Expression of RFC/SLC19A1 is Associated with Tumor Type in Bladder Cancer Patients

Urinary bladder cancer (UBC) ranks ninth in worldwide cancer. In Egypt, the pattern of bladder cancer is unique in that both the transitional and squamous cell types prevail. Despite much research on the topic, it is still difficult to predict tumor progression, optimal therapy and clinical outcome. The reduced folate carrier (RFC/SLC19A1) is the major transport system for folates in mammalian cells and tissues. RFC is also the primary means of cellular uptake for antifolate cancer chemotherapeutic drugs, however, membrane transport of antifolates by RFC is considered as limiting to antitumor activity. The purpose of this study was to compare the mRNA expression level of RFC/SLC19A1 in urothelial and non-urothelial variants of bladder carcinomas. Quantification of RFC mRNA in the mucosa of 41 untreated bladder cancer patients was performed using RT-qPCR. RFC mRNA steady-state levels were ∼9-fold higher (N = 39; P<0.0001) in bladder tumor specimens relative to normal bladder mRNA. RFC upregulation was strongly correlated with tumor type (urothelial vs. non-urothelial; p<0.05) where median RFC mRNA expression was significantly (p<0.05) higher in the urothelial (∼14-fold) compared to the non-urothelial (∼4-fold) variant. This may account for the variation in response to antifolate-containing regimens used in the treatment of either type. RFC mRNA levels were not associated with tumor grade (I, II and III) or stage (muscle-invasive vs. non-muscle invasive) implying that RFC cannot be used for prognostic purposes in bladder carcinomas and its increased expression is an early event in human bladder tumors pathogenesis. Further, RFC can be considered as a potential marker for predicting response to antifolate chemotherapy in urothelial carcinomas

Nickel and Palladium Complexes with Reactive σ‐Metal‐Oxygen Covalent Bonds

This article reviews the chemistry of nickel and palladium complexes with terminally bound hydroxide and alkoxide ligands. The research carried out in our group is discussed in the context of the general literature. It is shown that suitable methods of synthesis, combined with the choice of adequate ligands allow the isolation of a range of stable complexes. This has enabled a detailed investigation of the chemical reactivity of the M¿O bonds, once believed to be intrinsically weak. The elucidation of trends in thermodynamic stability and kinetic lability is the key for a better understanding of the reactivity of this class of compounds, that combines basic and nucleophilic properties with typical organometallic patterns, like ß¿hydrogen elimination. Based on reversible acid¿base exchange and CO2 insertion reactions, we discuss how the polarity of the M¿OR bonds influence their relative stability, their hydrolytic sensitivity and their tendency to react with electrophiles.This work was supported by the Ministry of Science, Education and Universities of Spain (MCIU), the Spanish Research Agency (AEI), the European Union and the Polytechnic University of Valencia (UPV) through the Projects PGC2018‐095768‐B‐100 (MCIU‐AEI‐EU, granted to IIQ) and PAID‐06‐18 (UPV, granted to ITQ). LMMP gratefully thanks a “Juan de la Cierva” fellowship (IJCI‐2016‐27966)

Kinetics of Cisplatin Binding to Cellular DNA and Modulations by Thiol-Blocking Agents and Thiol Drugs

DNA platination by cisplatin (CDDP) was investigated in peripheral blood mononuclear cells and ovarian cancer cells using atomic absorption spectroscopy. Plots showing the amount of platinum (Pt) bound to DNA versus the molar concentration of cisplatin in the incubation medium ([CDDP]) were nonlinear. For [CDDP] \u3c about 5 μM, the amount of Pt bound to DNA increased slowly with added drug. However, for larger [CDDP], the slope of the plot increased significantly. To study the role of thiols in affecting cisplatin binding to DNA, cells were treated with N-ethylmaleimide, which modifies thiol groups, rendering them incapable of binding cisplatin. Analysis using high-pressure liquid chromatography showed that ∼99% of cellular glutathione was modified by Nethylmaleimide. A plot of the amount of Pt bound to DNA versus [CDDP] for thiol-blocked cells is linear, with a slope similar to that at unblocked cells at high [CDDP]. Neither S-2-(3 aminopropylamino)ethanethiol (WR-1065) nor mesna, when added at clinically achievable concentrations (i.e., \u3c ∼300 μM), affected DNA platination. However, D]NA platination was totally abolished by millimolar concentrations of the drug thiols (∼1.25 mM WR-1065 or ∼5 mM mesna). Thus, the data show that endogenous thiols intercept cellular cisplatin, but this mechanism is less important at high [CDDP]. Moreover, therapeutic concentrations of drug thiols do not significantly affect DNA platination. A simple model that reproduces the experimental results of the amount of cisplatin binding to DNA as a function of [CDDP], time, and thiol content is proposed. The model takes into account passage of cisplatin and thiols through the cell membrane, binding of cisplatin to cellular thiols, and platination of DNA

The origins of repetitive thought in rumination: Separating cognitive style from deficits in inhibitory control over memory

Background and objectives Rumination is a major contributor to the maintenance of affective disorders and has been linked to memory control deficits. However, ruminators often report intentionally engaging in repetitive thought due to its perceived benefits. Deliberate re-processing may lead to the appearance of a memory control deficit that is better explained as a difference in cognitive style. Methods Ninety-six undergraduate students volunteered to take part in a direct-suppression variant of the Think/No-Think paradigm after which they completed self-report measures of rumination and the degree to which they deliberately re-processed the to-be-suppressed items. Results We demonstrate a relation between rumination and impaired suppression-induced forgetting. This relation is robust even when controlling for deliberate re-processing of the to-be-suppressed items, a behavior itself related to both rumination and suppression. Therefore, whereas conscious fixation on to-be-suppressed items reduced memory suppression, it did not fully account for the relation between rumination and memory suppression. Limitations The current experiment employed a retrospective measure of deliberate re-processing in the context of an unscreened university sample; future research might therefore generalize our findings using an online measure of deliberate re-processing or within a clinical population. Conclusions We provide evidence that deliberate re-processing accounts for some – but not all – of the relation between rumination and suppression-induced forgetting. The present findings, observed in a paradigm known to engage top-down inhibitory modulation of mnemonic processing, provide the most theoretically focused evidence to date for the existence of a memory control deficit in rumination