There are no valid instruments to measure disease activity in Takayasu arteritis (TA). We aim to provide a valid measure to assess clinical disease activity with or without incorporating acute phase ...reactants.
The Indian Takayasu Clinical Activity Score (ITAS) was initially derived from disease manifestations scored in the Disease Extent Index (DEI.Tak). The ITAS was validated by a group of physicians scoring both live and paper cases for inter-rater reliability (IRR), convergence with BVAS, correlation with the Physician's Global Assessment (PGA) and ESR/CRP. It was further validated at a single centre in 177 patients for its ability to discriminate between active and inactive disease state at first visit and sensitivity to change in 132 active patients measured serially at two follow-up visits. ITAS-A also included graded scores for ESR/CRP.
The final ITAS2010 contains 44 items with 33 features arising from the cardiovascular system. Seven key items are weighted to score 2 and all others score 1 only. Inter-observer variability was highly satisfactory (IRR 0.97). The ITAS showed superior inter-rater agreement compared with the BVAS (IRR 0.9) and PGA (IRR 0.82). In the single-centre study, median ITAS scores at first visit were significantly higher in active disease (5.62 ± 3.14) compared with grumbling (3.36 ± 1.96) and inactive disease (1.27 ± 1.26, P < 0.0001). The therapy induced a significant decrease in the ITAS2010 but the higher ITAS-A scores remained elevated.
The ITAS2010, validated in over 300 TA patients and sensitive to change, is a useful measure of clinical disease activity for patient monitoring. Higher ITAS-A scores suggest poor control of active disease by current therapy.
Functional neuroimaging studies have demonstrated that following deafness, auditory regions can respond to tactile stimuli. However, research to date has not conclusively demonstrated the behavioral ...correlates of these functional changes, with most studies showing normal-like tactile capabilities in the deaf. It has recently been suggested that more cognitive and complex tactile processes, such as music perception, could help to uncover superior tactile capabilities in the deaf. Indeed, following deafness music seems to be perceived through vibration, but the extent to which they can perceive musical features though the tactile modality remains undetermined. The goal of this study was to investigate tactile identification of musical emotion in the deaf. Participants had to rate melodies based on their emotional perception. Stimuli were presented through an haptic glove. Data suggest that deaf and control participants were comparable in the identification of three of the four emotions tested (sad, fear/threat, peacefulness). However and most importantly, for the simplest emotion (happiness), significant differences emerged between groups, suggesting an improved tactile identification of musical emotion in the deaf. Results support the hypothesis that brain plasticity following deafness can lead to improved complex tactile ability.
The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type ...Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.
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•Mice expressing analog-sensitive Cdk1 allow identification of Cdk1 substrates•Many Cdk1 substrates in ESCs are chromatin-bound at poised or transcribed genes•Cdk1 phosphorylates a large number of epigenetic regulators•Cdk1 phosphorylates and inactivates H3K79 methyltransferase Dot1l
Cdk1 drives mitotic entry and progression. Michowski et al. generated mice expressing analog-sensitive Cdk1. The authors found that in embryonic stem cells, Cdk1 phosphorylates a large number of epigenetic regulators and controls the global epigenetic landscape. Decreased Cdk1 activity during differentiation allows coordinated expression of differentiation genes.
Breast sarcomas (BS) are rare cancers originating from mesenchymal breast tissue with a paucity of national population level data detailing their incidence and outcomes.
We performed an analysis of ...data collected by National Cancer Registration and Analysis Service (NCRAS) for patients diagnosed with BS between 2013 and 2018. Chi-square test was used to compare groups. Overall survival (OS) was calculated by Kaplan–Meier. Specialist sarcoma centres (SSC) were defined as centres with a sarcoma multidisciplinary team (MDT).
There were 684 patients with BS (357 malignant phyllodes tumours PTs, 238 vascular tumours, 93 other morphology) with a median age of 64 (range 14–96); 187 (27%) had received breast radiotherapy for a prior malignancy; 633 (92%) had resection of the tumour within 12 months of diagnosis. Five-year OS was 82%, 54% and 48% in patients with PT, vascular tumours and other sarcomas, respectively, and 55% for those with radiation-induced BS. Patients managed within SSC more frequently had a biopsy prior to surgery 83% versus 72%, p < 0.05) and were less likely to require multiple operations (26% versus 41%, p < 0.05). Tumour stage and grade data were not available.
This is the first population series evaluating incidence and outcomes for BS. Patients treated at non-specialist sarcoma centres (NSSCs) are less likely to have a biopsy prior to surgery and more likely to require multiple operations. Based on these observational data, we would recommend all BS are discussed at a sarcoma MDT meeting early in their pathway and surgery to be considered at SSC where possible.
•Incidence and outcomes for breast sarcoma in England during 2013–2018.•Patients managed in specialist centres had differing outcomes.•No difference in survival between radiation and non-radiation induced vascular tumours.•We would recommend that all patients with breast sarcoma are discussed at a sarcoma MDT.
Abstract
Recent borehole seismic deployments conducted along the Baribis Fault in northwestern Java reveal that it may be active. In this study, we exploit these data to locate proximal earthquakes ...using a relative relocation technique, estimate their moment magnitudes using a spectral fitting method and compute their focal mechanisms via waveform inversion. We observe that seismicity in the eastern part of the fault is significantly higher than in the west, where a previous GPS study of the region south of Jakarta demonstrated the existence of high compression rates. These observations imply that the western Baribis Fault is locked, and that neighbouring areas, including southern Jakarta and its surroundings, may be highly vulnerable to future sizeable earthquakes when accumulated elastic strain energy is eventually released during fault rupture. Significantly, the current generation of Indonesia’s national hazard maps have not considered seismicity along the Baribis Fault. Our new results therefore call for an urgent reappraisal of the seismic hazard in northwestern Java that carefully takes into account the Baribis Fault and its earthquake potential, particularly in light of its proximity to Jakarta, a megacity that lies at the heart of one of the most densely populated islands in the world.
We previously identified CLEC14A as a tumour endothelial marker. Here we show that CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a human umbilical vein endothelial cell ...spheroid-sprouting assay, we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a(+/+) and clec14a(-/-) mice revealed defects in sprouting angiogenesis in CLEC14A-deficient animals. Tumour growth was retarded and vascularity reduced in clec14a(-/-) mice. Pull-down and co-immunoprecipitation experiments confirmed that MMRN2 binds to the extracellular region of CLEC14A. The CLEC14A-MMRN2 interaction was interrogated using mouse monoclonal antibodies. Monoclonal antibodies were screened for their ability to block this interaction. Clone C4, but not C2, blocked CLEC14A-MMRN2 binding. C4 antibody perturbed tube formation and endothelial sprouting in vitro and in vivo, with a similar phenotype to loss of CLEC14A. Significantly, tumour growth was impaired in C4-treated animals and vascular density was also reduced in the C4-treated group. We conclude that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumour growth, which has the potential to be manipulated in future antiangiogenic therapy design.
The relative paucity of recent post‐subduction environments globally has meant that, so far, little is known about tectonic processes that occur during and after subduction termination, as previously ...convergent tectonic plates adjust to the new stress regime. The region of Southeast Asia that now encompasses northern Borneo has been host to two sequential episodes of subduction—both now terminated—since the mid‐Paleogene. It is expected that these processes will have left signatures in the fabric of the upper mantle, which are manifest in the form of seismic anisotropy. We investigate the evidence for, and alignment of, anisotropic fabrics by measuring the splitting of a family of teleseismic shear phases. These observations provide a measure of the orientation of the effective anisotropic elastic tensor, in the form of the orientation of the fast shear‐wave polarization, ϕ, and add constraints on the strength of the anisotropic fabric, in the form of the delay time, δt. We observe two principal trends across northern Borneo that appear to be confined to the lithosphere. These patterns are likely related to tectonic processes associated with subduction, continental collision, and oceanic basin formation, events that can exert primary influence on the formation of post‐subduction settings.
Plain Language Summary
This study is concerned with understanding what happens to the upper 200 km of the Earth when subduction—the process by which one plate pushes beneath another and sinks into the Earth's interior—stops. We measure a property of the rock in the upper 200 km called seismic anisotropy, which tells us how fast earthquake waves move when traveling or polarized in one direction compared to another. Seismic anisotropy can inform us about both large‐scale plate tectonic events in recent geological history (10s of millions of years) and present‐day deformation. Northern Borneo has undergone two phases of active subduction followed by termination in the last 25 million years, making it one of the few places on Earth where we can explore this important stage of the subduction cycle. We find that tectonic compression and extension events related to termination and post‐subduction processes have left strong imprints in the upper 100 km of the Earth, leaving little‐to‐no remnants of signals we might have expected to observe from the active phase of subduction.
Key Points
New catalog of shear‐wave splitting measurements from a dense network in post‐subduction setting
Two trends in the fast orientations, corresponding to fabric generated by subduction termination and post‐subduction processes
Seismic anisotropy is limited to the lithosphere beneath northern Borneo, with no strong signal in radial anisotropy of simple asthenospheric flow
During a large-scale radiological event such as an improvised nuclear device detonation, many survivors will be shielded from radiation by environmental objects, and experience only partial-body ...irradiation (PBI), which has different consequences, compared with total-body irradiation (TBI). In this study, we tested the hypothesis that applying machine learning to a combination of radiation-responsive biomarkers (ACTN1, DDB2, FDXR) and B and T cell counts will quantify and distinguish between PBI and TBI exposures. Adult C57BL/6 mice of both sexes were exposed to 0, 2.0-2.5 or 5.0 Gy of half-body PBI or TBI. The random forest (RF) algorithm trained on ½ of the data reconstructed the radiation dose on the remaining testing portion of the data with mean absolute error of 0.749 Gy and reconstructed the product of dose and exposure status (defined as 1.0 × Dose for TBI and 0.5 × Dose for PBI) with MAE of 0.472 Gy. Among irradiated samples, PBI could be distinguished from TBI: ROC curve AUC = 0.944 (95% CI: 0.844-1.0). Mouse sex did not significantly affect dose reconstruction. These results support the hypothesis that combinations of protein biomarkers and blood cell counts can complement existing methods for biodosimetry of PBI and TBI exposures.
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