To establish a preoperative decision model for accurate indication of systemic therapy in early-stage breast cancer using multiparametric MRI at 7-tesla field strength.
Patients eligible for ...breast-conserving therapy were consecutively included. Patients underwent conventional diagnostic workup and one preoperative multiparametric 7-tesla breast MRI. The postoperative (gold standard) indication for systemic therapy was established from resected tumor and lymph-node tissue, based on 10-year risk-estimates of breast cancer mortality and relapse using Adjuvant! Online. Preoperative indication was estimated using similar guidelines, but from conventional diagnostic workup. Agreement was established between preoperative and postoperative indication, and MRI-characteristics used to improve agreement. MRI-characteristics included phospomonoester/phosphodiester (PME/PDE) ratio on 31-phosphorus spectroscopy (31P-MRS), apparent diffusion coefficients on diffusion-weighted imaging, and tumor size on dynamic contrast-enhanced (DCE)-MRI. A decision model was built to estimate the postoperative indication from preoperatively available data.
We included 46 women (age: 43-74yrs) with 48 invasive carcinomas. Postoperatively, 20 patients (43%) had positive, and 26 patients (57%) negative indication for systemic therapy. Using conventional workup, positive preoperative indication agreed excellently with positive postoperative indication (N = 8/8; 100%). Negative preoperative indication was correct in only 26/38 (68%) patients. However, 31P-MRS score (p = 0.030) and tumor size (p = 0.002) were associated with the postoperative indication. The decision model shows that negative indication is correct in 21/22 (96%) patients when exempting tumors larger than 2.0cm on DCE-MRI or with PME>PDE ratios at 31P-MRS.
Preoperatively, positive indication for systemic therapy is highly accurate. Negative indication is highly accurate (96%) for tumors sized ≤2,0cm on DCE-MRI and with PME≤PDE ratios on 31P-MRS.
We present the performance of a semantic segmentation network, sparsessnet, that provides pixel-level classification of MicroBooNE data. The MicroBooNE experiment employs a liquid argon time ...projection chamber for the study of neutrino properties and interactions. sparsessnet is a submanifold sparse convolutional neural network, which provides the initial machine learning based algorithm utilized in one of MicroBooNEs νe-appearance oscillation analyses. The network is trained to categorize pixels into five classes, which are reclassified into two classes more relevant to the current analysis. The output of sparsessnet is a key input in further analysis steps. This technique, used for the first time in liquid argon time projection chambers data and is an improvement compared to a previously used convolutional neural network, both in accuracy and computing resource utilization. The accuracy achieved on the test sample is ≥ 99 %. For full neutrino interaction simulations, the time for processing one image is ≈ 0.5 sec , the memory usage is at 1 GB level, which allows utilization of most typical CPU worker machine.
We have generated a panel of mAbs that identify three presumably novel human dendritic cell Ags: BDCA-2, BDCA-3, and BDCA-4. In blood, BDCA-2 and BDCA-4 are expressed on CD11c(-) CD123(bright) ...plasmacytoid dendritic cells, whereas BDCA-3 is expressed on small population of CD11c(+) CD123(-) dendritic cells. All three Ags are not detectable on a third blood dendritic cell population, which is CD1c(+) CD11c(bright) CD123(dim), or on any other cells in blood. BDCA-4 is also expressed on monocyte-derived and CD34(+) cell-derived dendritic cells. Expression of all three Ags dramatically changes once blood dendritic cells undergo in vitro maturation. BDCA-2 is completely down-regulated on plasmacytoid CD11c(-) CD123(bright) dendritic cells, expression of BDCA-3 is up-regulated on both plasmacytoid CD11c(-) CD123(bright) dendritic cells and CD1c(+) CD11c(bright) CD123(dim) dendritic cells, and expression of BDCA-4 is up-regulated on CD1c(+) CD11c(bright) CD123(dim) dendritic cells. BDCA-2 is rapidly internalized at 37 degrees C after mAb labeling. The three presumably novel Ags serve as specific markers for the respective subpopulations of blood dendritic cells in fresh blood and will be of great value for their further analysis and to evaluate their therapeutic potential.
Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a meager prognosis due to its chemotherapy resistance. A new treatment method may be magnetic fluid hyperthermia (MFH). Magnetoliposomes (ML), ...consisting of superparamagnetic iron oxide nanoparticles (SPION) stabilized with a phospholipid-bilayer, are exposed to an alternating magnetic field (AMF) to generate heat. To optimize this therapy, we investigated the effects of MFH on human PDAC cell lines and 3D organoid cultures.
ML cytotoxicity was tested on Mia PaCa-2 and PANC-1 cells and on PDAC 3D organoid cultures, generated from resected tissue of patients. The MFH was achieved by AMF application with an amplitude of 40-47 kA/m and a frequency of 270 kHz. The MFH effect on the cell viability of the cell lines and the organoid cultures was investigated at two different time points. Clonogenic assays evaluated the impairment of colony formation. Altering ML set-ups addressed differences arising from intra- vs extracellular ML locations.
Mia PaCa-2 and PANC-1 cells showed no cytotoxic effects at ML concentrations up to 300 µg(Fe)/mL and 225 µg(Fe)/mL, respectively. ML at a concentration of 225 µg(Fe)/mL were also non-toxic for PDAC organoid cultures. MFH treatment using exclusively extracellular ML presented the highest impact on cell viability. Clonogenic assays demonstrated remarkable impairment as long-term outcome in MFH-treated PDAC cell lines. Additionally, we successfully treated PDAC organoids with extracellular ML-derived MFH, resulting in notably reduced cell viabilities 2h and 24 h post treatment. Still, PDAC organoids seem to partly recover from MFH after 24 h as opposed to conventional 2D-cultures.
Treatment with MFH strongly diminished pancreatic cancer cell viability in vitro, making it a promising treatment strategy. As organoids resemble the more advanced in vivo conditions better than conventional 2D cell lines, our organoid model holds great potential for further investigations.
Precise calorimetric reconstruction of 5–50 MeV electrons in liquid argon time projection chambers (LArTPCs) will enable the study of astrophysical neutrinos in DUNE and could enhance the physics ...reach of oscillation analyses. Liquid argon scintillation light has the potential to improve energy reconstruction for low-energy electrons over charge-based measurements alone. Here we demonstrate light-augmented calorimetry for low-energy electrons in a single-phase LArTPC using a sample of Michel electrons from decays of stopping cosmic muons in the LArIAT experiment at Fermilab. Michel electron energy spectra are reconstructed using both a traditional charge-based approach as well as a more holistic approach that incorporates both charge and light. A maximum-likelihood fitter, using LArIAT's well-tuned simulation, is developed for combining these quantities to achieve optimal energy resolution. A sample of isolated electrons is simulated to better determine the energy resolution expected for astrophysical electron-neutrino charged-current interaction final states. In LArIAT, which has very low wire noise and an average light yield of 18 pe / MeV , an energy resolution of σ / E ≃ 9.3 % / √ E ⊕ 1.3 % is achieved. Samples are then generated with varying wire noise levels and light yields to gauge the impact of light-augmented calorimetry in larger LArTPCs. At a charge-readout signal-to-noise of S / N ≃ 30 , for example, the energy resolution for electrons below 40 MeV is improved by ≈ 10 % , ≈ 20 % , and ≈ 40 % over charge-only calorimetry for average light yields of 10 pe / MeV , 20 pe / MeV , and 100 pe / MeV , respectively.
We report on the expected sensitivity of dedicated scintillator-based detectors at the LHC for elementary particles with charges much smaller than the electron charge. The dataset provided by a ...prototype scintillator-based detector is used to characterize the performance of the detector and provide an accurate background projection. Detector designs, including a novel slab detector configuration, are considered for the data taking period of the LHC to start in 2022 (Run 3) and for the high luminosity LHC. With the Run 3 dataset, the existence of new particles with masses between 10 MeV and 45 GeV could be excluded at 95% confidence level for charges between 0.003 e and 0.3 e, depending on their mass. With the high luminosity LHC dataset, the expected limits would reach between 10 MeV and 80 GeV for charges between 0.0018 e and 0.3 e, depending on their mass.
Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like ABC, germinal-center ...B-cell-like GCB, and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics.
We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88
and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition.
We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).
The MINERvA Collaboration reports a novel study of neutrino-nucleus charged-current deep inelastic scattering (DIS) using the same neutrino beam incident on targets of polystyrene, graphite, iron, ...and lead. Results are presented as ratios of C, Fe, and Pb to CH. The ratios of total DIS cross sections as a function of neutrino energy and flux-integrated differential cross sections as a function of the Bjorken scaling variable x are presented in the neutrino-energy range of 5-50 GeV. Based on the predictions of charged-lepton scattering ratios, good agreement is found between the data and prediction at medium x and low neutrino energy. However, the ratios appear to be below predictions in the vicinity of the nuclear shadowing region, x<0.1. This apparent deficit, reflected in the DIS cross-section ratio at high E sub(nu), is consistent with previous MINERvA observations B. Tice et al.(MINERvA Collaboration), Phys. Rev. Lett. 112, 231801 (2014). and with the predicted onset of nuclear shadowing with the axial-vector current in neutrino scattering.
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