[Molecular diagnostics enable targeted therapies for anaplastic and poorly differentiated thyroid cancer]. / Molekylär diagnostik ger bättre behandling av tyreoideacancer.

Anaplastic and poorly differentiated thyroid cancer (ATC, PDTC) are rare and highly aggressive tumors that historically have been associated with a short life expectancy and low chance of cure. Molecular pathology and the introduction of highly effective targeted drugs have revolutionized the possibilities of management of patients with ATC and PDTC, with BRAF and MEK inhibitors as the most prominent example. Here we provide updated recommendations regarding diagnostics and management, including primary surgical management and targeted therapies based on specific molecular pathological findings.

Effects of Implementation of European Thyroid Imaging Reporting and Data System Risk Stratification in a Thyroid Cancer Program in Western Sweden: A Retrospective Cohort Study.

OBJECTIVE: The European Thyroid Imaging Reporting and Data System (EU-TIRADS) allows for selective fine needle aspiration cytology (FNAC). In 2017, EU-TIRADS was implemented as part of a nationwide standardized care bundle for thyroid cancer in Western Sweden with a population of approximately 1.7 million. The objective of this study was to investigate the clinical value of EU-TIRADS attempting to reduce the number of unnecessary FNACs in referred patients with thyroid nodules. METHODS: The study cohort consisted of all patients referred to Sahlgrenska University Hospital due to a palpable, newly detected or growing thyroid nodules or a positron emission tomography-positive finding for examination with thyroid ultrasound and selective cytology between 2018 and 2022. Medical records on EU-TIRADS classification, corresponding FNAC results, and histopathologic diagnosis were retrospectively collected. Adherence to the EU-TIRADS guidelines, use of selective FNAC, and rate of malignancy in patients who underwent surgery were assessed. RESULTS: In total, 1246 thyroid nodules in 990 patients were evaluated. The distributions of EU-TIRADS 2 to 5 (number [percentage]) for all examined nodules were 63 (5%), 462 (37%), 443 (36%), and 278 (22%), respectively. FNAC was omitted in 7% of the investigated patients. FNAC was performed in 124 nodules (10%) despite not fulfilling the EU-TIRADS criteria or absence of positron emission tomography-positive findings. The rate of malignancy was 33% and 1/50 in patients who underwent "unnecessary" FNAC. CONCLUSION: Implementation of EU-TIRADS in routine management of thyroid nodules led to the selective use of FNAC; however, the clinical impact was limited. This study provides real-world data on the value and magnitude of diagnostic improvement by implementing EU-TIRADS in clinical practice.

Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor.

Cells of origin in cancer determine tumor phenotypes, but whether lineage-defining transcription factors might influence tissue specificity of tumorigenesis among organs with similar developmental traits are unknown. We demonstrate here that tumor development and progression markedly differ in lung and thyroid targeted by Braf mutation in Nkx2.1CreERT2 mice heterozygous for Nkx2-1. In absence of tamoxifen, non-induced Nkx2.1CreERT2;BrafCA/+ mutants developed multiple full-blown lung adenocarcinomas with a latency of 1-3 months whereas thyroid tumors were rare and constrained, although minute BrafCA activation documented by variant allele sequencing was similar in both tissues. Induced oncogene activation accelerated neoplastic growth only in the lungs. By contrast, NKX2-1+ progenitor cells were equally responsive to constitutive expression of mutant Braf during lung and thyroid development. Both lung and thyroid cells transiently downregulated NKX2-1 in early tumor stages. These results indicate that BRAFV600E-induced tumorigenesis obey organ-specific traits that might be differentially modified by a shared lineage factor.

Enzyme kinetics by GH7 cellobiohydrolases on chromogenic substrates is dictated by non-productive binding: insights from crystal structures and MD simulation.

Cellobiohydrolases (CBHs) in the glycoside hydrolase family 7 (GH7) (EC3.2.1.176) are the major cellulose degrading enzymes both in industrial settings and in the context of carbon cycling in nature. Small carbohydrate conjugates such as p-nitrophenyl-ß-d-cellobioside (pNPC), p-nitrophenyl-ß-d-lactoside (pNPL) and methylumbelliferyl-ß-d-cellobioside have commonly been used in colorimetric and fluorometric assays for analysing activity of these enzymes. Despite the similar nature of these compounds the kinetics of their enzymatic hydrolysis vary greatly between the different compounds as well as among different enzymes within the GH7 family. Through enzyme kinetics, crystallographic structure determination, molecular dynamics simulations, and fluorometric binding studies using the closely related compound o-nitrophenyl-ß-d-cellobioside (oNPC), in this work we examine the different hydrolysis characteristics of these compounds on two model enzymes of this class, TrCel7A from Trichoderma reesei and PcCel7D from Phanerochaete chrysosporium. Protein crystal structures of the E212Q mutant of TrCel7A with pNPC and pNPL, and the wildtype TrCel7A with oNPC, reveal that non-productive binding at the product site is the dominating binding mode for these compounds. Enzyme kinetics results suggest the strength of non-productive binding is a key determinant for the activity characteristics on these substrates, with PcCel7D consistently showing higher turnover rates (kcat ) than TrCel7A, but higher Michaelis-Menten (KM ) constants as well. Furthermore, oNPC turned out to be useful as an active-site probe for fluorometric determination of the dissociation constant for cellobiose on TrCel7A but could not be utilized for the same purpose on PcCel7D, likely due to strong binding to an unknown site outside the active site.

Pelvic U-Net: multi-label semantic segmentation of pelvic organs at risk for radiation therapy anal cancer patients using a deeply supervised shuffle attention convolutional neural network.

BACKGROUND: Delineation of organs at risk (OAR) for anal cancer radiation therapy treatment planning is a manual and time-consuming process. Deep learning-based methods can accelerate and partially automate this task. The aim of this study was to develop and evaluate a deep learning model for automated and improved segmentations of OAR in the pelvic region. METHODS: A 3D, deeply supervised U-Net architecture with shuffle attention, referred to as Pelvic U-Net, was trained on 143 computed tomography (CT) volumes, to segment OAR in the pelvic region, such as total bone marrow, rectum, bladder, and bowel structures. Model predictions were evaluated on an independent test dataset (n = 15) using the Dice similarity coefficient (DSC), the 95th percentile of the Hausdorff distance (HD95), and the mean surface distance (MSD). In addition, three experienced radiation oncologists rated model predictions on a scale between 1-4 (excellent, good, acceptable, not acceptable). Model performance was also evaluated with respect to segmentation time, by comparing complete manual delineation time against model prediction time without and with manual correction of the predictions. Furthermore, dosimetric implications to treatment plans were evaluated using different dose-volume histogram (DVH) indices. RESULTS: Without any manual corrections, mean DSC values of 97%, 87% and 94% were found for total bone marrow, rectum, and bladder. Mean DSC values for bowel cavity, all bowel, small bowel, and large bowel were 95%, 91%, 87% and 81%, respectively. Total bone marrow, bladder, and bowel cavity segmentations derived from our model were rated excellent (89%, 93%, 42%), good (9%, 5%, 42%), or acceptable (2%, 2%, 16%) on average. For almost all the evaluated DVH indices, no significant difference between model predictions and manual delineations was found. Delineation time per patient could be reduced from 40 to 12 min, including manual corrections of model predictions, and to 4 min without corrections. CONCLUSIONS: Our Pelvic U-Net led to credible and clinically applicable OAR segmentations and showed improved performance compared to previous studies. Even though manual adjustments were needed for some predicted structures, segmentation time could be reduced by 70% on average. This allows for an accelerated radiation therapy treatment planning workflow for anal cancer patients.

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development.

Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF-mutant lineage becomes a cancerized lineage. The TgCreERT2;BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.

Volumetric modulated arc therapy dose prediction and deliverable treatment plan generation for prostate cancer patients using a densely connected deep learning model.

BACKGROUND AND PURPOSE: Radiation therapy treatment planning is a manual, time-consuming task that might be accelerated using machine learning algorithms. In this study, we aimed to evaluate if a triplet-based deep learning model can predict volumetric modulated arc therapy (VMAT) dose distributions for prostate cancer patients. MATERIALS AND METHODS: A modified U-Net was trained on triplets, a combination of three consecutive image slices and corresponding segmentations, from 160 patients, and compared to a baseline U-Net. Dose predictions from 17 test patients were transformed into deliverable treatment plans using a novel planning workflow. RESULTS: The model achieved a mean absolute dose error of 1.3%, 1.9%, 1.0% and ≤ 2.6% for clinical target volume (CTV) CTV_D100%, planning target volume (PTV) PTV_D98%, PTV_D95% and organs at risk (OAR) respectively, when compared to the clinical ground truth (GT) dose distributions. All predicted distributions were successfully transformed into deliverable treatment plans and tested on a phantom, resulting in a passing rate of 100% (global gamma, 3%, 2 mm, 15% cutoff). The dose difference between deliverable treatment plans and GT dose distributions was within 4.4%. The difference between the baseline model and our improved model was statistically significant (p < 0.05) for CVT_D100%, PTV_D98% and PTV_D95%. CONCLUSION: Triplet-based training improved VMAT dose distribution predictions when compared to 2D. Dose predictions were successfully transformed into deliverable treatment plans using our proposed treatment planning procedure. Our method may automate parts of the workflow for external beam prostate radiation therapy and improve the overall treatment speed and plan quality.

Asynchrony of Apical Polarization, Luminogenesis, and Functional Differentiation in the Developing Thyroid Gland.

Follicular thyroid tissue originates from progenitors derived from a midline endodermal primordium. Current understanding infers that folliculogenesis in the embryonic thyroid designates the latest morphogenetic event taking place after the final anatomical shape and position of the gland is established. However, this concept does not consider the fact that the thyroid isthmus develops chronologically before the lobes and also contains all progenitors required for lobulation. To elucidate whether cells committed to a thyroid fate might be triggered to differentiate asynchronously related to maturation and developmental stage, mouse embryonic thyroid tissues from E12.5-17.5 were subjected to immunofluorescent labeling of biomarkers (progenitors: NKX2-1; differentiation: thyroglobulin/TG); folliculogenesis: E-cadherin/CDH1; luminogenesis: mucin 1/MUC1; apical polarity: pericentrin/PCNT; basement membrane: laminin; growth: Ki67), quantitative RT-PCR analysis (Nkx2.1, Tg, Muc1) and transmission electron microscopy. Tg expression was detectable as early as E12.5 and gradually increased >1000-fold until E17.5. Muc1 and Nkx2.1 transcript levels increased in the same time interval. Prior to lobulation (E12.5-13.5), MUC1 and TG distinguished pre-follicular from progenitor cells in the developing isthmus characterized by intense cell proliferation. Luminogenesis comprised redistribution of MUC1+ vesicles or vacuoles, transiently associated with PCNT, to the apical cytoplasm and the subsequent formation of MUC1+ nascent lumens. Apical polarization of pre-follicular cells and lumen initiation involved submembraneous vesicular traffic, reorganization of adherens junctions and ciliogenesis. MUC1 did not co-localize with TG until a lumen with a MUC1+ apical membrane was established. MUC1 delineated the lumen of all newly formed follicles encountered in the developing lobes at E15.5-17.5. Folliculogenesis started before establishment of a complete follicular basal lamina. These observations indicate that embryonic thyroid differentiation is an asynchronous process consistent with the idea that progenitors attaining a stationary position in the connecting isthmus portion undergo apical polarization and generate follicles already at a primordial stage of thyroid development, i.e. foregoing growth of the lobes. Although the thyroid isthmus eventually comprises minute amounts of the total thyroid volume and contributes little to the overall hormone production, it is of principal interest that local cues related to the residence status of cells - independently of a prevailing high multiplication rate - govern the thyroid differentiation program.

Immunity of nanoscale magnetic tunnel junctions with perpendicular magnetic anisotropy to ionizing radiation.

Spin transfer torque magnetic random access memory (STT-MRAM) is a promising candidate for next generation memory as it is non-volatile, fast, and has unlimited endurance. Another important aspect of STT-MRAM is that its core component, the nanoscale magnetic tunneling junction (MTJ), is thought to be radiation hard, making it attractive for space and nuclear technology applications. However, studies on the effects of ionizing radiation on the STT-MRAM writing process are lacking for MTJs with perpendicular magnetic anisotropy (pMTJs) required for scalable applications. Particularly, the question of the impact of extreme total ionizing dose on perpendicular magnetic anisotropy, which plays a crucial role on thermal stability and critical writing current, remains open. Here we report measurements of the impact of high doses of gamma and neutron radiation on nanoscale pMTJs used in STT-MRAM. We characterize the tunneling magnetoresistance, the magnetic field switching, and the current-induced switching before and after irradiation. Our results demonstrate that all these key properties of nanoscale MTJs relevant to STT-MRAM applications are robust against ionizing radiation. Additionally, we perform experiments on thermally driven stochastic switching in the gamma ray environment. These results indicate that nanoscale MTJs are promising building blocks for radiation-hard non-von Neumann computing.

Why Medical Students Choose to Use or Not to Use a Web-Based Electrocardiogram Learning Resource: Mixed Methods Study.

BACKGROUND: Electrocardiogram (ECG) interpretation is a core competence and can make a significant difference to patient outcomes. However, ECG interpretation is a complex skill to learn, and research has showed that students often lack enough competence. Web-based learning has been shown to be effective. However, little is known regarding why and how students use Web-based learning when offered in a blended learning situation. OBJECTIVE: The aim of this paper was to study students' use of Web-based ECG learning resources which has not previously been studied in relation to study strategies. METHODS: A qualitative explanatory design using mixed methods was adopted to explore how medical students reason around their choice to use or not to use a Web-based ECG learning resource. Overall, 15 of 33 undergraduate medical students attending a course in clinical medicine were interviewed. Data on usage of the resource were obtained via the learning management system for all students. At the final examination, all the students answered a questionnaire on study strategies and questions about internet access and estimated their own skills in ECG interpretation. Furthermore, study strategies and use patterns were correlated with results from an ECG Objective Structured Clinical Examination (OSCE) and a written course examination. RESULTS: In total, 2 themes were central in the students' reasoning about usage of Web-based ECG: assessment of learning needs and planning according to learning goals. Reasons for using the Web resource were to train in skills, regarding it as a valuable complement to books and lectures. The main reasons for not using the resource were believing they already had good enough skills and a lack of awareness of its availability. Usage data showed that 21 students (63%) used the Web resource. Of these, 11 were minimal users and 10 were major users based on usage activity. Large variations were found in the time spent in different functional parts of the resource. No differences were found between users and nonusers regarding the OSCE score, final examination score, self-estimate of knowledge, or favoring self-regulated learning. CONCLUSIONS: To use or not to use a Web-based ECG learning resource is largely based on self-regulated learning aspects. Decisions to use such a resource are based on multifactorial aspects such as experiences during clinical rotations, former study experiences, and perceived learning needs. The students' own judgment of whether there was a need for a Web-based resource to achieve the learning goals and to pass the examination was crucial for their decisions to use it or not. An increased understanding of students' regulation of learning and awareness of variations in their ECG learning needs can contribute to the improvement of course design for blended learning of ECG contexts for medical students.

Complexation of High-Valency Mid-Actinides by a Lipophilic Schiff Base Ligand: Synthesis, Structural Characterization, and Progress toward Selective Extraction.

Separation of U, Np, and Pu from used nuclear fuel (UNF) would result in lower long-term radiotoxicity, alleviating constraints on the storage and handling of the material. The complexity of UNF requires several industrial-scale processes with multiple waste streams. A one-step solution to the group removal of the elements, U-Pu, is desirable. Here we present a possible solution to group actinide separation utilizing the unique dioxy conformation of An(V/VI) cations and demonstrate the ability of a tetradentate lipophilic Schiff base ligand (L) to yield isostructural complexes of the general formula [(AnVIO2)(L)(CH3CN)] (where An = U, Np, or Pu). Extraction of An(VI) with the ligand follows the order U > Pu > Np, likely reflecting the decreased stability of the hexavalent actinide across the series. While the results indicate a promising path toward a one-step process, further improvement in the ligand stability and control of the redox chemistry is required.

Pharmacological Treatment in Forensic Psychiatry-A Systematic Review.

Background: Pharmacological treatment is of great importance in forensic psychiatry, and the vast majority of patients are treated with antipsychotic agents. There are several systematic differences between general and forensic psychiatric patients, e.g. severe violent behavior, the amount of comorbidity, such as personality disorders and/or substance abuse. Based on that, it is reasonable to suspect that effects of pharmacological treatments also may differ. The objective of this systematic review was to investigate the effects of pharmacological interventions for patients within forensic psychiatry. Methods: The systematic review protocol was pre-registered in PROSPERO (CRD42017075308). Six databases were used for literature search on January 11, 2018. Controlled trials from forensic psychiatric care reporting on the effects of antipsychotic agents, mood stabilizers, benzodiazepines, antidepressants, as well as pharmacological agents used for the treatment of addiction or ADHD, were included. Two authors independently reviewed the studies, evaluated risk of bias and assessed certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: The literature search resulted in 1783 records (titles and abstracts) out of which 10 studies were included. Most of the studies included were retrospective and non-randomized. Five of them focused on treatment with clozapine and the remaining five on other antipsychotics or mood stabilizers. Five studies with a high risk of bias indicated positive effects of clozapine on time from treatment start to discharge, crime-free time, time from discharge to readmission, improved clinical functioning, and reduction in aggressive behavior. Psychotic symptoms after treatment were more pronounced in the clozapine group. Mainly due to the high risk of bias the reliability of the evidence for all outcomes was assessed as very low. Conclusion: This systematic review highlights the shortage of knowledge on the effectiveness of pharmacological treatment within forensic psychiatry. Due to very few studies being available in this setting, as well as limitations in their execution and reporting, it is challenging to overview the outcomes of pharmacological interventions in this context. The frequent use of antipsychotics, sometimes in combination with other pharmacological agents, in this complex and heterogeneous patient group, calls for high-quality studies performed in this specific setting.

Microscopic Behaviors of Tri- n-Butyl Phosphate, n-Dodecane, and Their Mixtures at Air/Liquid and Liquid/Liquid Interfaces: An AMBER Polarizable Force Field Study.

In solvent extraction processes for recovering metal ions from used nuclear fuel, as well as other industrial applications, a better understanding of the metal complex phase transfer phenomenon would greatly aid ligand design and process optimization. We have approached this challenge by utilizing the classical molecular dynamics simulations technique to gain visual appreciation of the vapor/liquid and liquid/liquid interface between tri- n-butyl phosphate (TBP) and n-dodecane with air and water. In this study, we successfully reparameterized polarizable force fields for TBP and n-dodecane that accurately reproduced several of their thermophysical properties such as density, heat of vaporization, and dipole moment. Our models were able to predict the surface and interfacial tension of different systems when compared to experimental results that were also performed by us. Through this study, we gained atomistic understanding of the behaviors of TBP and n-dodecane at the interface against air and water, useful in further computational studies of such systems. Finally, our studies indicate that the initial configuration of a simulation may have a large effect on the final result.

A Path Loss and Shadowing Model for Multilink Vehicle-to-Vehicle Channels in Urban Intersections.

The non line-of-sight (NLOS) scenario in urban intersections is critical in terms of traffic safety-a scenario where Vehicle-to-Vehicle (V2V) communication really can make a difference by enabling communication and detection of vehicles around building corners. A few NLOS V2V channel models exist in the literature but they all have some form of limitation, and therefore further research is need. In this paper, we present an alternative NLOS path loss model based on analysis from measured V2V communication channels at 5.9 GHz between six vehicles in two urban intersections. We analyze the auto-correlation of the large scale fading process and the influence of the path loss model on this. In cases where a proper model for the path loss and the antenna pattern is included, the de-correlation distance for the auto-correlation is as low as 2⁻4 m, and the cross-correlation for the large scale fading between different links can be neglected. Otherwise, the de-correlation distance has to be much longer and the cross-correlation between the different communication links needs to be considered separately, causing the computational complexity to be unnecessarily large. With these findings, we stress that vehicular ad-hoc network (VANET) simulations should be based on the current geometry, i.e., a proper path loss model should be applied depending on whether the V2V communication is blocked or not by other vehicles or buildings.

Molecular Dynamics Investigations of Dibutyl-phosphoric Acid-Parameterization and Dimerization.

A reparameterized molecular dynamics force field for dibutyl-phosphoric acid (HDBP) has been developed. Parameterization was done using the general Amber force field, as a starting point. The density and dipole moment of bulk phase simulations compare well to that of known experimental values, and the heat of vaporization is comparable to an estimated empirical value. All values have been optimized to within 4%. The newly optimized force field was validated against the self-diffusion coefficient, matching experimental data to within 18%, which is a significant improvement compared to the nonoptimized force field. Further, a potential of mean force study was carried out to understand the behavior of hydrogen bonds in HDBP dimers. This required the determination of hydrogen bonding criteria that captures the behavior of the HDBP dimer and is reported in this work as well.

Accuracy, Repeatability, and Limitations for Determination of Chemical Activities from Vapor Pressure Osmometry.

Vapor pressure osmometry presents a convenient method to measure chemical activity. The work presented here was carried out to provide confidence in using this technique for a VPO model that does not utilize the "hanging-drop" method. While validation studies are available for certain models of vapor pressure osmometers, none were located for the UIC Jupiter 833 osmometer. This study addresses that need by providing a comparison between original experimental data on sodium chloride, calcium chloride, and sodium sulfate solutions to values calculated using the Pitzer equations. A comparison is also made for experimental data on sucrose with a literature correlation. This study briefly reviews the assumptions going into the equation used to relate the osmometer signal to the diluent activity in order to identify potential sources of the error and the noise in the data. The experimental data shows that the UIC 833 osmometer yields diluent activity values accurate to an average of 0.02%, allowing calculation of osmotic coefficients and solute activity coefficients. Further studies need to be conducted on the accuracy at concentrations above 1.4 m. Qualitatively, however, comparison suggests the UIC Jupiter 833 osmometer yields more scatter in the experimental data than the Knauer instruments. Using more uniform mesh caps on the thermistors could possibly reduce that scatter. Finally, we show that replacing the glass thermistors with in-house made thermistors with Teflon incorporated in the structure give reproducible results and that certain modifications to the design are possible without losing accuracy in the measurements.