 9-mer. A 9-mer control duplex and cisplatin-modified 9-mer were first prepared and HPLC purified. After method development using an 11-mer duplex, analysis of the 9-mer duplexes was performed. 1 H NMR was the primary analysis component, with experiments including melting experiments, 2D NOESY and COSY experiments and base pair opening experiments. It was found that the cisplatin-modified duplex is less stable than the control by about 10°C, which is not surprising given the nature by which platinum disrupts the helical structure of DNA. Base pair opening experiments were not performed on the modified duplex, however base pair opening experiments on the control duplex were performed, and the data were collected for future analysis

Acute kidney injury in renal transplant recipients undergoing cardiac surgery

BACKGROUND: Acute kidney injury (AKI) is a key risk factor for chronic kidney disease in the general population, but has not been investigated in detail among renal transplant recipients (RTRs). We investigated the incidence, severity and risk factors for AKI following cardiac surgery among RTRs compared with non-RTRs with otherwise similar clinical characteristics. METHODS: We conducted a retrospective cohort study of RTRs (n = 83) and non-RTRs (n = 83) who underwent cardiac surgery at two major academic medical centers. Non-RTRs were matched 1:1 to RTRs by age, preoperative (preop) estimated glomerular filtration rate and type of cardiac surgery. We defined AKI according to Kidney Disease: Improving Global Outcomes criteria. RESULTS: RTRs had a higher rate of AKI following cardiac surgery compared with non-RTRs [46% versus 28%; adjusted odds ratio 2.77 (95% confidence interval 1.36-5.64)]. Among RTRs, deceased donor (DD) versus living donor (LD) status, as well as higher versus lower preop calcineurin inhibitor (CNI) trough levels, were associated with higher rates of AKI (57% versus 33% among DD-RTRs versus LD-RTRs; P = 0.047; 73% versus 36% among RTRs with higher versus lower CNI trough levels, P = 0.02). The combination of both risk factors (DD status and higher CNI trough level) had an additive effect (88% AKI incidence among patients with both risk factors versus 25% incidence among RTRs with neither risk factor, P = 0.004). CONCLUSIONS: RTRs have a higher risk of AKI following cardiac surgery compared with non-RTRs with otherwise similar characteristics. Among RTRs, DD-RTRs and those with higher preop CNI trough levels are at the highest risk

Iron, Hepcidin, and Death in Human AKI

BACKGROUND: Iron is a key mediator of AKI in animal models, but data on circulating iron parameters in human AKI are limited. METHODS: We examined results from the ARF Trial Network study to assess the association of plasma catalytic iron, total iron, transferrin, ferritin, free hemoglobin, and hepcidin with 60-day mortality. Participants included critically ill patients with AKI requiring RRT who were enrolled in the study. RESULTS: Of the 807 study participants, 409 (51%) died by day 60. In both unadjusted and multivariable adjusted models, higher plasma concentrations of catalytic iron were associated with a significantly greater risk of death, as were lower concentrations of hepcidin. After adjusting for other factors, patients with catalytic iron levels in the highest quintile versus the lowest quintile had a 4.06-fold increased risk of death, and patients with hepcidin levels in the lowest quintile versus the highest quintile of hepcidin had a 3.87-fold increased risk of death. These findings were consistent across multiple subgroups. Other iron markers were also associated with death, but the magnitude of the association was greatest for catalytic iron and hepcidin. Higher plasma concentrations of catalytic iron and lower concentrations of hepcidin are each independently associated with mortality in critically ill patients with AKI requiring RRT. CONCLUSIONS: These findings suggest that plasma concentrations of catalytic iron and hepcidin may be useful prognostic markers in patients with AKI. Studies are needed to determine whether strategies to reduce catalytic iron or increase hepcidin might be beneficial in this patient population