Hsp90 inhibition sensitizes DLBCL cells to cisplatin

PURPOSE: Platinum-containing therapy is standard treatment for relapsed Diffuse Large B-Cell Lymphoma (DLBCL). However, the efficacy of treatment is limited by drug resistance leading to relapse. Cisplatin resistance has been linked to impairments of the DNA damage response, and several DNA repair proteins have been identified as clients of the molecular chaperone Hsp90. Here, we investigated the combinatory treatment of cisplatin and the Hsp90 inhibitor, 17AAG, in DLBCL cells to evaluate if inhibition of Hsp90 could sensitize DLBCL cells to cisplatin treatment. METHODS: Cell viability was assessed for cisplatin and 17AAG as monotherapies and for 25 different combinations in 7 DLBCL cell lines, where the Bliss Independence Model and the Combination Index were applied to assess their interaction. Induction of apoptosis and DNA damage response were evaluated by measuring Annexin V and γH2AX levels after 48 h of exposure. RESULTS: 17AAG synergized with cisplatin in DLBCL cells as detected in both interaction assessment models, resulting in a lower viability after 48 h for the combination-treated cells compared to both vehicle and single drug-treated cells. The combination also induced a stronger apoptotic response and an increase in DNA damage in 17AAG, cisplatin- and combination-treated cells compared to vehicle-treated cells, with the effect of the combination generally being higher than compared to both single drugs. CONCLUSION: This study demonstrates that 17AAG sensitizes DLBCL cells to cisplatin treatment. This effect is correlated with increased apoptotic and DNA damage response, potentially mediated by downregulation of Hsp90 clients in DNA repair pathways. Thus, cisplatin resistance could plausibly be overcome by combining the treatment with an Hsp90 inhibiting drug. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-022-04407-5

Influence of ghrelin on the central serotonergic signaling system in mice

AbstractThe central ghrelin signaling system engages key pathways of importance for feeding control, recently shown to include those engaged in anxiety-like behavior in rodents. Here we sought to determine whether ghrelin impacts on the central serotonin system, which has an important role in anxiety. We focused on two brain areas, the amygdala (of importance for the mediation of fear and anxiety) and the dorsal raphe (i.e. the site of origin of major afferent serotonin pathways, including those that project to the amygdala). In these brain areas, we measured serotonergic turnover (using HPLC) and the mRNA expression of a number of serotonin-related genes (using real-time PCR). We found that acute central administration of ghrelin to mice increased the serotonergic turnover in the amygdala. It also increased the mRNA expression of a number of serotonin receptors, both in the amygdala and in the dorsal raphe. Studies in ghrelin receptor (GHS-R1A) knock-out mice showed a decreased mRNA expression of serotonergic receptors in both the amygdala and the dorsal raphe, relative to their wild-type littermates. We conclude that the central serotonin system is a target for ghrelin, providing a candidate neurochemical substrate of importance for ghrelin's effects on mood

Network modeling of the transcriptional effects of copy number aberrations in glioblastoma

DNA copy number aberrations (CNAs) are a characteristic feature of cancer genomes. In this work, Rebecka Jörnsten, Sven Nelander and colleagues combine network modeling and experimental methods to analyze the systems-level effects of CNAs in glioblastoma

The influence of outdoor education on students´ learning in science

Sammandrag Denna kunskapsöversikt är skriven med syftet att besvara frågan om på vilka sätt utomhuspedagogik kan påverka elevers lärande inom de naturorienterande ämnena.  Metoden som har använts för att samla in kunskaper inom området är en systematisk litteraturstudie. Informationssökning har genomförts via databaserna ERIC via EBSCO, ERC, SwePub och sekundärsökning utifrån valda artiklars referenslistor.  Källorna som har samlats in har sedan sammanställts, analyserats och diskuterats i relation till frågeställningen.  Resultatet visar att utomhuspedagogik har en positiv påverkan på elever gällande deras lärande men även deras intresse och motivation i ämnet. Det går dock inte att utesluta att traditionell undervisning hade kunnat generera liknande resultat. Av studien framgick det även andra aspekter av utomhuspedagogik, däribland att elevers fysiska och psykiska hälsa förbättrades. Vidare visar resultatet att lärare spelar en viktig roll när det gäller utomhuspedagogik, men att många lärare ställer sig tveksamma till tidsåtgången som krävs vid planering av utomhusundervisning. Slutsatsen som kan dras av kunskapsöversiktens innehåll är att utomhuspedagogik påverkar elevers lärande och att fördelarna är många. Därför bör lärare överväga att i större utsträckning använda sig av utomhuspedagogik i sin yrkesprofession.

A bendamustine resistance gene signature in diffuse large B-cell lymphoma and multiple myeloma

Aim: Bendamustine is primarily used for treatment of indolent lymphomas but has shown efficacy in some patients with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Molecular-based patient stratification for identification of resistant patients, who will benefit from alternative treatments, is important. The aim of this study was to develop a resistance gene signature (REGS) from bendamustine dose-response assays in cultures of DLBCL and MM cell lines, enabling prediction of bendamustine response in DLBCL and MM patients.Methods: Bendamustine response was determined in 14 DLBCL and 11 MM cell lines. Using baseline gene expression profiles and degree of growth inhibition after bendamustine exposure, a bendamustine REGS was developed and examined for the risk stratification potential in DLBCL (n = 971) and MM (n = 1,126) patients divided into prognostic subtypes.Results: Bendamustine resistance significantly correlated with resistance to cyclophosphamide in DLBCL and melphalan in MM cell lines. The bendamustine REGS showed significantly lower bendamustine resistance probabilities in DLBCL patients with GCB subtype tumors and in tumors of the differentiation dependent centrocyte and plasmablast subtypes. In MM patients, pre-BII classified tumors displayed high bendamustine resistance probabilities and the plasma cell subtype had lower bendamustine resistance probability than memory cells. Furthermore, tumors belonging to the 4p14, MAF, and D2 TC subclasses consistently displayed high bendamustine resistance probabilities.Conclusion: Significant differences in predicted response to bendamustine were found in molecular subtypes of DLBCL and MM, encouraging validation in prospective bendamustine-treated cohorts with available gene expression profiles and follow-up data

Efficient experimental screening.

<p>A: Principal difference between systematic screening (testing all pairs sequentially) and guided screening (letting discovered synergistic pairs, marked as red X's guide the subsequent steps of the screening process). B: We characterize the screening process by the fractional discovery rate attained at experimental fraction , where denotes the screening efficiency. In a screening process with high value, a large fraction of all synergies is found by testing a small fraction of all possible target pairs. corresponds to systematic screening. C: A simple protocol to increase is to direct the screen towards targets that seem prone to synergism. For this, we propose a sampling protocol based on Bayesian estimates of a target's propensity to interact. D: We use a beta-prior with parameters , where is the number of targets. A flat prior () reduces performance.</p

Predicting synergism scores from highly incomplete data via cyclical set projection.

<p>A: To improve screening efficiency further, we introduce a projection-based predictor of synergism scores. An initial guess of a synergism score matrix is projected first onto the set , which corresponds to known interaction scores, then onto the set , which contains matrices of approximately low rank, and finally onto , holding the matrices consistent with known functional similarity. The projections are applied cyclically until convergence to a final prediction of is reached, which is guaranteed due to convexity of the three sets (here illustrating convergence in one iteration). B: Prediction accuracy in five glioblastoma cell lines and reference data sets. Comparison between our projection-based method and two state-of-the-art methods for interaction score imputation methods, LLS and EMDI. Generally, set based projections outperform the other methods (predictions correlate more with true values), especially when the screened fraction is small.</p

Improving screening efficiency by combining propensity-based sampling with interaction score prediction via matrix completion.

<p>A: We extend the simpler protocol (propensity-based sampling only, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068598#pone-0068598-g001" target="_blank">Figure 1C</a>), adding a projection-based predictor to choose likely synergistic pairs (steps 3 and 4). If the prediction-driven screening discovery rate is higher than the preceding propensity-based screening, a new prediction-driven screening cycle is started (step 5). We switch between propensity-based sampling and prediction to increase the fractional discovery rate. B: Fractional discovery rate across 9 data sets show marked improvement over brute-force screening. C: Estimates of the screening efficiency demonstrate that the full protocol (steps 1–5) gives better performance than propensity-based sampling only (steps 1–2). Yellow block: additional contribution by projecting onto in the largest yeast SGA screen.</p