Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations ...typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.
As consolidation therapy for acute myeloid leukemia (AML), allogeneic hematopoietic stem-cell transplantation provides a benefit in part by means of an immune-mediated graft-versus-leukemia effect. ...We hypothesized that the immune-mediated selective pressure imposed by allogeneic transplantation may cause distinct patterns of tumor evolution in relapsed disease.
We performed enhanced exome sequencing on paired samples obtained at initial presentation with AML and at relapse from 15 patients who had a relapse after hematopoietic stem-cell transplantation (with transplants from an HLA-matched sibling, HLA-matched unrelated donor, or HLA-mismatched unrelated donor) and from 20 patients who had a relapse after chemotherapy. We performed RNA sequencing and flow cytometry on a subgroup of these samples and on additional samples for validation.
On exome sequencing, the spectrum of gained and lost mutations observed with relapse after transplantation was similar to the spectrum observed with relapse after chemotherapy. Specifically, relapse after transplantation was not associated with the acquisition of previously unknown AML-specific mutations or structural variations in immune-related genes. In contrast, RNA sequencing of samples obtained at relapse after transplantation revealed dysregulation of pathways involved in adaptive and innate immunity, including down-regulation of major histocompatibility complex (MHC) class II genes ( HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) to levels that were 3 to 12 times lower than the levels seen in paired samples obtained at presentation. Flow cytometry and immunohistochemical analysis confirmed decreased expression of MHC class II at relapse in 17 of 34 patients who had a relapse after transplantation. Evidence suggested that interferon-γ treatment could rapidly reverse this phenotype in AML blasts in vitro.
AML relapse after transplantation was not associated with the acquisition of relapse-specific mutations in immune-related genes. However, it was associated with dysregulation of pathways that may influence immune function, including down-regulation of MHC class II genes, which are involved in antigen presentation. These epigenetic changes may be reversible with appropriate therapy. (Funded by the National Cancer Institute and others.).
The recurrent nova M31N 2008-12a experiences annual eruptions, contains a near-Chandrasekhar-mass white dwarf, and has the largest mass accretion rate in any nova system. In this paper, we present ...Hubble Space Telescope (HST) WFC3/UVIS photometry of the late decline of the 2015 eruption. We couple these new data with archival HST observations of the quiescent system and Keck spectroscopy of the 2014 eruption. The late-time photometry reveals a rapid decline to a minimum luminosity state, before a possible recovery/rebrightening in the run up to the next eruption. Comparison with accretion disk models supports the survival of the accretion disk during the eruptions, and uncovers a quiescent disk mass accretion rate of the order of 10 − 6 M yr − 1 , which may rise beyond 10 − 5 M yr − 1 during the super-soft source phase-both of which could be problematic for a number of well-established nova eruption models. Such large accretion rates, close to the Eddington limit, might be expected to be accompanied by additional mass loss from the disk through a wind and even through collimated outflows. The archival HST observations, combined with the disk modeling, provide the first constraints on the mass donor: L donor = 103 − 11 + 12 L , R donor = 14.14 − 0.47 + 0.46 R , and T eff , donor = 4890 110 K, which may be consistent with an irradiated M31 red-clump star. Such a donor would require a system orbital period 5 days. Our updated analysis predicts that the M31N 2008-12a WD could reach the Chandrasekhar mass in < 20 kyr.
Testosterone and alendronate have been identified as two bone healing compounds which, when combined, synergistically stimulate bone regeneration. This study describes the development of a novel ...ultrasonic spray coating for sustained release of ancillary amounts of testosterone and alendronate encapsulated in PLGA 5004A as a carrier. Due to the low amounts of testosterone and alendronate used, sensitive in vitro assays were developed to determine in vitro release. The ultrasonic spray coating technology was optimized for coating titanium screws and pericardial collagen membranes, with the aim to improve osseo-integration and (guided) bone regeneration, respectively, without interfering with their primary mode of action. In vitro release analysis of collagen membranes and screws showed up to 21 days sustained release of the compounds without a burst release. Subsequent preclinical studies in rat and rabbit models indicated that testosterone and alendronate coated membranes and screws significantly improved bone regeneration in vivo. Coated membranes significantly improved the formation of new bone in a critical size calvarial defect model in rats (by 160% compared to controls). Coated screws implanted in rabbit femoral condyles significantly improved bone implant contact (69% vs 54% in controls), bone mineral density (121%) and bone volume (119%) up to 1.3 mm from the implant. Based on the results obtained, we suggest that implants or membranes enabled with local sustained delivery of ancillary amounts of testosterone and alendronate can be a promising system to stimulate local bone regeneration resulting in improved osseo-integration of implants and improved healing of bone defects and fractures.
The COHERENT experiment is well poised to test sub-GeV dark matter models using detectors sensitive to coherent elastic neutrino-nucleus scattering (CEvNS) in the π+ decay-at-rest (π-DAR) neutrino ...beam produced by the Spallation Neutron Source. We show a planned 750-kg single-phase liquid argon scintillation detector would place leading limits on scalar light dark matter models for dark matter particles produced through vector and leptophobic portals in the absence of other effects beyond the standard model. The characteristic timing profile of a π-DAR beam allows a unique opportunity for constraining systematic uncertainties on the standard model background using a time window where dark matter signal is not expected, enhancing expected sensitivity. Additionally, we discuss future prospects which show that an on-axis CEvNS detector would probe the thermal abundance for a scalar dark matter candidate for all couplings α′ ≤ 1 for 15 MeV dark matter with just 1.0 tonne-yr of exposure with increased exposure testing a wider range of dark matter masses and spins.
We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four ...were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.
Our goal was to describe the prospective risk and timing of symptomatic hemorrhage in a large cohort of followed patients with intracerebral cavernous malformations (ICMs).
All patients between 1989 ...and 1999 with the radiographic diagnosis of intracerebral cavernous malformation were identified retrospectively. The records and radiographic data were reviewed, and follow-up after diagnosis was obtained. An incidence rate was used to calculate annual risk of symptomatic hemorrhage. Predictive factors for outcomes used univariate and multivariable analysis with p < 0.05.
A total of 292 patients were identified (47.3%male) with 2,035 patient years of follow-up. Seventy-four patients presented with hemorrhage, 108 with symptoms not related to hemorrhage (seizure or focal deficit), and 110 as asymptomatic. The overall annual rate of hemorrhage in those presenting initially with hemorrhage, with symptoms not related to hemorrhage, or as an incidental finding was 6.19%, 2.18%, and 0.33%, respectively. Patients who presented initially with symptomatic hemorrhage (hazard ratio 5.14; 95% confidence interval CI 2.54-10.4; p < 0.001) were at higher risk for future hemorrhage, and hemorrhage risk decreased with time. Male gender (hazard ratio 2.36; 95% CI 1.14-4.89; p = 0.02), and multiplicity of ICMs (hazard ratio 2.65; 95% CI 1.30-5.43; p = 0.01) also increased the risk of hemorrhage. The median time from first to second hemorrhage was 8 months.
This study provides an estimate of prospective annual symptomatic hemorrhage risk in patients with ICMs stratified by initial presenting symptom. Prior hemorrhage, male gender, and multiplicity of ICMs may predict future hemorrhage. Hemorrhage risk decreases with time in those initially presenting with hemorrhage.
Single plate osteosynthesis is commonly employed when performing surgical stabilization of midshaft clavicle fractures. In recent years, a smaller structural low-profile double plating technique has ...been described as a possible solution for the high removal rates associated with single plating. A previous meta-analysis has demonstrated that low-profile double plating attains the same healing rates as single plating without a higher chance of fracture-related infections. This meta-analysis, however, was based on relatively small studies. Therefore, a multicentre prospective natural experiment was designed using natural variation in treatment regimens and geographical location of the trauma as treatment allocation mechanism to compare both treatments on a larger scale. This manuscript describes its protocol. This study will determine whether low-profile double plating has significant clinical and cost-effective benefits over single plating techniques in midshaft clavicle fractures. The study will also give insight in the performance of a natural experiment study design for orthopedic trauma research.
The COHERENT Collaboration searched for scalar dark matter particles produced at the Spallation Neutron Source with masses between 1 and 220 MeV/c^{2} using a CsINa scintillation detector sensitive ...to nuclear recoils above 9 keV_{nr}. No evidence for dark matter is found and we thus place limits on allowed parameter space. With this low-threshold detector, we are sensitive to coherent elastic scattering between dark matter and nuclei. The cross section for this process is orders of magnitude higher than for other processes historically used for accelerator-based direct-detection searches so that our small, 14.6 kg detector significantly improves on past constraints. At peak sensitivity, we reject the flux consistent with the cosmologically observed dark-matter concentration for all coupling constants α_{D}<0.64, assuming a scalar dark-matter particle. We also calculate the sensitivity of future COHERENT detectors to dark-matter signals which will ambitiously test multiple dark-matter spin scenarios.
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