TOTEM: a multi-cancer detection and localization approach using circulating tumor DNA methylation markers.

BACKGROUND: Detection of cancer and identification of tumor origin at an early stage improve the survival and prognosis of patients. Herein, we proposed a plasma cfDNA-based approach called TOTEM to detect and trace the cancer signal origin (CSO) through methylation markers. METHODS: We performed enzymatic conversion-based targeted methylation sequencing on plasma cfDNA samples collected from a clinical cohort of 500 healthy controls and 733 cancer patients with seven types of cancer (breast, colorectum, esophagus, stomach, liver, lung, and pancreas) and randomly divided these samples into a training cohort and a testing cohort. An independent validation cohort of 143 healthy controls, 79 liver cancer patients and 100 stomach cancer patients were recruited to validate the generalizability of our approach. RESULTS: A total of 57 multi-cancer diagnostic markers and 873 CSO markers were selected for model development. The binary diagnostic model achieved an area under the curve (AUC) of 0.907, 0.908 and 0.868 in the training, testing and independent validation cohorts, respectively. With a training specificity of 98%, the specificities in the testing and independent validation cohorts were 100% and 98.6%, respectively. Overall sensitivity across all cancer stages was 65.5%, 67.3% and 55.9% in the training, testing and independent validation cohorts, respectively. Early-stage (I and II) sensitivity was 50.3% and 45.7% in the training and testing cohorts, respectively. For cancer patients correctly identified by the binary classifier, the top 1 and top 2 CSO accuracies were 77.7% and 86.5% in the testing cohort (n = 148) and 76.0% and 84.0% in the independent validation cohort (n = 100). Notably, performance was maintained with only 21 diagnostic and 214 CSO markers, achieving a training AUC of 0.865, a testing AUC of 0.866, and an integrated top 2 accuracy of 83.1% in the testing cohort. CONCLUSIONS: TOTEM demonstrates promising potential for accurate multi-cancer detection and localization by profiling plasma methylation markers. The real-world clinical performance of our approach needs to be investigated in a much larger prospective cohort.

Deep-learning based broadband reflection reduction metasurface.

Reflection reduction metasurface (RRM) has been drawing much attention due to its potential application in stealth technology. However, the traditional RRM is designed mainly based on trial-and-error approaches, which is time-consuming and leads to inefficiency. Here, we report the design of a broadband RRM based on deep-learning methodology. On one hand, we construct a forward prediction network that can forecast the polarization conversion ratio (PCR) of the metasurface in a millisecond, demonstrating a higher efficiency than traditional simulation tools. On the other hand, we construct an inverse network to immediately derive the structure parameters once a target PCR spectrum is given. Thus, an intelligent design methodology of broadband polarization converters has been established. When the polarization conversion units are arranged in chessboard layout with 0/1 form, a broadband RRM is achieved. The experimental results show that the relative bandwidth reaches 116% (reflection<-10 dB) and 107.4% (reflection<-15 dB), which demonstrates a great advantage in bandwidth compared with the previous designs.

Experimental demonstration of an ultra-thin radar-infrared bi-stealth rasorber.

We propose a radar-infrared bi-stealth rasorber that not only provides broad microwave absorptivity and low infrared emissivity but also possesses a microwave transmission window at low frequency. It is composed of three functional layers, which are carefully designed to independently control the infrared emission, microwave absorption, and transmission, respectively. The structure exhibits broadband (8.1-19.3 GHz) and high-efficiency (>90%) absorption. A transmission window appears at low frequency with a transmission peak of 80% at 2.68 GHz. The thermal emissivity of the structure is about 0.27 in the atmosphere window, which is close to that of metal. Moreover, the total thickness of the proposed structure is only 3.713 mm. The low-infrared-emissivity, high-microwave-absorption and frequency-selective-transmission properties promise it will find potential applications in various stealth fields.

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Ultra-broadband linear polarization converter based on anisotropic metasurface.

Through the manipulation of co-polarized reflection and cross-polarized reflection from a periodic array of metal-dielectric-metal resonators, a plethora of unprecedented metamaterial devices have been successfully demonstrated, such as perfect absorber and polarization converter. Recently, some broadband absorbers based on anisotropic resonators have been reported, which are actually poor absorbers when the cross-polarized reflection is considered. Here, we demonstrate that an ultra-wideband and high-efficiency reflective cross-polarization convertor can be achieved by breaking the symmetry of the resonator unit of a perfect absorber. Simulation results show that the polarization conversion ratio of the proposed metasurface is above 90% in the frequency range from 6.67 to 17.1 GHz and the relative bandwidth reaches 87.7%. The experimental results are in good agreement with the simulation results. The method paves a new way for the design of broadband polarization convertor, which can also be extended to the terahertz band.

Ultra-broadband wide-angle linear polarization converter based on H-shaped metasurface.

We report the design, fabrication, and measurement of an ultra-broadband wide-angle reflective cross-polarization convertor using the compact H-shaped metasurface. The significant bandwidth expansion is attributed to the four electromagnetic resonances generated in an H-shaped unit. The simulation results show that the polarization conversion ratio (PCR) of the proposed metasurface is above 90% in the frequency range from 7 to 19.5 GHz and the relative bandwidth reaches 94%. The proposed metasurface is valid for a wide range of incident angles, and the mean polarization conversion ratio remains 80% even though the incident angle reaches 41.5°. The experimental results are in good agreement with the simulation results. Compared with the previous designs, the proposed linear polarization converter has a simple geometry but an excellent performance and hence has potential applications in microwave communications, remote sensors, and imaging systems.

Ultra-broadband infrared metasurface absorber.

By using sub-wavelength resonators, metamaterial absorber shows great potential in many scientific and technical applications due to its perfect absorption characteristics. For most practical applications, the absorption bandwidth is one of the most important performance metrics. In this paper, we demonstrate the design of an ultra-broadband infrared absorber based on metasurface. Compared with the prior work [Opt. Express22(S7), A1713-A1724 (2014)], the proposed absorber shows more than twice the absorption bandwidth. The simulated total absorption exceeds 90% from 7.8 to 12.1 um and the full width at half maximum is 50% (from 7.5 to 12.5 µm), which is achieved by using a single layer of metasurface. Further study demonstrates that the absorption bandwidth can be greatly expanded by using two layers of metasurface, i.e. dual-layered absorber. The total absorption of the dual-layered absorber exceeds 80% from 5.2 to 13.7 um and the full width at half maximum is 95% (from 5.1 to 14.1 µm), much greater than those previously reported for infrared spectrum. The absorption decreases with fluctuations as the incident angle increases but remains quasi-constant up to relatively large angles.

Electromagnetic wave rotators with homogeneous, nonmagnetic, and isotropic materials.

We propose a novel optical transformation to design an arbitrary N-sided regular polygonal rotator, which demonstrates that the inhomogeneity of a rotator can be completely removed, and only anisotropy is needed to rotate wavefronts without any perturbance. An N-sided regular polygonal rotator will give rise to a rotation angle of 360°/N, thereby leading to a series of discrete rotation angles with different choices of N. Practical realization of such homogeneous rotators is suggested by using only four kinds of nonmagnetic isotropic dielectrics throughout. The dielectrics can be easily arranged in a planarly stratified configuration due to all the flat boundaries, which makes the rotator much easier in fabrication and application. Full-wave simulation validates the proposed scheme applicable to both passive object and active source with excellent performance.

Creation of vectorial bottle-hollow beam using radially or azimuthally polarized light.

We propose a single-beam generation scheme to obtain a bottle-hollow (BH) beam using a binary phase mask and a focusing lens. The resulting BH beam is shown to possess an open bottle-shaped null intensity region, which has two hollow tube-shaped null intensity regions located on two opposite sides of this bottle. It is found that this scheme works identically under incident illumination with radial or azimuthal polarization. Another advantage of this scheme is that the same binary mask can be employed as a focusing lens with different choices of numerical aperture (NA). Furthermore, we observe that the length of the BH beam is inversely proportional to NA2 while the diameters of both the bottle and hollow regions are inversely proportional to NA; thereby leading to an adjustable BH beam. This BH beam may find attractive applications in noninvasive manipulation of microscopic particles over large distances.

Experimental demonstration of a bilayer thermal cloak.

Invisibility has attracted intensive research in various communities, e.g., optics, electromagnetics, acoustics, thermodynamics, dc, etc. However, many experimental demonstrations have only been achieved by virtue of simplified approaches due to the inhomogeneous and extreme parameters imposed by the transformation-optic method, and usually require a challenging realization with metamaterials. In this Letter, we demonstrate a bilayer thermal cloak made of bulk isotropic materials, and it has been validated as an exact cloak. We experimentally verified its ability to maintain the heat front and its heat protection capabilities in a 2D proof-of-concept experiment. The robustness of this scheme is validated in both 2D (including oblique heat front incidence) and 3D configurations. The proposed scheme may open a new avenue to control the diffusive heat flow in ways inconceivable with phonons, and also inspire new alternatives to the functionalities promised by transformation optics.

Genome-Scale Multimodal Analysis of Cell-Free DNA Whole-Methylome Sequencing for Noninvasive Esophageal Cancer Detection.

PURPOSE: Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection. MATERIALS AND METHODS: Enzymatic conversion-mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model. RESULTS: ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue-specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates. CONCLUSION: This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.

Phase-preserved optical elevator.

The unique superiority of transformation optics devices designed from coordinate transformation is their capability of recovering both ray trajectory and optical path length in light manipulation. However, very few experiments have been done so far to verify this dual-recovery property from viewpoints of both ray trajectory and optical path length simultaneously. The experimental difficulties arise from the fact that most previous optical transformation optics devices only work at the nano-scale; the lack of intercomparison between data from both optical path length and ray trajectory measurement in these experiments obscured the fact that the ray path was subject to a subwavelength lateral shift that was otherwise not easily perceivable and, instead, was pointed out theoretically [B. Zhang et al. Phys. Rev. Lett. 104, 233903, 2010]. Here, we use a simple macroscopic transformation optics device of phase-preserved optical elevator, which is a typical birefringent optical phenomenon that can virtually lift an optical image by a macroscopic distance, to demonstrate decisively the unique optical path length preservation property of transformation optics. The recovery of ray trajectory is first determined with no lateral shift in the reflected ray. The phase preservation is then verified with incoherent white-light interferometry without ambiguity and phase unwrapping.

An investigation of the flexural behaviour of large-span prestressed and steel-reinforced concrete slabs.

The prestressed and steel-reinforced concrete slab (PSRCS) is an innovative composite structural member offering high load capacity and stiffness and exceptional anti-crack performance, making it a leading trend in composite structures. This paper presents the derived calculation formulas for bearing capacity, section stiffness, mid-span deflection of PSRCS. Additionally, a numerical analysis of PSRCS is conducted using ABAQUS software, with several models created to systematically investigate bearing capacity, section stiffness, anti-crack performance, and failure mode. Concurrently, PSRCS member parameters are analyzed for optimal design, and the results of finite element (FE) calculations are compared with theoretical formula calculations. The results demonstrate that PSRCS exhibits superior load capacity, section stiffness, and anti-crack performance comparing to conventional slabs. The parametric analysis offers optimal design for each parameter and presents the corresponding recommended span-to-depth ratios for various spans in PSRCS applications.

Iron colloidal transport mechanisms and sequestration of As, Ni, and Cu along AMD-induced environmental gradients.

Colloids are common in mine waters and their chemistry and interactions are critical aspects of metal(loid)s cycling. Previous studies mostly focus on the colloidal transport of metal(loid)s in zones where rivers and soil profiles receive acid mine drainage (AMD). However, there is limited knowledge of the colloid and the associated toxic element behavior as the effluent flows through the coal waste dump, where a geochemical gradient is produced due to AMD reacting with waste rocks which have high acid-neutralization effects. Here, we investigated the geochemistry of Fe and co-occurring elements As, Ni, and Cu along the coal waste dump, in aqueous, colloidal, and precipitate phases, using micro/ultrafiltration combined with STEM, AFM-nanoIR, SEM-EDS, XRD, and FTIR analysis. The results demonstrated that a fast attenuation of H+, SO42-, and metal(loid)s happened as the effluent flowed through the waste-rock dump. The Fe, As, Ni, and Cu were distributed across all colloidal sizes and primarily transported in the nano-colloidal phase (3 kDa-0.1 µm). An increasing pH induced a higher percentage of large Fe colloid fractions (> 0.1 µm) associated with greater sequestration of trace metals, and the values for As from 39.5 % to 54.4 %, Ni from 40.8 % to 75.7 %, and Cu from 43.7 % to 56.0 %, respectively. The Fe-bearing colloids in AMD upstream (pH ≤ 3.0) were primarily composed of Fe-O-S and Fe-O-C with minor Al-Si-O and Ca-O-S, while in less acidic and alkaline sections (pH ≥ 4.1), they were composed of Fe-O with minor Ca-O-S. The iron colloid agglomerates associated with As, Ni, and Cu precipitated coupling the transformation of jarosite, and schwertmannite to ferrihydrite, goethite, and gypsum. These results demonstrate that the formation and transformation of Fe-bearing colloids response to this unique geochemical gradient help to understand the natural metal(loid)s attenuation along the coal waste dump.

Multimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization.

Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.

Pan-cancer landscape of abnormal ctDNA methylation across human tumors.

BACKGROUND: The aim of this paper is to explore the correlation between circulating tumor DNA (ctDNA) methylation and mutations and its value in clinical early cancer screening. METHODS: We performed target region methylation sequencing and genome sequencing on plasma samples. Methylation models to distinguish cancer from healthy individuals have been developed using hypermethylated genes in tumors and validated in training set and prediction set. RESULTS: We found that patients with cancer had higher levels of ctDNA methylation compared to healthy individuals. The level of ctDNA methylation in cell cycle, p53, Notch pathway in pan-cancer was significantly correlated with the number of mutations, and mutation frequency. Methylation burden in some tumors was significantly correlated with tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1. The ctDNA methylation differences in cancer patients were mainly concentrated in the Herpes simplex virus 1 infection pathway. The area under curve (AUC) of the training and prediction sets of the methylation model distinguishing cancer from healthy individuals were 0.93 and 0.92, respectively. CONCLUSION: Our study provides a landscape of methylation levels of important pathways in pan-cancer. ctDNA methylation significantly correlates with mutation type, frequency and number, providing a reference for clinical application of ctDNA methylation in early cancer screening.

Gain-assisted transformation optics.

Loss severely degrades the cloaking effect of the device designed by traditional transformation. In this letter, we propose gain-assisted transformation optics to overcome the loss problem by introducing gain media into a spherical cloak. The gain media, which can amplify the electromagnetic fields, is controlled precisely to compensate the inherent loss in experimental realization of cloaks. We discuss the significance of controlling embedded gain materials in the context of the inverse design mechanism, which allows us to wisely select realizable materials with constant gain and loss along the radius. For practical realizations, isotropic spherical gain-assisted cloak is designed. Full-wave simulations validate the proposed design concept, which can be utilized to alleviate the inevitable loss problem in transformational optical devices.

Homogeneous and isotropic bends to tunnel waves through multiple different/equal waveguides along arbitrary directions.

We propose a novel optical transformation to design homogeneous isotropic bends connecting multiple waveguides of different cross sections which can ideally tunnel the wave along any directions through multiple waveguides. First, the general expressions of homogeneous and anisotropic parameters in the bend region are derived. Second, the anisotropic material can be replaced by only two kinds of isotropic materials and they can be easily arranged in planarly stratified configuration. Finally, an arbitrary bender with homogeneous and isotropic materials is constructed, which can bend electromagnetic wave to any desired directions. To achieve the utmost aim, an advanced method is proposed to design nonmagnetic, isotropic and homogeneous bends that can bend waves along arbitrary directions. More importantly, all of the proposed bender has compact shape due to all flat boundaries, while the wave can still be perfectly tunneled without mode distortion. Numerical results validate these functionalities, which make the bend much easier in fabrication and application.

Adaptive waveguide bends with homogeneous, nonmagnetic, and isotropic materials.

We propose a method for adaptive waveguide bends using homogeneous, nonmagnetic, and isotropic materials, which simplifies the parameters of the bends to the utmost extent. The proposed bend has an adaptive and compact shape because of all the flat boundaries. The nonmagnetic property is realized by selecting OB'/OC = 0.5. Only two nonmagnetic isotropic dielectrics are needed throughout, and the transmission is not sensitive to nonmagnetic isotropic dielectrics. Results validate and illustrate these functionalities, which make the bend much easier to fabricate and apply, owing to its simple parameters, compact shape, and versatility in connecting different waveguides.

Thermal Cloak: Theory, Experiment and Application.

In the past two decades, owing to the development of metamaterials and the theoretical tools of transformation optics and the scattering cancellation method, a plethora of unprecedented functional devices, especially invisibility cloaks, have been experimentally demonstrated in various fields, e.g., electromagnetics, acoustics, and thermodynamics. Since the first thermal cloak was theoretically reported in 2008 and experimentally demonstrated in 2012, great progress has been made in both theory and experiment. In this review, we report the recent advances in thermal cloaks, including the theoretical designs, experimental realizations, and potential applications. The three areas are classified according to the different mechanisms of heat transfer, namely, thermal conduction, thermal convection, and thermal radiation. We also provide an outlook toward the challenges and future directions in this fascinating area.