Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma ...cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.
Alternative splicing plays a pivotal role in tumorigenesis and proliferation. However, its pattern and pathogenic role has not been systematically analyzed in multiple myeloma or its subtypes. ...Alternative splicing profiles for 598 newly diagnosed myeloma patients with comprehensive genomic annotation identified primary translocations, 1q amplification, and DIS3 events to have more differentially spliced events than those without. Splicing levels were correlated with expression of splicing factors. Moreover, the non-homologous end joining pathway was an independent factor that was highly associated with splicing frequency as well as an increased number of structural variants. We therefore identify an axis of high-risk disease encompassing expression of the non-homologous end joining pathway, increase structural variants, and increased alternative splicing that are linked together. This indicates a joint pathogenic role for DNA damage response and alternative RNA processing in myeloma.
Disuse of a muscle group, which occurs during bedrest, spaceflight, and limb immobilization, results in atrophy. It is unclear, however, if the magnitude of decline in skeletal muscle quality is ...similar to that for muscle size. The purpose of this study was to examine the effects of two weeks of knee joint immobilization on vastus lateralis and rectus femoris echo intensity and cross-sectional area.
Thirteen females (mean ± SD age = 21 ± 2 years) underwent two weeks of left knee joint immobilization via ambulating on crutches and use of a brace. B-mode ultrasonography was utilized to obtain transverse plane images of the immobilized and control vastus lateralis and rectus femoris at pretest and following immobilization. Effect size statistics and two-way repeated measures analyses of variance were used to interpret the data.
No meaningful changes were demonstrated for the control limb and the rectus femoris of the immobilized limb. Analyses showed a large increase in vastus lateralis echo intensity (i.e., decreased muscle quality) for the immobilized limb (
= .006, Cohen's
= .918). For vastus lateralis cross-sectional area, no time × limb interaction was observed (
= .103), but the effect size was moderate (
= .570). There was a significant association between the increase in vastus lateralis echo intensity and the decrease in cross-sectional area (
= - .649,
= .016).
In female participants, two weeks of knee joint immobilization resulted in greater deterioration of muscle quality than muscle size. Echo intensity appears to be an attractive clinical tool for monitoring muscle quality during disuse.
The April 11, 2012, magnitude 8.6 earthquake off the northern coast of Sumatra generated a tsunami that was recorded at sea‐level stations as far as 4800 km from the epicenter and at four ocean ...bottom pressure sensors (DARTs) in the Indian Ocean. The governments of India, Indonesia, Sri Lanka, Thailand, and Maldives issued tsunami warnings for their coastlines. The United States' Pacific Tsunami Warning Center (PTWC) issued an Indian Ocean‐wide Tsunami Watch Bulletin in its role as an Interim Service Provider for the region. Using an experimental real‐time tsunami forecast model (RIFT), PTWC produced a series of tsunami forecasts during the event that were based on rapidly derived earthquake parameters, including initial location and Mwp magnitude estimates and the W‐phase centroid moment tensor solutions (W‐phase CMTs) obtained at PTWC and at the U. S. Geological Survey (USGS). We discuss the real‐time forecast methodology and how successive, real‐time tsunami forecasts using the latest W‐phase CMT solutions improved the accuracy of the forecast.
Key Points
Tsunami forecast in real time
Using recent advances in seismology for source determination
Improve the accuracy of tsunami forecasting and warning
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A FDG-PET/CT image feature with optimal prognostic potential for locally-advanced non-small cell lung cancer (LA-NSCLC) patients has yet to be identified, and neither has the optimal time for ...FDG-PET/CT response assessment; furthermore, nodal features have been largely ignored in the literature. We propose to identify image features or imaging time point with maximal prognostic power.
Consecutive consenting patients with LA-NSCLC receiving curative intent CRT were enrolled. 4DPET/4DCT scans were acquired 0, 2, 4, and 7 weeks during IMRT treatment. Eleven image features and their rates of change were recorded for each time point and tested for each of the possible outcome 2 years post CRT using the Kaplan–Meier method.
32 consecutive patients were recruited, 27 completing all scans. Restricting analysis to 4DPET/4DCT features and rates of change with p < 0.005, several volume-based features and their rates of change reached significance. Image features involving nodal disease were the only ones associated with overall survival.
Several 4DPET/CT features and rates of change can reach significant association (p < 0.005) with outcomes, including overall survival, at many time points. The optimal time for adaptive CRT is therefore not constrained uniquely on imaging.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Biallelic TP53 inactivation is the most important high-risk factor associated with poor survival in multiple myeloma. Classical biallelic TP53 inactivation has been defined as simultaneous mutation ...and copy number loss in most studies; however, numerous studies have demonstrated that other factors could lead to the inactivation of TP53. Here, we hypothesized that novel biallelic TP53 inactivated samples existed in the multiple myeloma population. A random forest regression model that exploited an expression signature of 16 differentially expressed genes between classical biallelic TP53 and TP53 wild-type samples was subsequently established and used to identify novel biallelic TP53 samples from monoallelic TP53 groups. The model reflected high accuracy and robust performance in newly diagnosed relapsed and refractory populations. Patient survival of classical and novel biallelic TP53 samples was consistently much worse than those with mono-allelic or wild-type TP53 status. We also demonstrated that some predicted biallelic TP53 samples simultaneously had copy number loss and aberrant splicing, resulting in overexpression of high-risk transcript variants, leading to biallelic inactivation. We discovered that splice site mutation and overexpression of the splicing factor MED18 were reasons for aberrant splicing. Taken together, our study unveiled the complex transcriptome of TP53, some of which might benefit future studies targeting abnormal TP53.
The ocean is key to understanding societal threats including climate change, sea level rise, ocean warming, tsunamis, and earthquakes. Because the ocean is difficult and costly to monitor, we lack ...fundamental data needed to adequately model, understand, and address these threats. One solution is to integrate sensors into future undersea telecommunications cables. This is the mission of the SMART subsea cables initiative (Science Monitoring And Reliable Telecommunications). SMART sensors would “piggyback” on the power and communications infrastructure of a million kilometers of undersea fiber optic cable and thousands of repeaters, creating the potential for seafloor-based global ocean observing at a modest incremental cost. Initial sensors would measure temperature, pressure, and seismic acceleration. The resulting data would address two critical scientific and societal issues: the long-term need for sustained climate-quality data from the under-sampled ocean (e.g., deep ocean temperature, sea level, and circulation), and the near-term need for improvements to global tsunami warning networks. A Joint Task Force (JTF) led by three U.N. agencies (ITU/WMO/UNESCO-IOC) is working to bring this initiative to fruition. This paper explores the ocean science and early warning improvements available from SMART cable data, and the societal, technological, and financial elements of realizing such a global network. Simulations show that deep ocean temperature and pressure measurements can improve estimates of ocean circulation and heat content, and cable-based pressure and seismic-acceleration sensors can improve tsunami warning times and earthquake parameters. The technology of integrating these sensors into fiber optic cables is discussed, addressing sea and land-based elements plus delivery of real-time open data products to end users. The science and business case for SMART cables is evaluated. SMART cables have been endorsed by major ocean science organizations, and JTF is working with cable suppliers and sponsors, multilateral development banks and end-users to incorporate SMART capabilities into future cable projects. By investing now, we can build up a global ocean network of long-lived SMART cable sensors, creating a transformative addition to the global ocean observing system.
Six‐channel seismic reflection data reveal a magma chamber reflector beneath the Malaguana‐Gadao Ridge, the southernmost segment of the spreading center in the Mariana Trough. For most of its length ...the spreading center in this active back‐arc basin is morphologically similar to slow spreading mid‐ocean ridges, having a deep central graben flanked by a zone of abyssal hill fabric. This southernmost segment, however, has a broad, smooth cross section, lacks a deep central graben, and is thus similar in morphology to fast spreading ridges (e.g., the East Pacific Rise). We identify a magma chamber at 1.5 s two‐way travel time below the crest of the ridge. Observations from remotely operated vehicles along the ridge reveal not only fresh pillows, lobate, and sheet lava flows but also an abundance of volcaniclastic debris and intense hydrothermal activity. These observations, together with the “fast spreading” morphology of the ridge, suggest that this segment has a considerably higher magma supply than is typical in the Mariana Trough. We suggest that the volcanic arc or enhanced melting of a hydrated mantle is supplying volatile‐rich magma as evidenced by a highly negative coefficient of reflection, −0.42, for this MCR and the presence of evolved, highly vesicular lava and volcaniclastic materials. The southeastern Mariana back‐arc basin spreading ridge does not compare readily with mechanical models for global mid‐ocean ridge data sets because of marked asymmetry in both volcanism and deformation that may be the consequence of slab‐related geometry in this part of the convergent margin system.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In gated radiotherapy, the accuracy of treatment delivery is determined by the accuracy with which both the imaging and treatment beams are gated. Time delays are of four types: (1) beam on imaging ...time delay is the time between the target entering the gated region and the first gated image acquisition; (2) beam off imaging time delay is the time between the target exiting a gated region and the last image acquisition; (3) beam on treatment time delay is the time between the target entering the gated region and the treatment beam on; and (4) beam off treatment time delay is the time between the target exiting the gated region and treatment beam off. Asynchronous time delays for the imaging and treatment systems may increase the required internal target volume (ITV) margin. We measured time delay on three fluoroscopy systems, and three linear accelerator treatment beams, varying gating type (amplitude vs. phase), beam energy, dose rate, and period. The average beam on imaging time delays were −0.04±0.05sec (amplitude, 1 SD), −0.11±0.04sec (phase); while the average beam off imaging time delays were −0.18±0.08sec (amplitude) and −0.15±0.04sec (phase). The average beam on treatment time delays were +0.09±0.02sec (amplitude, 1 SD), +0.10±0.03sec (phase); while the average beam off time delays for treatment beams were +0.08±0.02sec (amplitude) and +0.07±0.02sec (phase). The negative value indicates the images were acquired early, and the positive values show the treatment beam was triggered late. We present a technique for calculating the margin necessary to account for time delays. We found that the difference between these imaging and treatment time delays required a significant increase in the ITV margin in the direction of tumor motion at the gated level.
PACS number: 87.53.Dq
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In reply to Masjedi et al Carlone, Marco; Yang, Ray; Hyde, Derek ...
Medical physics (Lancaster),
April 2024, 2024-Apr, 2024-04-00, 20240401, Volume:
51, Issue:
4
Journal Article
Peer reviewed
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
