Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic ...landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid ...tic disorders.
Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks.
Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures.
Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.
Despite growing concerns that some digital algorithm-reliant fertility awareness-based methods of pregnancy prevention are marketed in an inaccurate, opaque, and potentially harmful manner online, ...there has been limited systematic examination of such marketing practices. This article therefore provides an empirical examination of how social media influencers have promoted the fertility tracking tool Daysy on Instagram. We investigate: (1) how the tool is framed in relation to pregnancy prevention using Health Belief Model (HBM) constructs, and (2) the promotional and disclosure practices adopted by influencers.
We collected Instagram posts mentioning Daysy made between June 2018 and May 2022 using the tool CrowdTangle. Using a qualitative content analysis approach, we coded a random sample of 400 Daysy posts. This yielded 122 Instagram influencer posts promoting Daysy for pregnancy prevention that we coded for promotional content and HBM constructs.
Posts originated primarily from Europe (
= 62, 50.82%) and the United States (
= 37, 30.33%). Findings indicate that barriers to use (
= 18, 15.57%) and the severity of risks from unplanned pregnancy (
= 8, 6.56%) were rarely conveyed, whereas benefits of use (
= 122, 100%) and the severity of risks of hormonal contraception (
= 31, 25.41%) were covered more extensively. Only about one third of posts disclosed any formal relationship to the brand Daysy.
With many posts emphasizing benefits and obscuring potential limitations, we argue that accurate and transparent information about the effectiveness and limitations of fertility tracking technologies is critical for supporting informed decision-making and, as such, should remain a public health priority.
We report the first measurement of the average of the electron-proton and positron-proton elastic scattering cross sections. This lepton charge-averaged cross section is insensitive to the leading ...effects of hard two-photon exchange, giving more robust access to the proton's electromagnetic form factors. The cross section was extracted from data taken by the OLYMPUS experiment at DESY, in which alternating stored electron and positron beams were scattered from a windowless gaseous hydrogen target. Elastic scattering events were identified from the coincident detection of the scattered lepton and recoil proton in a large-acceptance toroidal spectrometer. The luminosity was determined from the rates of Møller, Bhabha, and elastic scattering in forward electromagnetic calorimeters. The data provide some selectivity between existing form factor global fits and will provide valuable constraints to future fits.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
The purpose of this study was to determine changes in neurocognitive, psychosocial, and balance functioning in collegiate male and female soccer players across three consecutive years of baseline ...testing compared with a control group of noncontact athletes.
Generalized estimating equations were used to compare changes in annual, preseason baseline measures of neurocognitive function, neurobehavioral and psychological symptoms, and postural stability between collegiate soccer players ( n = 75; 51 68% female soccer players) and noncontact athletes ( n = 210; 133 63% female noncontact athletes) across three consecutive years.
Among all participants, the group-time interaction was not significant for any outcome measures. Overall, soccer players reported lower (better) Brief Symptom Inventory 18 Depression ( P = 0.004, Exp(B) = 0.36, 95% confidence interval CI = 0.18-0.73), Global Severity Index ( P = 0.006, Exp(B) = 0.53, 95% CI = 0.33-0.84), and Post-Concussion Symptom Scale Symptom Severity ( P < 0.001, Exp(B) = 0.45, 95% CI = 0.22-0.95) scores than noncontact athletes. No other outcome measures were different between soccer players and noncontact athletes.
Among collegiate athletes, soccer players report similar or better psychosocial functioning and symptom scores than noncontact athletes. Importantly, neurocognitive functioning, neurobehavioral and psychological symptoms, and postural stability do not worsen over time in collegiate soccer players relative to their noncontact counterparts. Our findings suggest that despite possible exposure to repetitive head impacts, collegiate soccer players do not exhibit changes in observable function and symptoms across multiple seasons.
GridPP: the UK grid for particle physics Britton, D.; Cass, A.J.; Clarke, P.E.L. ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
06/2009, Volume:
367, Issue:
1897
Journal Article
Peer reviewed
The start-up of the Large Hadron Collider (LHC) at CERN, Geneva, presents a huge challenge in processing and analysing the vast amounts of scientific data that will be produced. The architecture of ...the worldwide grid that will handle 15 PB of particle physics data annually from this machine is based on a hierarchical tiered structure. We describe the development of the UK component (GridPP) of this grid from a prototype system to a full exploitation grid for real data analysis. This includes the physical infrastructure, the deployment of middleware, operational experience and the initial exploitation by the major LHC experiments.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
To determine the microbiologie spectrum and antibiotic susceptibilities of infecting organisms in postoperative endophthalmitis and to evaluate the effects of operative factors on the microbiologie ...spectrum.
Patients with bacterial endophthalmitis presenting within six weeks of cataract extraction or secondary intraocular lens implantation (IOL) were evaluated. Cultures and Gram stains were performed on intraocular specimens and susceptibility tests on the isolates.
Confirmed microbiologie growth was demonstrated from intraocular specimens from 291 of 420 patients (69.3%). Gram-positive bacteria were isolated from 274 patients (94.2%) with confirmed growth and gram-negative bacteria from 19 (6.5%). Two hundred twenty-six of the 323 isolates obtained (70.0%) were gram-positive, coagulase-negative micrococci, 32 (9.9%) Stapfiylococcus aureus, 29 (9.0%) Streptococcus species, seven (2.2%) Enterococcus species, ten (3.1%) miscellaneous gram-positive species, and 19 (5.9%) gram-negative species. All gram-positive isolates tested were susceptible to vancomycin. Seventeen gram-negative isolates (89%) were susceptible to both amikacin and ceftazidime and two (11%) were resistant to both. Anterior chamber or secondary IOL implantations were associated with higher rates of infection with gram-positives other than coagulase-negative micrococci than were posterior chamber IOL implantations (P = .022) or primary cataract extractions (P = .024).
Gram-positive, coagulasenegative micrococci predominated in this series. Vancomycin was active against all gram-positive isolates tested. Amikacin and ceftazidime showed equivalent activity against gram-negative isolates. Secondary or anterior chamber lens implantations were associated with a possible spectrum shift toward gram-positive organisms other than the coagulase-negative micrococci.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In situ LA‐ICP‐MS monazite geochronology from a garnet‐bearing diatexite within the Moine Supergroup (Glenfinnan Group) NW Scotland records three temporally distinct metamorphic events within a ...single garnet porphyroblast. The initial growth of garnet occurred in the interval c. 825–780 Ma, as recorded by monazite inclusions located in the garnet core. Modelled P–T conditions based on the preserved garnet core composition indicate an initially comparatively high geothermal gradient regime and peak conditions of ∼650 °C and 7 kbar. Monazite within a compositionally distinct second shell of garnet has an age of 724 ± 6 Ma. This is indistinguishable from a SIMS age of 725 ± 4 Ma obtained from metamorphic zircon in the sample, which is interpreted to record the timing of migmatization. This second stage of garnet growth occurred on a P–T path from ∼6 kbar and 650 °C rising to ∼9 kbar and 700 °C, with the peak conditions associated with partial melting. A third garnet zone which forms the rim contains monazite with an age of 464 ± 3 Ma. Monazite in the surrounding matrix has an age of 462 ± 2 Ma. This corresponds well with a U–Pb SIMS zircon age of 463 ± 4 Ma obtained from a deformed pegmatite that was emplaced during widespread folding and reworking of the migmatite fabric. The P–T conditions associated with the final phase of garnet growth were ∼7 kbar and 650 °C. The monazite ages coupled with the phase relations modelled from this multistage garnet indicate that it records two Neoproterozoic tectonothermal events as well as the widespread Ordovician Grampian event associated with Caledonian orogenesis. Thus, this single garnet records much of the Neoproterozoic to Ordovician thermal history in NW Scotland, and highlights the long history of porphyroblast growth that can be revealed by in situ isotopic dating and associated P–T modelling. This approach has the potential to reveal much of the thermal architecture of Neoproterozoic events within the Moine Supergroup, despite intense Caledonian reworking, if suitable textural and mineralogical relationships can be indentified elsewhere.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Many oncogenic signals originate from abnormal protein-protein interactions that are potential targets for small molecule inhibitors. However, the therapeutic disruption of these interactions has ...proved elusive. We report here that the naturally-occurring triterpenoid celastrol is an inhibitor of the c-Myc (Myc) oncoprotein, which is over-expressed in many human cancers. Most Myc inhibitors prevent the association between Myc and its obligate heterodimerization partner Max via their respective bHLH-ZIP domains. In contrast, we show that celastrol binds to and alters the quaternary structure of the pre-formed dimer and abrogates its DNA binding. Celastrol contains a reactive quinone methide group that promiscuously forms Michael adducts with numerous target proteins and other free sulfhydryl-containing molecules. Interestingly, triterpenoid derivatives lacking the quinone methide showed enhanced specificity and potency against Myc. As with other Myc inhibitors, these analogs rapidly reduced the abundance of Myc protein and provoked a global energy crisis marked by ATP depletion, neutral lipid accumulation, AMP-activated protein kinase activation, cell cycle arrest and apoptosis. They also inhibited the proliferation of numerous established human cancer cell lines as well as primary myeloma explants that were otherwise resistant to JQ1, a potent indirect Myc inhibitor. N-Myc amplified neuroblastoma cells showed similar responses and, in additional, underwent neuronal differentiation. These studies indicate that certain pharmacologically undesirable properties of celastrol such as Michael adduct formation can be eliminated while increasing selectivity and potency toward Myc and N-Myc. This, together with their low in vivo toxicity, provides a strong rationale for pursuing the development of additional Myc-specific triterpenoid derivatives.
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