The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next ...generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
Abstract
Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or ...L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed.
We report terahertz (THz) light-induced second harmonic generation, in superconductors with inversion symmetry that forbid even-order nonlinearities. The THz second harmonic emission vanishes above ...the superconductor critical temperature and arises from precession of twisted Anderson pseudospins at a multicycle, THz driving frequency that is not allowed by equilibrium symmetry. We explain the microscopic physics by a dynamical symmetry breaking principle at sub-THz-cycle by using quantum kinetic modeling of the interplay between strong THz-lightwave nonlinearity and pulse propagation. The resulting nonzero integrated pulse area inside the superconductor leads to light-induced nonlinear supercurrents due to subcycle Cooper pair acceleration, in contrast to dc-biased superconductors, which can be controlled by the band structure and THz driving field below the superconducting gap.
Objectives: To examine the prevalence of sarcopenia and sarcopenic obesity (SO) as defined by different indices, including appendicular skeletal muscle mass (ASM)/height2, skeletal muscle mass index ...(SMI) and residuals for Korean adults, and to explore the association between SO and metabolic syndrome. Methods: Our study sample included 526 participants (328 women, 198 men) for whom complete data on body composition were collected using available dual X-ray absorptiometry. Modified National Cholesterol Education Program Adult Treatment Panel III criteria were used to identify the individuals with metabolic syndrome. Results: The prevalence of sarcopenia and SO is higher in older adults. Using two s.d. of ASM/height2 below reference values from young, healthy adults as a definition of sarcopenia, the prevalence of sarcopenia and SO was 6.3% and 1.3% in older (60 years) men and 4.1% and 0.8% in older women, respectively. The prevalence of sarcopenia using the residuals method was 15.4% in older men and 22.3% in older women. In addition, using two s.d. of SMI, the prevalence of sarcopenia and SO was 5.1% and 5.1%, respectively, in older men and 14.2% and 12.5%, respectively, in older women. Among women, SO subjects defined by the SMI had three times the risk of metabolic syndrome (odds ratios (OR)=3.24, 95% confidence interval (CI)=1.21-8.66) and non-sarcopenic obese subjects had approximately twice the risk of metabolic syndrome (OR=2.17, 95% CI=1.22-3.88) compared with normal subjects. Similar trends were observed in men. Conclusion: The prevalence and cutoff values of sarcopenia and SO in the Korean population were evaluated using different methods. Among the different indices of sarcopenia and SO, SO only defined using the SMI was associated with the risk of metabolic syndrome. As the Korean population gets older and more obese, the problematics of SO need to be elucidate.
We present results on light weakly interacting massive particle (WIMP) searches with annual modulation (AM) analysis on data from a 1-kg mass p-type point-contact germanium detector of the CDEX-1B ...experiment at the China Jinping Underground Laboratory. Datasets with a total live time of 3.2 yr within a 4.2-yr span are analyzed with analysis threshold of 250 eVee. Limits on WIMP-nucleus (χ-N) spin-independent cross sections as function of WIMP mass (m_{χ}) at 90% confidence level (C.L.) are derived using the dark matter halo model. Within the context of the standard halo model, the 90% C.L. allowed regions implied by the DAMA/LIBRA and CoGeNT AM-based analysis are excluded at >99.99% and 98% C.L., respectively. These results correspond to the best sensitivity at m_{χ}<6 GeV/c^{2} among WIMP AM measurements to date.
The ability to manipulate nanoscopic matter precisely is critical for the development of active nanosystems. Optical tweezers are excellent tools for transporting particles ranging in size from ...several micrometres to a few hundred nanometres. Manipulation of dielectric objects with much smaller diameters, however, requires stronger optical confinement and higher intensities than can be provided by these diffraction-limited systems. Here we present an approach to optofluidic transport that overcomes these limitations, using sub-wavelength liquid-core slot waveguides. The technique simultaneously makes use of near-field optical forces to confine matter inside the waveguide and scattering/adsorption forces to transport it. The ability of the slot waveguide to condense the accessible electromagnetic energy to scales as small as 60 nm allows us also to overcome the fundamental diffraction problem. We apply the approach here to the trapping and transport of 75-nm dielectric nanoparticles and -DNA molecules. Because trapping occurs along a line, rather than at a point as with traditional point traps, the method provides the ability to handle extended biomolecules directly. We also carry out a detailed numerical analysis that relates the near-field optical forces to release kinetics. We believe that the architecture demonstrated here will help to bridge the gap between optical manipulation and nanofluidics.
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