The viral protein corona directs viral pathogenesis and amyloid aggregation

Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. In addition, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid beta-peptide (A beta(42)), a major constituent of amyloid plaques in Alzheimer's disease, in vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.Peer reviewe

Non-targeted transcriptomic effects upon thyroid irradiation: similarity between in-field and out-of-field responses varies with tissue type

Non-targeted effects can induce responses in tissues that have not been exposed to ionizing radiation.Despite their relevance for risk assessment, few studies have investigated these effects in vivo. Inparticular, these effects have not been studied in context with thyroid exposure, which can occur e.g.during irradiation of head and neck tumors. To determine the similarity between in-field and out-offieldresponses in normal tissue, we used a partial body irradiation setup with female mice where thethyroid region, the thorax and abdomen, or all three regions were irradiated. After 24h, transcriptionalregulation in the kidney cortex, kidney medulla, liver, lungs, spleen, and thyroid was analyzed usingmicroarray technology. Thyroid irradiation resulted in transcriptional regulation in the kidney medullaand liver that resembled regulation upon direct exposure of these tissues regarding both strength ofresponse and associated biological function. The kidney cortex showed fewer similarities between thesetups, while the lungs and spleen showed little similarity between in-field and out-of-field responses.Interestingly, effects were generally not found to be additive. Future studies are needed to identifythe molecular mechanisms that mediate these systemic effects, so that they may be used as targets tominimize detrimental side effects in radiotherapy

Identification of Potential MR-Derived Biomarkers for Tumor Tissue Response to 177Lu-Octreotate Therapy in an Animal Model of Small Intestine Neuroendocrine Tumor

Magnetic resonance (MR) methods enable noninvasive, regional tumor therapy response assessment, but associations between MR parameters, underlying biology, and therapeutic effects must be investigated. The aim of this study was to investigate response assessment efficacy and biological associations of MR parameters in a neuroendocrine tumor (NET) model subjected to radionuclide treatment. Twenty-one mice with NETs received 177Lu-octreotate at day 0. MR experiments (day −1, 1, 3, 8, and 13) included T2-weighted, dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) and relaxation measurements (T1/T2*). Tumor tissue was analyzed using proteomics. MR-derived parameters were evaluated for each examination day and for different radial distances from the tumor center. Response assessment efficacy and biological associations were evaluated using feature selection and protein expression correlations, respectively. Reduced tumor growth rate or shrinkage was observed until day 8, followed by reestablished growth in most tumors. The most important MR parameter for response prediction was DCE-MRI–derived pretreatment signal enhancement ratio (SER) at 40% to 60% radial distance, where it correlated significantly also with centrally sampled protein CCD89 (association: DNA damage and repair, proliferation, cell cycle arrest). The second most important was changed diffusion (D) between day −1 and day 3, at 60% to 80% radial distance, where it correlated significantly also with peripherally sampled protein CATA (association: oxidative stress, proliferation, cell cycle arrest, apoptotic cell death). Important information regarding tumor biology in response to radionuclide therapy is reflected in several MR parameters, SER and D in particular. The spatial and temporal information provided by MR methods increases the sensitivity for tumor therapy response

Deconvolution of expression microarray data reveals ¹³¹I-induced responses otherwise undetected in thyroid tissue

<div><p>High-throughput gene expression analysis is increasingly used in radiation research for discovery of damage-related or absorbed dose-dependent biomarkers. In tissue samples, cell type-specific responses can be masked in expression data due to mixed cell populations which can preclude biomarker discovery. In this study, we deconvolved microarray data from thyroid tissue in order to assess possible bias from mixed cell type data. Transcript expression data [GSE66303] from mouse thyroid that received 5.9 Gy from ¹³¹I over 24 h (or 0 Gy from mock treatment) were deconvolved by cell frequency of follicular cells and C-cells using csSAM and R and processed with Nexus Expression. Literature-based signature genes were used to assess the relative impact from ionizing radiation (IR) or thyroid hormones (TH). Regulation of cellular functions was inferred by enriched biological processes according to Gene Ontology terms. We found that deconvolution increased the detection rate of significantly regulated transcripts including the biomarker candidate family of kallikrein transcripts. Detection of IR-associated and TH-responding signature genes was also increased in deconvolved data, while the dominating trend of TH-responding genes was reproduced. Importantly, responses in biological processes for DNA integrity, gene expression integrity, and cellular stress were not detected in convoluted data–which was in disagreement with expected dose-response relationships–but upon deconvolution in follicular cells and C-cells. In conclusion, previously reported trends of ¹³¹I-induced transcriptional responses in thyroid were reproduced with deconvolved data and usually with a higher detection rate. Deconvolution also resolved an issue with detecting damage and stress responses in enriched data, and may reduce false negatives in other contexts as well. These findings indicate that deconvolution can optimize microarray data analysis of heterogeneous sample material for biomarker screening or other clinical applications.</p></div

Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.

Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients

Transcriptional response in normal mouse tissues after i.v. 211At administration - response related to absorbed dose, dose rate, and time

BackgroundIn cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after 211At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from 211At in normal mouse tissues.MethodsFemale BALB/c nude mice were intravenously injected with 1.7 kBq 211At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms.ResultsResponses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions.ConclusionsThis study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after 211At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy.Keywords: Astatine-211; Ionizing radiation; Normal tissue response; Radionuclide therapy; Biomark