Highly charged compounds typically suffer from low membrane permeability and thus are generally regarded as sub-optimal drug candidates. Nonetheless, the highly charged drug fosmidomycin and its more active methyl-derivative FR900098 have proven parasiticidal activity against erythrocytic stages of the malaria parasite Plasmodium falciparum. Both compounds target the isoprenoid biosynthesis pathway present in bacteria and plastid-bearing organisms, like apicomplexan parasites. Surprisingly, the compounds are inactive against a range of apicomplexans replicating in nucleated cells, including Toxoplasma gondii. Since non-infected erythrocytes are impermeable for FR90098, we hypothesized that these drugs are taken up only by erythrocytes infected with Plasmodium. We provide evidence that radiolabeled FR900098 accumulates in theses cells as a consequence of parasite-induced new properties of the host cell, which coincide with an increased permeability of the erythrocyte membrane. Babesia divergens, a related parasite that also infects human erythrocytes and is also known to induce an increase in membrane permeability, displays a similar susceptibility and uptake behavior with regard to the drug. In contrast, Toxoplasma gondii-infected cells do apparently not take up the compounds, and the drugs are inactive against the liver stages of Plasmodium berghei, a mouse malaria parasite. Our findings provide an explanation for the observed differences in activity of fosmidomycin and FR900098 against different Apicomplexa. These results have important implications for future screens aimed at finding new and safe molecular entities active against P. falciparum and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery.

Liver-stage development of Plasmodium parasites represents a dramatic expansion phase for the malarial parasite between vector transmission and onset

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis that is frequently diagnosed at an advanced stage. Although less common than other malignant diseases, it currently ranks as the fourth most common cause of cancer-related death in the European Union with a five-year survival rate of below 9%. Surgical resection, followed by adjuvant chemotherapy, remains the only potentially curative treatment but only a minority of patients is diagnosed with locally resectable, non-metastatic disease. Patients with advanced disease are treated with chemotherapy but high rates of treatment resistance and unfavorable side-effect profiles of some of the used regimens remain major challenges. Biomarkers reflect pathophysiological or physiological processes linked to a disease and can be used as diagnostic, prognostic and predictive tools. Thus, accurate biomarkers can allow for better patient stratification and guide therapy choices. Currently, the only broadly used biomarker for PDAC, CA 19-9, has multiple limitations and the need for novel biomarkers is urgent. In this review, we highlight the current situation, recent discoveries and developments in the field of biomarkers of PDAC and their potential clinical applications.

Malaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that are regarded to be “clinically and diagnostically silent.” Merozoites, which egress from hepatocytes, infect erythrocytes in periodic cycles and induce disease. How the host innate immune system contributes to disease outcomes and to the induction of effector cells during malaria remains unclear. Likewise, how the initial liver stages may shape responses to blood-stage parasites is unknown. Here, using both sporozoite- and blood-stage-induced infections with the rodent malaria parasite Plasmodium berghei ANKA, we show that the MyD88 and Toll-like receptor 2/4 (TLR2/4) pathways play critical roles in the development of experimental cerebral malaria (ECM). Strikingly, an absolute dependence on MyD88 and TLR2/4 was observed when infections were initiated with sporozoites. In addition, we show that caspase-1 activation of interleukin-1β (IL-1β) and IL-18, which is associated with the inflammasome pathway, does not contribute to P. berghei ANKA-induced immunopathology. Consistent with these data, prophylactic cover with the IL-1β antagonist anakinra did not reduce the incidence of ECM. Therefore, we propose that protection against ECM due to loss of TLR signaling functions is caused by effector mechanisms other than IL-1β activation.