Dental pulp pluripotent-like stem cells (DPPSC), a new stem cell population with chromosomal stability and osteogenic capacity for biomaterials evaluation

Background: Biomaterials are widely used to regenerate or substitute bone tissue. In order to evaluate their potential use for clinical applications, these need to be tested and evaluated in vitro with cell culture models. Frequently, immortalized osteoblastic cell lines are used in these studies. However, their uncontrolled proliferation rate, phenotypic changes or aberrations in mitotic processes limits their use in long-term investigations. Recently, we described a new pluripotent-like subpopulation of dental pulp stem cells derived from the third molars (DPPSC) that shows genetic stability and shares some pluripotent characteristics with embryonic stem cells. In this study we aim to describe the use of DPPSC to test biomaterials, since we believe that the biomaterial cues will be more critical in order to enhance the differentiation of pluripotent stem cells. Methods: The capacity of DPPSC to differentiate into osteogenic lineage was compared with human sarcoma osteogenic cell line (SAOS-2). Collagen and titanium were used to assess the cell behavior in commonly used biomaterials. The analyses were performed by flow cytometry, alkaline phosphatase and mineralization stains, RT-PCR, immunohistochemistry, scanning electron microscopy, Western blot and enzymatic activity. Moreover, the genetic stability was evaluated and compared before and after differentiation by short-comparative genomic hybridization (sCGH). Results: DPPSC showed excellent differentiation into osteogenic lineages expressing bone-related markers similar to SAOS-2. When cells were cultured on biomaterials, DPPSC showed higher initial adhesion levels. Nevertheless, their osteogenic differentiation showed similar trend among both cell types. Interestingly, only DPPSC maintained a normal chromosomal dosage before and after differentiation on 2D monolayer and on biomaterials. Conclusions: Taken together, these results promote the use of DPPSC as a new pluripotent-like cell model to evaluate the biocompatibility and the differentiation capacity of biomaterials used in bone regeneration

Mu2e Technical Design Report

The Mu2e experiment at Fermilab will search for charged lepton flavor violation via the coherent conversion process mu- N --> e- N with a sensitivity approximately four orders of magnitude better than the current world's best limits for this process. The experiment's sensitivity offers discovery potential over a wide array of new physics models and probes mass scales well beyond the reach of the LHC. We describe herein the preliminary design of the proposed Mu2e experiment. This document was created in partial fulfillment of the requirements necessary to obtain DOE CD-2 approval.Comment: compressed file, 888 pages, 621 figures, 126 tables; full resolution available at http://mu2e.fnal.gov; corrected typo in background summary, Table 3.

Impact of cross-section uncertainties on supernova neutrino spectral parameter fitting in the Deep Underground Neutrino Experiment

A primary goal of the upcoming Deep Underground Neutrino Experiment (DUNE) is to measure the $\mathcal{O}(10)$ MeV neutrinos produced by a Galactic core-collapse supernova if one should occur during the lifetime of the experiment. The liquid-argon-based detectors planned for DUNE are expected to be uniquely sensitive to the $\nu_e$ component of the supernova flux, enabling a wide variety of physics and astrophysics measurements. A key requirement for a correct interpretation of these measurements is a good understanding of the energy-dependent total cross section $\sigma(E_\nu)$ for charged-current $\nu_e$ absorption on argon. In the context of a simulated extraction of supernova $\nu_e$ spectral parameters from a toy analysis, we investigate the impact of $\sigma(E_\nu)$ modeling uncertainties on DUNE's supernova neutrino physics sensitivity for the first time. We find that the currently large theoretical uncertainties on $\sigma(E_\nu)$ must be substantially reduced before the $\nu_e$ flux parameters can be extracted reliably: in the absence of external constraints, a measurement of the integrated neutrino luminosity with less than 10\% bias with DUNE requires $\sigma(E_\nu)$ to be known to about 5%. The neutrino spectral shape parameters can be known to better than 10% for a 20% uncertainty on the cross-section scale, although they will be sensitive to uncertainties on the shape of $\sigma(E_\nu)$. A direct measurement of low-energy $\nu_e$-argon scattering would be invaluable for improving the theoretical precision to the needed level.Comment: 25 pages, 21 figure

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

Human dental pulp pluripotent-like stem cells promote wound healing and muscle regeneration

Background: Dental pulp represents an easily accessible autologous source of adult stem cells. A subset of these cells, named dental pulp pluripotent-like stem cells (DPPSC), shows high plasticity and can undergo multiple population doublings, making DPPSC an appealing tool for tissue repair or maintenance. Methods: DPPSC were harvested from the dental pulp of third molars extracted from young patients. Growth factors released by DPPSC were analysed using antibody arrays. Cells were cultured in specific differentiation media and their endothelial, smooth and skeletal muscle differentiation potential was evaluated. The therapeutic potential of DPPSC was tested in a wound healing mouse model and in two genetic mouse models of muscular dystrophy (Scid/mdx and Sgcb-null Rag2-null γc-null). Results: DPPSC secreted several growth factors involved in angiogenesis and extracellular matrix deposition and improved vascularisation in all three murine models. Moreover, DPPSC stimulated re-epithelialisation and ameliorated collagen deposition and organisation in healing wounds. In dystrophic mice, DPPSC engrafted in the skeletal muscle of both dystrophic murine models and showed integration in muscular fibres and vessels. In addition, DPPSC treatment resulted in reduced fibrosis and collagen content, larger cross-sectional area of type II fast-glycolytic fibres and infiltration of higher numbers of proangiogenic CD206+ macrophages. Conclusions: Overall, DPPSC represent a potential source of stem cells to enhance the wound healing process and slow down dystrophic muscle degeneration

Bendamustine, bortezomib and prednisone for the treatment of newly diagnosed multiple myeloma patients: results of a prospective phase 2 Spanish/Pethema trial

Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diag- nosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamus- tine (90 mg/m2 on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was per- formed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be bet- ter reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross-resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401

Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials

Abstract The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease

The X/Gamma-ray Imaging Spectrometer (XGIS) on-board THESEUS: Design, main characteristics, and concept of operation

THESEUS (Transient High Energy Sky and Early Universe Surveyor) is one of the three missions selected by ESA as fifth medium class mission (M5) candidates in its Cosmic Vision science program, currently under assessment in a phase A study with a planned launch date in 2032. THESEUS is designed to carry on-board two wide and deep sky monitoring instruments for X/gamma-ray transients detection: a wide-field soft X-ray monitor with imaging capability (Soft X-ray Imager, SXI, 0.3 - 5 keV), a hard X-ray, partially-imaging spectroscopic instrument (X and Gamma Imaging Spectrometer, XGIS, 2 keV - 10 MeV), and an optical/near-IR telescope with both imaging and spectroscopic capability (InfraRed Telescope, IRT, 0.7 - 1.8 \ub5m). The spacecraft will be capable of performing fast repointing of the IRT to the error region provided by the monitors, thus allowing it to detect and localize the transient sources down to a few arcsec accuracy, for immediate identification and redshift determination. The prime goal of the XGIS will be to detect transient sources, with monitoring timescales down to milliseconds, both independently of, or following up, SXI detections, and identify the sources performing localisation at <15 arcmin and characterize them over a broad energy band, thus providing also unique clues to their emission physics. The XGIS system consists of two independent but identical coded mask cameras, arranged to cover 2 steradians. The XGIS will exploit an innovative technology coupling Silicon Drift Detectors (SDD) with crystal scintillator bars and a very low-noise distributed front-end electronics (ORION ASICs), which will produce a position sensitive detection plane, with a large effective area over a huge energy band (from soft X-rays to soft gamma-rays) with timing resolution down to a few \ub5s. Here is presented an overview of the XGIS instrument design, its configuration, and capabilities

The X/Gamma-ray Imaging Spectrometer (XGIS) on-board THESEUS: Design, main characteristics, and concept of operation

THESEUS (Transient High Energy Sky and Early Universe Surveyor) is one of the three missions selected by ESA as fifth medium class mission (M5) candidates in its Cosmic Vision science program, currently under assessment in a phase A study with a planned launch date in 2032. THESEUS is designed to carry on-board two wide and deep sky monitoring instruments for X/gamma-ray transients detection: a wide-field soft X-ray monitor with imaging capability (Soft X-ray Imager, SXI, 0.3 - 5 keV), a hard X-ray, partially-imaging spectroscopic instrument (X and Gamma Imaging Spectrometer, XGIS, 2 keV - 10 MeV), and an optical/near-IR telescope with both imaging and spectroscopic capability (InfraRed Telescope, IRT, 0.7 - 1.8 \ub5m). The spacecraft will be capable of performing fast repointing of the IRT to the error region provided by the monitors, thus allowing it to detect and localize the transient sources down to a few arcsec accuracy, for immediate identification and redshift determination. The prime goal of the XGIS will be to detect transient sources, with monitoring timescales down to milliseconds, both independently of, or following up, SXI detections, and identify the sources performing localisation at <15 arcmin and characterize them over a broad energy band, thus providing also unique clues to their emission physics. The XGIS system consists of two independent but identical coded mask cameras, arranged to cover 2 steradians. The XGIS will exploit an innovative technology coupling Silicon Drift Detectors (SDD) with crystal scintillator bars and a very low-noise distributed front-end electronics (ORION ASICs), which will produce a position sensitive detection plane, with a large effective area over a huge energy band (from soft X-rays to soft gamma-rays) with timing resolution down to a few \ub5s. Here is presented an overview of the XGIS instrument design, its configuration, and capabilities