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Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Purpose: To design, fabricate and characterize 3D printed, anatomically realistic, compressed breast phantoms for digital mammography (DM) and digital breast tomosynthesis (DBT) x-ray imaging. Materials: We realized 3D printed phantoms simulating healthy breasts, via fused deposition modeling (FDM), with a layer resolution of 0.1 mm and 100% infill density, using a dual extruder printer. The digital models were derived from a public dataset of segmented clinical breast computed tomography scans. Three physical phantoms were printed in polyethylene terephthalate (PET), acrylonitrile–butadiene–styrene (ABS), or in polylactic-acid (PLA) materials, using ABS as a substitute for adipose tissue, and PLA or PET filaments for replicating glandular and skin tissues. 3D printed phantoms were imaged at three clinical centers with DM and DBT scanners, using typical spectra. Anatomical noise of the manufactured phantoms was evaluated via the estimates of the β parameter both in DM images and in images acquired via a clinical computed tomography (CT) scanner. Results: DM and DBT phantom images showed an inner texture qualitatively similar to the images of a clinical DM or DBT exam, suitably reproducing the glandular structure of their computational phantoms. β parameters evaluated in DM images of the manufactured phantoms ranged between 2.84 and 3.79; a lower β was calculated from the CT scan. Conclusions: FDM 3D printed compressed breast phantoms have been fabricated using ABS, PLA and PET filaments. DM and DBT images with clinical x-ray spectra showed realistic textures. These phantoms appear promising for clinical applications in quality assurance, image quality and dosimetry assessments.

The aim of this study was to evaluate the impact of the intraoperative PTH (ioPTH) monitoring in the success of parathyroidectomy based on the concordant or indeterminate preoperative imaging studies of localization and the performed surgical choices.Fourthy-seven patients who received parathyroidectomy operations were divided in four groups: concordance of the imaging and ioPTH, concordance of the imaging and no ioPTH, indeterminate imaging and ioPTH and indeterminate imaging and no ioPTH.Overall, patients in whom ioPTH monitoring was not performed were healed in 89.47% of cases, while the percentage of recovery in patients receiving ioPTH was 85.71%. There were no differences in the changes in strategy or in the cure rates with the use of ioPTH.No significant differences were found, independently from the preoperative imaging agreement, in either the cure rate or in the change of intraoperative strategy through the use of the ioPTH dosage.

Objective. We present a method for personalized organ dose estimates obtained before the computed tomography (CT) exam, via 3D optical body scanning and Monte Carlo (MC) simulations. Approach. A voxelized phantom is derived by adapting a reference phantom to the body size and shape measured with a portable 3D optical scanner, which returns the 3D silhouette of the patient. This was used as an external rigid envelope for incorporating a tailored version of the internal body anatomy derived from a phantom dataset (National Cancer Institute, NIH, USA) matched for gender, age, weight, and height. The proof-of-principle was conducted on adult head phantoms. The Geant4 MC code provided estimates of the organ doses from 3D absorbed dose maps in the voxelized body phantom. Main results. We applied this approach for head CT scanning using an anthropomorphic voxelized head phantom derived from 3D optical scans of manikins. We compared the estimates of head organ doses with those provided by the NCICT 3.0 software (NCI, NIH, USA). Head organ doses differed up to 38% using the proposed personalized estimate and MC code, with respect to corresponding estimates calculated for the standard (non-personalized) reference head phantom. Preliminary application of the MC code to chest CT scans is shown. Real-time pre-exam personalized CT dosimetry is envisaged with adoption of a Graphics Processing Unit-based fast MC code. Significance. The developed procedure for personalized organ dose estimates before the CT exam, introduces a new approach for realistic description of size and shape of patients via voxelized phantoms specific for each patient.

PURPOSE To present a dataset of computational digital breast phantoms derived from high-resolution three-dimensional (3D) clinical breast images for the use in virtual clinical trials in two-dimensional (2D) and 3D x-ray breast imaging. ACQUISITION AND VALIDATION METHODS Uncompressed computational breast phantoms for investigations in dedicated breast CT (BCT) were derived from 150 clinical 3D breast images acquired via a BCT scanner at UC Davis (California, USA). Each image voxel was classified in one out of the four main materials presented in the field of view: fibroglandular tissue, adipose tissue, skin tissue, and air. For the image classification, a semi-automatic software was developed. The semi-automatic classification was compared via manual glandular classification performed by two researchers. A total of 60 compressed computational phantoms for virtual clinical trials in digital mammography (DM) and digital breast tomosynthesis (DBT) were obtained from the corresponding uncompressed phantoms via a software algorithm simulating the compression and the elastic deformation of the breast, using the tissue's elastic coefficient. This process was evaluated in terms of glandular fraction modification introduced by the compression procedure. The generated cohort of 150 uncompressed computational breast phantoms presented a mean value of the glandular fraction by mass of 12.3%; the average diameter of the breast evaluated at the center of mass was 105 mm. Despite the slight differences between the two manual segmentations, the resulting glandular tissue segmentation did not consistently differ from that obtained via the semi-automatic classification. The difference between the glandular fraction by mass before and after the compression was 2.1% on average. The 60 compressed phantoms presented an average glandular fraction by mass of 12.1% and an average compressed thickness of 61 mm. DATA FORMAT AND ACCESS The generated digital breast phantoms are stored in DICOM files. Image voxels can present one out of four values representing the different classified materials: 0 for the air, 1 for the adipose tissue, 2 for the glandular tissue, and 3 for the skin tissue. The generated computational phantoms datasets were stored in the Zenodo public repository for research purposes (http://doi.org/10.5281/zenodo.4529852, http://doi.org/10.5281/zenodo.4515360). POTENTIAL APPLICATIONS The dataset developed within the INFN AGATA project will be used for developing a platform for virtual clinical trials in x-ray breast imaging and dosimetry. In addition, they will represent a valid support for introducing new breast models for dose estimates in 2D and 3D x-ray breast imaging and as models for manufacturing anthropomorphic physical phantoms.

Purpose People with drug-refractory epilepsy are potential candidates for surgery. In many cases, epileptogenic zone localization requires intracranial investigations, e.g., via ElectroCorticoGraphy (ECoG), which uses subdural electrodes to map eloquent areas of large cortical regions. Precise electrodes localization on cortical surface is mandatory to delineate the seizure onset zone. Simple thresholding operations performed on patients’ computed tomography (CT) volumes recognize electrodes but also other metal objects (e.g., wires, stitches), which need to be manually removed. A new automated method based on shape analysis is proposed, which provides substantially improved performances in ECoG electrodes recognition. Methods The proposed method was retrospectively tested on 24 CT volumes of subjects with drug-refractory focal epilepsy, presenting a large number (> 1700) of round platinum electrodes. After CT volume thresholding, six geometric features of voxel clusters (volume, symmetry axes lengths, circularity and cylinder similarity) were used to recognize the actual electrodes among all metal objects via a Gaussian support vector machine (G-SVM). The proposed method was further tested on seven CT volumes from a public repository. Simultaneous recognition of depth and ECoG electrodes was also investigated on three additional CT volumes, containing penetrating depth electrodes. Results The G-SVM provided a 99.74% mean classification accuracy across all 24 single-patient datasets, as well as on the combined dataset. High accuracies were obtained also on the CT volumes from public repository (98.27% across all patients, 99.68% on combined dataset). An overall accuracy of 99.34% was achieved for the recognition of depth and ECoG electrodes. Conclusions The proposed method accomplishes automated ECoG electrodes localization with unprecedented accuracy and can be easily implemented into existing software for preoperative analysis process. The preliminary yet surprisingly good results achieved for the simultaneous depth and ECoG electrodes recognition are encouraging. Ethical approval n°NCT04479410 by “IRCCS Neuromed” (Pozzilli, Italy), 30th July 2020.

Objective. To measure the monoenergetic x-ray linear attenuation coefficient, μ, of fused deposition modeling (FDM) colored 3D printing materials (ABS, PLAwhite, PLAorange, PET and NYLON), used as adipose, glandular or skin tissue substitutes for manufacturing physical breast phantoms. Approach. Attenuation data (at 14, 18, 20, 24, 28, 30 and 36 keV) were acquired at Elettra synchrotron radiation facility, with step-wedge objects, using the Lambert–Beer law and a CCD imaging detector. Test objects were 3D printed using the Ultimaker 3 FDM printer. PMMA, Nylon-6 and high-density polyethylene step objects were also investigated for the validation of the proposed methodology. Printing uniformity was assessed via monoenergetic and polyenergetic imaging (32 kV, W/Rh). Main results. Maximum absolute deviation of μ for PMMA, Nylon-6 and HD-PE was 5.0%, with reference to literature data. For ABS and NYLON, μ differed by less than 6.1% and 7.1% from that of adipose tissue, respectively; for PET and PLAorange the difference was less than 11.3% and 6.3% from glandular tissue, respectively. PLAorange is a good substitute of skin (differences from −9.4% to +1.2%). Hence, ABS and NYLON filaments are suitable adipose tissue substitutes, while PET and PLAorange mimick the glandular tissue. PLAwhite could be printed at less than 100% infill density for matching the attenuation of glandular tissue, using the measured density calibration curve. The printing mesh was observed for sample thicknesses less than 60 mm, imaged in the direction normal to the printing layers. Printing dimensional repeatability and reproducibility was less 1%. Significance. For the first time an experimental determination was provided of the linear attenuation coefficient of common 3D printing filament materials with estimates of μ at all energies in the range 14–36 keV, for their use in mammography, breast tomosynthesis and breast computed tomography investigations.

Supplementary methods for the article "Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress".

The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop the first small-molecule NUDT15 inhibitors to elucidate its biological functions, and potentially for improving NUDT15-dependent chemotherapeutics. Lead compound TH1760, demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We further employed thiopurine potentiation as a proxy functional read-out and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity is via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.

Background. The aim of this observational study was to investigate for which nodules a better response to radiofrequency thermoablation (RFA) for nonfunctioning benign thyroid nodules is likely. Methods. Aesthetic score, compressive score, and volume of 32 benign nodules from 32 patients were registered during follow-up at baseline, 1, 3, 6, and 12 months. Results. A volume reduction rate (VRR) of 72.56% at 12 months after the procedure ( P = .009) was registered. A significant ( P < .001) improvement in the compressive and aesthetic scores was observed. Nodules with a baseline volume 20 mL ( P = .037). Conclusions. RFA was shown to be a safe and effective procedure for the management of benign thyroid nodules and that there is a correlation between the initial size of the nodule and the response to treatment.

Maria Belland Olsen,1,2 Camilla Huse,1,2 Mirta Mittelstedt Leal de Sousa,3,4 Sarah Louise Murphy,1,2 Antonio Sarno,3,5 Tobias Sebastian Obermann,3 Kuan Yang,1 Jan Cato Holter,2,6 Marte Jøntvedt Jørgensen,2,7 Erik Egeland Christensen,2,7 Wei Wang,3 Ping Ji,3 Lars Heggelund,8,9 Hedda Hoel,1,10 Anne Margarita Dyrhol-Riise,2,7 Ida Gregersen,1 Pål Aukrust,1,2,11 Magnar Bjørås,3,6 Bente Halvorsen,1,2 Tuva Børresdatter Dahl12 1Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 3Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 4Proteomics and Modomics Experimental Core Facility (PROMEC), NTNU, Trondheim, Norway; 5Department of Fisheries and New Biomarine Industry, SINTEF Ocean, Trondheim, Norway; 6Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; 7Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway; 8Department of Internal Medicine, Vestre Viken Hospital Trust, Drammen, Norway; 9Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway; 10Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway; 11Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway; 12Division of Critical Care and Emergencies, Oslo University Hospital, Oslo, NorwayCorrespondence: Tuva Børresdatter Dahl, Division of Critical Care and Emergencies and Research Institute of Internal Medicine, Oslo University Hospital, Sognsvannsveien 20, Oslo, Norway, Tel +4723072786, Email t.b.dahl@medisin.uio.noPurpose: Reactive oxygen species (ROS) are an important part of the inflammatory response during infection but can also promote DNA damage. Due to the sustained inflammation in severe Covid-19, we hypothesized that hospitalized Covid-19 patients would be characterized by increased levels of oxidative DNA damage and dysregulation of the DNA repair machinery.Patients and Methods: Levels of the oxidative DNA lesion 8-oxoG and levels of base excision repair (BER) proteins were measured in peripheral blood mononuclear cells (PBMC) from patients (8-oxoG, n = 22; BER, n = 17) and healthy controls (n = 10) (Cohort 1). Gene expression related to DNA repair was investigated in two independent cohorts of hospitalized Covid-19 patients (Cohort 1; 15 patents and 5 controls, Cohort 2; 15 patients and 6 controls), and by publicly available datasets.Results: Patients and healthy controls showed comparable amounts of oxidative DNA damage as assessed by 8-oxoG while levels of several BER proteins were increased in Covid-19 patients, indicating enhanced DNA repair in acute Covid-19 disease. Furthermore, gene expression analysis demonstrated regulation of genes involved in BER and double strand break repair (DSBR) in PBMC of Covid-19 patients and expression level of several DSBR genes correlated with the degree of respiratory failure. Finally, by re-analyzing publicly available data, we found that the pathway Hallmark DNA repair was significantly more regulated in circulating immune cells during Covid-19 compared to influenza virus infection, bacterial pneumonia or acute respiratory infection due to seasonal coronavirus.Conclusion: Although beneficial by protecting against DNA damage, long-term activation of the DNA repair machinery could also contribute to persistent inflammation, potentially through mechanisms such as the induction of cellular senescence. However, further studies that also include measurements of additional markers of DNA damage are required to determine the role and precise molecular mechanisms for DNA repair in SARS-CoV-2 infection.Keywords: Covid-19, oxidative stress, DNA damage, DNA repair, base excision repair, double strand break repair

Ballan wrasse (Labrus bergylta) is in the limelight of aquaculture research due to the species role as cleaner fish in salmon aquaculture. A major drawback is that the salmon industry still depends on wild caught fish as there are still many unsolved challenges in ballan wrasse aquaculture, amongst them the determination of egg quality. We measured a range of different egg quality markers on 6 different batches of eggs from ballan wrasse. Additionally, we performed lipidomics on these eggs to test whether their lipid profiles relate to, and can be thereby used as, a predictor for egg quality. We identified relationships between several lipid species and physiological and morphological egg quality markers, and the lipids grouped into two groups. The first group consisted of a diverse blend of 32 lipids, and was positively correlated with size related measures while it was negatively related to measures describing metabolic activity. It consisted of phosphatidylcholines (PC), lysophosphatidylcholine (lysoPC), and triacylglicerids (TAG) and three different sphingomyelins (SM). The second group consisted of 24 lipid species, and showed the inverse pattern, positive relationships with metabolic activity and negative relationships to size related measures. This group of lipid species contained several phosphatidylethanolamines (PE) and free fatty acids. These lipid species may be proposed as key egg quality markers which ultimately can be used by the aquaculture industry to select high quality egg batches in hatcheries.

Purpose: To evaluate the bias to the mean glandular dose (MGD) estimates introduced by the homogeneous breast models in digital breast tomosynthesis (DBT) and to have an insight into the glandular dose distributions in 2D (digital mammography, DM) and 3D (DBT and breast dedicated CT, BCT) x-ray breast imaging by employing breast models with realistic glandular tissue distribution and organ silhouette. Methods: A Monte Carlo software for DM, DBT and BCT simulations was adopted for the evaluation of glandular dose distribution in 60 computational anthropomorphic phantoms. These computational phantoms were derived from 3D breast images acquired via a clinical BCT scanner. Results: g·c·s·T conversion coefficients based on homogeneous breast model led to a MGD overestimate of 18% in DBT when compared to MGD estimated via anthropomorphic phantoms; this overestimate increased up to 21% for recently computed DgNDBT conversion coefficients. The standard deviation of the glandular dose distribution in BCT resulted 60% lower than in DM and 55% lower than in DBT. The glandular dose peak – evaluated as the average value over the 5% of the gland receiving the highest dose – is 2.8 times the MGD in DM, this factor reducing to 2.6 and 1.6 in DBT and BCT, respectively. Conclusions: Conventional conversion coefficients for MGD estimates based on homogeneous breast models overestimate MGD by 18%, when compared to MGD estimated via anthropomorphic phantoms. The ratio between the peak glandular dose and the MGD is 2.8 in DM. This ratio is 8% and 75% higher than in DBT and BCT, respectively.

The use of cleaner fish, such as the ballan wrasse (Labrus bergylta), is important for combatting the sea lice problem in salmonid cage farming. Ballan wrasse is the only wrasse species that is cultivated, though only about 50% of the approx. 3 million ballan wrasse used in 2020 was produced by aquaculture. The major obstacle for large scale cultivation of ballan wrasse is the difficult first feeding phase and a lack of functional feeding protocols. Like most pelagic marine fish larvae, ballan wrasse do not accept inert diets as first feed, and feeding regimes based on rotifers and Artemia (brine shrimps) usually lead to mixed results and are far from being optimal nutrition for the larvae. In a 48-day start feeding experiment, we studied the feasibility of replacing rotifers by an Experimental cirriped diet or copepod nauplii (Acartia tonsa) and replacing Artemia by nauplii of the cirriped Semibalanus balanoides. Later, all treatments received the same formulated diets. We sampled larvae at each feed transition to analyze different response variables such as growth, morphometry, gene expression, lipidomics, histology, and microbiology. We found significant differences in survival rates and growth. Larvae fed copepods as the first diet had significantly higher survival rates than larvae start-fed on either rotifers or small experimental cirripeds, and this pattern was also reflected in early growth and bone development. Gut histology at the end of the experiment (48 days after hatching) showed a more developed intestinal tissue in the larval group fed copepods first and cirripeds as the second diet compared to the other larval groups. Gene expression at day 48 post hatch still revealed pronounced differences between the larval group first fed on rotifers and larvae from the other three feeding regimes which received natural, unenriched diets. Even weeks after receiving the same formulated diets, lipidomics analyses revealed that several lipid species correlated either negatively or positively with larval growth rates or mortality. Our results are a clear indication for nutritional programming, pointing towards the importance the first diet has for the further life of a fish.

Lumpfish (Cyclopterus lumpus) serves an important role as cleaner fish for removing salmon lice in salmon aquaculture. For this use, cultivated lumpfish are preferred over wild-caught fish to avoid overexploitation of natural stocks and provide a stable production of good quality eggs and larvae. To support this, high quality eggs containing the necessary building blocks to support high fertilization success, development into a normal embryo and high hatching success is needed. Ova from wild-caught and captive lumpfish females were collected and assessed to identify how wild and domesticated lumpfish differ in terms of ova lipid profiles, egg and larvae quality. Wild-caught lumpfish displayed higher fertilization and hatching success compared to captive lumpfish, whereas other biological variables like egg size, egg/larvae dry weight and respiration, and larval morphometry, were not significantly different between wild and captive lumpfish. Ova lipid profiles (total lipid, lipid classes, fatty acid composition and lipidomics) can separate egg batches based on their geographic origin of wild-caught females and composition of diets used for captive broodstock (lipid and carbohydrate content). Multivariate statistics were applied to identify lipid markers that can be used to predict the quality of lumpfish ova. Lumpfish ova lipidomic profiles covaried with several biological parameters, indicating that the former can be used to predict the latter. Lumpfish eggs were mostly composed of triacylglycerides (TAGs) with some phosphatidylethanolamines (PEs) and phosphatidylcholines (PCs), and their lipid profiles were more sensitive to the different origins, mother weight/size and fertilization success than variables such as eggs size or larvae morphometric measures. PC and PE content of lumpfish eggs were positively correlated to both hatching success and fertilization rates, thus the lipidomic profiles, with some key highlighted lipid species were putative predictors of egg quality. Ova lipid profiling and egg quality in wild and captive lumpfish, Cyclopterus lumpus (Linnaeus, 1758)

Computational reproductions of medical imaging tests, a form of virtual clinical trials (VCTs), are increasingly being used, particularly in breast imaging research. The accuracy of the computational platform that is used for the imaging and dosimetry simulation processes is a fundamental requirement. Moreover, for practical usage, the imaging simulation computation time should be compatible with the clinical workflow. We compared three different platforms for in-silico X-ray 3D breast imaging: the Agata (University & INFN Napoli) that was based on the Geant4 toolkit and running on a CPU-based server architecture; the XRMC Monte Carlo (University of Cagliari) that was based on the use of variance reduction techniques, running on a CPU hardware; and the Monte Carlo code gCTD (University of Texas Southwestern Medical Center) running on a single GPU platform with CUDA environment. The tests simulated the irradiation of cylindrical objects as well as anthropomorphic breast phantoms and produced 2D and 3D images and 3D maps of absorbed dose. All the codes showed compatible results in terms of simulated dose maps and imaging values within a maximum discrepancy of 3%. The GPU-based code produced a reduction of the computation time up to factor 104, and so permits real-time VCT studies for X-ray breast imaging.

Purpose We present the development and the current state of the MaXIMA Breast Lesions Models Database, which is intended to provide researchers with both segmented and mathematical computer-based breast lesion models with realistic shape. Methods The database contains various 3D images of breast lesions of irregular shapes, collected from routine patient examinations or dedicated scientific experiments. It also contains images of simulated tumour models. In order to extract the 3D shapes of the breast cancers from patient images, an in-house segmentation algorithm was developed for the analysis of 50 tomosynthesis sets from patients diagnosed with malignant and benign lesions. In addition, computed tomography (CT) scans of three breast mastectomy cases were added, as well as five whole-body CT scans. The segmentation algorithm includes a series of image processing operations and region-growing techniques with minimal interaction from the user, with the purpose of finding and segmenting the areas of the lesion. Mathematically modelled computational breast lesions, also stored in the database, are based on the 3D random walk approach. Results The MaXIMA Imaging Database currently contains 50 breast cancer models obtained by segmentation of 3D patient breast tomosynthesis images; 8 models obtained by segmentation of whole body and breast cadavers CT images; and 80 models based on a mathematical algorithm. Each record in the database is supported with relevant information. Two applications of the database are highlighted: inserting the lesions into computationally generated breast phantoms and an approach in generating mammography images with variously shaped breast lesion models from the database for evaluation purposes. Both cases demonstrate the implementation of multiple scenarios and of an unlimited number of cases, which can be used for further software modelling and investigation of breast imaging techniques. The created database interface is web-based, user friendly and is intended to be made freely accessible through internet after the completion of the MaXIMA project. Conclusions The developed database will serve as an imaging data source for researchers, working on breast diagnostic imaging and on improving early breast cancer detection techniques, using existing or newly developed imaging modalities.

Accurate dynamic three-dimensional (4D) imaging of the heart of small rodents is required for the preclinical study of cardiac biomechanics and their modification under pathological conditions, but technological challenges are met in laboratory practice due to the very small size and high pulse rate of the heart of mice and rats as compared to humans. In 4D X-ray microtomography (4D μCT), the achievable spatio-temporal resolution is hampered by limitations in conventional X-ray sources and detectors. Here, we propose a proof-of-principle 4D μCT platform, exploiting the unique spatial and temporal features of novel concept, all-optical X-ray sources based on Thomson scattering (TS). The main spatial and spectral properties of the photon source are investigated using a TS simulation code. The entire data acquisition workflow has been also simulated, using a novel 4D numerical phantom of a mouse chest with realistic intra- and inter-cycle motion. The image quality of a typical single 3D time frame has been studied using Monte Carlo simulations, taking into account the effects of the typical structure of the TS X-ray beam. Finally, we discuss the perspectives and shortcomings of the proposed platform.

Item does not contain fulltext Breast computed tomography (BCT) is an emerging application of X-ray tomography in radiological practice. A few clinical prototypes are under evaluation in hospitals and new systems are under development aiming at improving spatial and contrast resolution and reducing delivered dose. At the same time, synchrotron-radiation phase-contrast mammography has been demonstrated to offer substantial advantages when compared with conventional mammography. At Elettra, the Italian synchrotron radiation facility, a clinical program of phase-contrast BCT based on the free-space propagation approach is under development. In this paper, full-volume breast samples imaged with a beam energy of 32 keV delivering a mean glandular dose of 5 mGy are presented. The whole acquisition setup mimics a clinical study in order to evaluate its feasibility in terms of acquisition time and image quality. Acquisitions are performed using a high-resolution CdTe photon-counting detector and the projection data are processed via a phase-retrieval algorithm. Tomographic reconstructions are compared with conventional mammographic images acquired prior to surgery and with histologic examinations. Results indicate that BCT with monochromatic beam and free-space propagation phase-contrast imaging provide relevant three-dimensional insights of breast morphology at clinically acceptable doses and scan times.

RNA modifications are essential for proper RNA processing, quality control, and maturation steps. In the last decade, some eukaryotic DNA repair enzymes have been shown to have an ability to recognize and process modified RNA substrates and thereby contribute to RNA surveillance. Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) is a base excision repair enzyme that not only recognizes and removes uracil and oxidized pyrimidines from DNA but is also able to process modified RNA substrates. SMUG1 interacts with the pseudouridine synthase dyskerin (DKC1), an enzyme essential for the correct assembly of small nucleolar ribonucleoproteins (snRNPs) and ribosomal RNA (rRNA) processing. Here, we review rRNA modifications and RNA quality control mechanisms in general and discuss the specific function of SMUG1 in rRNA metabolism. Cells lacking SMUG1 have elevated levels of immature rRNA molecules and accumulation of 5-hydroxymethyluridine (5hmU) in mature rRNA. SMUG1 may be required for post-transcriptional regulation and quality control of rRNAs, partly by regulating rRNA and stability.

X-ray breast imaging techniques are an essential part of breast cancer screening programs and their improvements lead to gain in performance and accuracy. Radiation dose estimate and control play an important role in digital mammography and digital breast tomosynthesis investigations, since the risk of radioinduced cancer to the gland must be contained and dose delivered to the gland must be declared in the medical report. The actual dosimetric protocols suggest the assessment of radiation dose by means of Monte Carlo calculation on digital breast phantoms, providing the assumption of the homogeneous mixture of glandular and adipose tissues within the breast organ, leading to a drastic approximation. In line with the trend of other research groups, with the aim of improving the Monte Carlo model, in the current work a new heterogeneous digital breast model is proposed, involving a voxelized approach and disengaging from the concept of homogeneous phantom. The proposed model is based on new findings in the literature and after a validation process, the model is adopted to evaluate mean glandular dose discrepancies with the traditional model which is adopted in clinic for decades.

A high proportion of the total microplastic (MP) load in the marine environment has been identified as microfibers (MFs), with polyester (PET) and polyamide (PA) typically found in the highest abundance. The potential for negative environmental impacts from MPs may be dependent on their degree of degradation in the environment, which is influenced by both intrinsic properties (polymer type, density, size, additive chemicals) and extrinsic environmental parameters. Most polymer products break down slowly through a combination of environmental processes, but UV degradation can be a significant source of degradation. The current study aimed to investigate the effect of UV irradiance on the degradation of natural (wool) and synthetic (PET and PA) MFs. Degradation of MFs was conducted in seawater under environmentally relevant accelerated exposure conditions using simulated sunlight. After 56 days of UV exposure, PA primarily exhibited changes in surface morphology with no significant fragmentation observed. PET and wool fibers exhibited both changes in surface morphology and fragmentation into smaller particles. A range of molecular degradation products were identified in seawater leachates after UV exposure, with increasing abundance over the duration of the experiment. Furthermore, a variety of additive chemicals were shown to leach from the MFs into seawater. While some of these chemicals were also susceptible to UV degradation and some are expected to biodegrade rapidly, others may be persistent and contribute to the overall load of chemical pollution in the marine environment. https://doi.org/10.1016/j.scitotenv.2020.143170 0048-9697/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

To evaluate the functional and oncologic outcomes of adjuvant (chemo)radiation [(C)RT] after open partial horizontal laryngectomies (OPHLs). Multicenter retrospective evaluation of 130 patients (116 males, 14 females) submitted between 1995 and 2017 to OPHL Types II and III for laryngeal cancer and receiving adjuvant (C)RT for one or more of the following risk factors at histopathologic examination of the surgical specimen: pT4a and/or > pN2a categories, close/positive resection margins, or presence of both perineural (PNI) and lympho-vascular invasion (LVI). The primary study endpoints were evaluation of the presence of tracheostomy and/or gastrostomy at last follow-up, and calculation of laryngo-esophageal dysfunction-free survival (LEDFS). Mean age of the study cohort was 60.8 ± 8.9 years (median, 62; interquartile range [IQR], 13). Mean follow-up was 50.7 ± 39.4 months (range 24–188; median, 38; IQR, 51). Adjuvant therapy consisted of CRT in 53 (41%) patients, and RT alone in 77 (59%). Five-year LEDFS was 85%. Overall survival was 71.5%, while 13% of patients remained tracheostomy- and 3% gastrostomy-dependent at the last follow-up. The only significant variable in predicting survival (p = 0.020) was tracheostomy dependence: it was maintained in 7.5% of subjects after OPHL Type II and in 34% of those submitted to OHPL Type III (p

Micro- and macroalgae are a great and important source of raw material for manufacturing of bioactives and ingredients for food, feed, cosmetics, or pharmaceuticals. Macroalgae (or seaweeds) have been harvested locally from wild stocks in smaller volumes for a long time, and a production chain based on cultivated seaweed for the harvest of considerably larger amounts is in progress for several species. Microalgae and cyanobacteria such as Spirulina have been produced in "backyard ponds" for use in food and feed also for a long time, and now we see the establishment of large production plants to control the cultivation process and increase the production yields. There is also a shift from harvesting or cultivation centered in warmer, sunnier areas to increasing exploitation of natural resources in temperate to boreal regions. In locations with strong seasonal variations in solar irradiance and temperatures, we need to develop procedures to maximize the biomass production in the productive seasons and ensure efficient stabilization of the biomass for year-round processing and product manufacturing. Industrialized biomass production and large-scale manufacturing of bioactives also mean that we must employ sustainable, cost-effective, and environmentally friendly processing methods, including stabilization and extraction methods such as ensiling and subcritical water extraction (SWE) and advanced analytic tools to characterize the products. These topics are focus areas of the Nordic Centre of Excellence (NCoE) NordAqua, and here we present a review of current activities in the field of micro- and macroalgae biomass production sectors illustrated with some of our experiences from the NordAqua consortium.

Many authors have investigated the most appropriate surgical approach to the deviated septum in childhood, considering the obligate mouth-breathing habit a possible cause of malocclusion and disharmonious development of the facial skeleton in growing kids. Nevertheless, controversies still remain about the long-term functional/esthetic results of such procedures, mainly due to the duration of the follow-up and possible confounding factors.111 Caucasian children (age range: 6-13 years) were submitted to a personal "Quick" septoplasty surgical technique between 2005 and 2010. Preoperative otorhinolaryngological examination using flexible nasal endoscopy, anterior active rhinomanometry (AAR), Nasal Obstruction Septoplasty Effectiveness (NOSE) questionnaire, and dentofacial evaluation (including cephalometry) were performed. Postoperative AAR, NOSE questionnaire and cephalometric assessment were carried out in all patients at the age of 18 years. Informed consent was obtained from children's parents as appropriate.No surgical complication was recorded. Among our patients, a significant (p 0.001) improvement of nasal breathing resistances at AAR and NOSE questionnaire scores was found after surgery. A significant improvement in cephalometric/dental parameters (gonial angle values, anterior facial height, prevalence of class I occlusion, maxillary intermolar width, and cross-bite frequency) was noticed after the follow-up with respect to preoperative conditions.The "Quick" septoplasty technique described is a practical and conservative procedure with a low complication rate that offers long-term favourable results for the correction of nasal septum deviations in children. Nasal-breathing restoration may favor a physiological and harmonious development of craniofacial and dental structures in offspring.

Purpose To develop a computerized detection system for the automatic classification of the presence/absence of mass lesions in digital breast tomosynthesis (DBT) annotated exams, based on a deep convolutional neural network (DCNN). Materials and Methods Three DCNN architectures working at image-level (DBT slice) were compared: two state-of-the-art pre-trained DCNN architectures (AlexNet and VGG19) customized through transfer learning, and one developed from scratch (DBT-DCNN). To evaluate these DCNN-based architectures we analysed their classification performance on two different datasets provided by two hospital radiology departments. DBT slice images were processed following normalization, background correction and data augmentation procedures. The accuracy, sensitivity, and area-under-the-curve (AUC) values were evaluated on both datasets, using receiver operating characteristic curves. A Grad-CAM technique was also implemented providing an indication of the lesion position in the DBT slice. Results Accuracy, sensitivity and AUC for the investigated DCNN are in-line with the best performance reported in the field. The DBT-DCNN network developed in this work showed an accuracy and a sensitivity of (90% ± 4%) and (96% ± 3%), respectively, with an AUC as good as 0.89 ± 0.04. A k-fold cross validation test (with k = 4) showed an accuracy of 94.0% ± 0.2%, and a F1-score test provided a value as good as 0.93 ± 0.03. Grad-CAM maps show high activation in correspondence of pixels within the tumour regions. Conclusions We developed a deep learning-based framework (DBT-DCNN) to classify DBT images from clinical exams. We investigated also a possible application of the Grad-CAM technique to identify the lesion position.

MutT homologue 1 (MTH1) removes oxidized nucleotides from the nucleotide pool and thereby prevents their incorporation into the genome and thereby reduces genotoxicity. We previously reported that MTH1 is an efficient catalyst of O6-methyl-dGTP hydrolysis suggesting that MTH1 may also sanitize the nucleotide pool from other methylated nucleotides. We here show that MTH1 efficiently catalyzes the hydrolysis of N6-methyl-dATP to N6-methyl-dAMP and further report that N6-methylation of dATP drastically increases the MTH1 activity. We also observed MTH1 activity with N6-methyl-ATP, albeit at a lower level. We show that N6-methyl-dATP is incorporated into DNA in vivo, as indicated by increased N6-methyl-dA DNA levels in embryos developed from MTH1 knock-out zebrafish eggs microinjected with N6-methyl-dATP compared with noninjected embryos. N6-methyl-dATP activity is present in MTH1 homologues from distantly related vertebrates, suggesting evolutionary conservation and indicating that this activity is important. Of note, N6-methyl-dATP activity is unique to MTH1 among related NUDIX hydrolases. Moreover, we present the structure of N6-methyl-dAMP–bound human MTH1, revealing that the N6-methyl group is accommodated within a hydrophobic active-site subpocket explaining why N6-methyl-dATP is a good MTH1 substrate. N6-methylation of DNA and RNA has been reported to have epigenetic roles and to affect mRNA metabolism. We propose that MTH1 acts in concert with adenosine deaminase-like protein isoform 1 (ADAL1) to prevent incorporation of N6-methyl-(d)ATP into DNA and RNA. This would hinder potential dysregulation of epigenetic control and RNA metabolism via conversion of N6-methyl-(d)ATP to N6-methyl-(d)AMP, followed by ADAL1-catalyzed deamination producing (d)IMP that can enter the nucleotide salvage pathway.

The aim of this work was to assess the performance of a prototype compact gamma camera (MediPROBE) based on a CdTe semiconductor hybrid pixel detector, for coded aperture imaging. This probe can be adopted for various tasks in nuclear medicine such as preoperative sentinel lymph node localization, breast imaging with 99mTc radiotracers and thyroid imaging, and in general in radioguided surgery tasks. The hybrid detector is an assembly of a 1-mm thick CdTe semiconductor detector bump-bonded to a photon-counting CMOS readout circuit of the Medipix2 series or energy-sensitive Timepix detector. MediPROBE was equipped with a set of two coded aperture masks with 0.07-mm or 0.08-mm diameter holes. We performed laboratory measurements of field of view, system spatial resolution, and signal-difference-to-noise ratio, by using gamma-emitting radioactive sources (109Cd, 125I, 241Am, 99mTc). The system spatial resolution in the lateral direction was 0.56 mm FWHM (coded aperture mask with holes of 0.08 mm and a 60 keV source) at a source-collimator distance of 50 mm and a field of view of 40 mm by side. Correspondingly, the longitudinal resolution in 3D source localization tasks was about 3 mm. MediPROBE showed a significant improvement in terms of spatial resolution when equipped with the high-resolution coded apertures, with respect to the performance previously reported with 1–2 mm pinhole apertures as well as with respect to adopting a 0.35 mm pinhole aperture.

Microplastic fibers (MPFs) from textiles significantly contribute to the microplastic (MP) load in many environmental matrices and have been shown to negatively impact the organisms therein. Most fate and effect studies to date rely on pristine reference MP materials that have limited relevance compared with the partially degraded MP particles and fibers typically present in the natural environment. The current study aimed to develop and validate a rapid method to generate environmentally relevant polyester (PET) MPF reference material with controllable levels of degradation. Importantly, the method produced the same degradation products (terephthalic acid (TA) and ethylene glycol (EG)) as those generated during natural UV (sunlight) exposure of PET. Alkaline hydrolysis provided linearly increasing degrees of degraded PET MPFs over just a few hours, with full decomposition into molecular fragments occurring after 3 h. The extent of physical degradation was determined by scanning electron microscopy, whereas chemical degradation was quantified by measuring the production of TA and EG degradation products. The proposed accelerated hydrolysis degradation method is relevant for producing partially degraded PET MPF reference materials for use in fate and effect studies.

This study relates to the INFN project SYRMA-3D for in vivo phase-contrast breast computed tomography using the SYRMEP synchrotron radiation beamline at the ELETTRA facility in Trieste, Italy. This peculiar imaging technique uses a novel dosimetric approach with respect to the standard clinical procedure. In this study, optimization of the acquisition procedure was evaluated in terms of dose delivered to the breast. An offline dose monitoring method was also investigated using radiochromic film dosimetry. Various irradiation geometries have been investigated for scanning the prone patient's pendant breast, simulated by a 14 cm-diameter polymethylmethacrylate cylindrical phantom containing pieces of calibrated radiochromic film type XR-QA2. Films were inserted mid-plane in the phantom, as well as wrapped around its external surface, and irradiated at 38 keV, with an air kerma value that would produce an estimated mean glandular dose of 5 mGy for a 14 cm-diameter 50% glandular breast. Axial scans were performed over a full rotation or over 180°. The results point out that a scheme adopting a stepped rotation irradiation represents the best geometry to optimize the dose distribution to the breast. The feasibility of using a piece of calibrated radiochromic film wrapped around a suitable holder around the breast to monitor the scan dose offline is demonstrated.