Explore the vast range of titles available.

The enzyme aminopeptidase N (APN, also known as CD13) is a Zn2+ dependent membrane‐bound ectopeptidase that degrades preferentially proteins and peptides with a N‐terminal neutral amino acid. Aminopeptidase N has been associated with the growth of different human cancers and suggested as a suitable target for anti‐cancerous therapy. Different approaches have been used to develop new drugs directed to this target, including enzyme inhibitors as well as APN‐targeted carrier constructs. This review discusses the prevalence and possible function of APN in malignant diseases, mainly solid tumors, as well as its “drugability” evaluated in preclinical in vivo models, and also provides a brief overview of current clinical trials focused on APN. (Cancer Sci 2011; 102: 501–508)

There is ample support for developmental regulation of glioblastoma stem cells. To examine how cell lineage controls glioblastoma stem cell function, we present a cross-species epigenome analysis of mouse and human glioblastoma stem cells. We analyze and compare the chromatin-accessibility landscape of nine mouse glioblastoma stem cell cultures of three defined origins and 60 patient-derived glioblastoma stem cell cultures by assay for transposase-accessible chromatin using sequencing. This separates the mouse cultures according to cell of origin and identifies three human glioblastoma stem cell clusters that show overlapping characteristics with each of the mouse groups, and a distribution along an axis of proneural to mesenchymal phenotypes. The epigenetic-based human glioblastoma stem cell clusters display distinct functional properties and can separate patient survival. Cross-species analyses reveals conserved epigenetic regulation of mouse and human glioblastoma stem cells. We conclude that epigenetic control of glioblastoma stem cells primarily is dictated by developmental origin which impacts clinically relevant glioblastoma stem cell properties and patient survival. The epigenetic regulation of glioblastoma stem cell (GSC) function remains poorly understood. Here, the authors compare the chromatin accessibility landscape of GSC cultures from mice and patients and suggest that the epigenome of GSCs is cell lineage-regulated and could predict patient survival.

The fluorometric microculture cytotoxicity assay (FMCA) is a nonclonogenic microplate-based cell viability assay used for measurement of the cytotoxic and/or cytostatic effect of different compounds in vitro . The assay is based on hydrolysis of the probe, fluorescein diacetate (FDA) by esterases in cells with intact plasma membranes. The assay is available as both a semiautomated 96-well plate setup and a 384-well plate version fully adaptable to robotics. Experimental plates are prepared with a small amount of drug solution and can be stored frozen. Cells are seeded on the plates and cell viability is evaluated after 72 h. The protocol described here is applicable both for cell lines and freshly prepared tumor cells from patients and is suitable both for screening in drug development and as a basis for a predictive test for individualization of anticancer drug therapy.

b-AP15 is a novel inhibitor of proteasome activity, with a different mechanism of action than the available and widely used proteasome inhibitors such as bortezomib. b-AP15 inhibits the deubiquitinating activity of the regulatory subunit of the proteasome, necessary for protein degradation, and induces cytotoxicity impairing tumor growth in mouse models. The compound may represent an alternative therapeutic approach with a broader spectrum of applicability than current proteasome inhibitors. Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles 1 , 2 . The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target 3 . Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle–associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2 . We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.

Background High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents. Methods We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death. Results The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model. Conclusion Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.

Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.

Urban flooding is a growing concern in Northern Europe. While all countries in this region invest substantial resources into urban flood risk management, all property owners have unequal opportunity to have their flood risk managed. This paper presents the notion of equity in the urban flood risk management, focusing on urban flood exposure and compensation after sewage surcharge on the 31 August 2014 cloudburst over Malmö in Sweden. All damage claims and the procedures assessing them were analysed based on the type of sewer system (combined or separated) that affected the properties. The results demonstrated considerable systemic inequity in both flood exposure and damage compensation. The owners of properties connected to combined systems were four times more likely to make a damage claim, while having their damage claims approved just over half as often, compared with owners of properties connected to separated sewage systems. Considering the multifaceted nature of both inequities and their possible resolution, current praxis is not sufficient for the management of future urban drainage systems; not only concerning changing climatic conditions but also concerning social conditions.

Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses.

Purpose Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. Methods A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy. Results Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. Conclusions Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.

We address an inference issue where the value of a covariate is measured at the date of the survey but is used to explain behavior that has occurred long before the survey. This causes bias because the value of the covariate does not follow the temporal order of events. We propose an expected likelihood approach to adjust for such bias and illustrate it with data on the effects of educational level achieved by the time of marriage on risks of divorce. For individuals with anticipatory educational level (whose reported educational level was completed after marriage), conditional probabilities of having attained the reported level before marriage are computed. These are then used as weights in the expected likelihood to obtain adjusted estimates of relative risks. For our illustrative data set, the adjusted estimates of relative risks of divorce did not differ significantly from those obtained from anticipatory analysis that ignores the temporal order of events. Our results are slightly different from those in two other studies that analyzed the same data set in a Bayesian framework, though the studies are not fully comparable to each other.