Gas-sieving (H2/CH4 selectivity up to 25) is observed from the intrinsic defects generated during the chemical-vapor deposition of graphene. Despite the ultralow porosity of 0.025%, an attractive H2 permeance (up to 4.1 × 10−7 mol m−2 s−1 Pa−1) is observed. Finally, we report ozone functionalization-based etching and pore-modification chemistry to etch hydrogen-selective pores, and to shrink the pore-size, improving H2 permeance (up to 300%) and H2/CH4 selectivity (up to 150%). Overall, the scalable transfer, etching, and functionalization methods developed herein are expected to bring nanoporous graphene membranes a step closer to reality.The single-layer graphene film, when incorporated with molecular-sized pores, is predicted to be the ultimate membrane. However, the major bottlenecks have been the crack-free transfer of large-area graphene on a porous support, and the incorporation of molecular-sized nanopores. Herein, we report a nanoporous-carbon-assisted transfer technique, yielding a relatively large area (1 mm Graphene shows great promise for gas separation applications, but obtaining large membranes that are free of cracks and tears remains highly challenging. Here, the authors realize monolayer, crack-free, millimeter-scale graphene membranes that exhibit selective gas permeation solely thanks to their intrinsic defects Several molecular simulations have shown that the two-dimensional nanopores in graphene can yield high gas permeance, orders of magnitude higher than that attainable with the conventional membranes11. Such high-flux membranes can considerably reduce the needed membrane area for separating a volume of a molecular mixture, addressing the problem of scale-up, a longstanding issue with the inorganic membranes. The thermal and chemical robustness and the high mechanical strength of the graphene lattice, even with a porosity as high as 5%13, makes it highly attractive for the gas separation. Recently, several etching methods for incorporating sub-nanometer pores in graphene lattice have been developed, leading to promising sieving performances for liquids and dissolved ions17. However, the demonstration of gas mixture separation from single-layer graphene membrane has remained a challenging task19. A proof-of-concept was demonstrated by measuring the deflation rate of a bilayer graphene microballoon, where pores were incorporated by multiple ultraviolet treatment20. In general, the molecular transport studies through single-layer graphene have been primarily carried out on micron-sized domains, attributing to the poor scalability of the micromechanical exfoliation, and the challenging transfer of the chemical-vapor deposition (CVD) derived graphene. Celebi et al. reported a 2500 μmμm2-sized bilayer graphene membrane by masking cracks in a graphene film by another graphene film21. Using focused-ion beam, an array of nanopores (>7.6 nm in diameter) were incorporated leading to an effusive gas transport. Recently, a centimeter-scale single-layer graphene membrane hosting molecular-sized pores was reported, however, the cracks generated during the transfer limited the separation selectivity close to that expected from the Knudsen diffusion 18. Overall, the demonstration of gas mixture separation from sufficiently-scaled single-layer graphene membrane has remained elusive. To develop graphene membranes, one needs to (a) transfer large-area graphene onto porous supports without generating cracks and tears, and (b) generate molecular-sized pores with a narrow pore-size-distribution (PSD). Development of such method would also allow one to study the gas transport mechanism (activated vs. surface vs. Knudsen transport), and effect of the competitive adsorption through the graphene nanopores.Atom-thick graphene film is the thinnest possible molecular barrier and therefore incorporated with molecular-sized pores, it can be regarded as the ultimate membrane2) single-layer CVD graphene onto a macroporous support (pore-opening of 5 µm) without generating cracks or tears, allowing observation of gas-sieving from the intrinsic defects of CVD graphene. An attractive H2 permeance (up to 4.1 × 10−7 mol m−2 s−1 Pa−1) is obtained despite the ultralow-density of the intrinsic defects (porosity of 0.025%). An activated gas transport is observed with an average activation energy for H2 transport across eight membranes being 20.2 ± 2.7 kJ/mole. The molecular-sized intrinsic defects yield an attractive separated selectivity, including those from the mixed gas feed (H2/CH4 separation factor up to 18). The membrane performance remains stable during several heating and cooling cycles (25–150 °C), and at least up to 7 bar of the transmembrane pressure difference. Finally, in the pursuit to increase the density of gas-selective pores, we also report an ozone functionalization-based etching and pore-modification chemistry, increasing the nanopore density and/or reducing the effective pore-size. A combination of higher selectivity, higher permeance, and higher selectivity/higher permeance is observed.Herein, we report a novel nanoporous-carbon-assisted graphene transfer technique that enables transfer of relatively large area  (PMMA) film). Subsequently, the metal foil is removed by etching the metal in an etchant bath leaving the polymer coated graphene floating on the bath. Finally, the floating film is scooped on top of the desired substrate, and the polymer film is dissolved away to expose the surface of graphene. This wet-transfer process has been proven to be quite successful in fabricating graphene-based devices on smooth non-porous substrates24. However, significant cracks and tears develop in the graphene film when a porous support is used, primarily because of a strong capillary force on the suspended graphene film during the solvent drying stage30. This issue can be mitigated if the mechanically reinforcing film is not removed, and yet somehow the graphene surface is exposed. Motivated by this, we developed a nanoporous carbon (NPC) film-assisted transfer method  images of the NPC/graphene film on Cu, and transmission electron microscopy (TEM) images of the transferred NPC/graphene film on a TEM grid revealed that the NPC film was 100 nm thick, and comprised of 20–30 nm sized nanopores , formed by etching of the graphene lattice in the presence of residual oxygen in the CVD chamber, and are promising for the gas separation. In the current study, the density of defects, estimated by the carbon amorphization trajectory34  revealed several sub-1-nm nanopores with a pore-density of 2.8 × 1011 cm−2  directly on the as-synthesized graphene supported on the Cu foil, we recently imaged the low-density of intrinsic defects in the CVD graphenem−2 Fig. . This sm2 permeance in the range of 5.2 × 10−9–7.2 × 10−8 mol m−2 s−1 Pa−1  with H2/CH4, H2/CO2, and He/H2 ideal selectivities ranging between 4.8–13.0, 3.1–7.2, and 0.7–2.0, respectively, at 25 °C 20. The H2/CH4 selectivity was lower than that from Bi-3.4 membrane20, indicating a wider PSD of intrinsic defects in CVD graphene, compared to PSD from pores incorporated in micromechanically exfoliated graphene. Based on the achieved H2/CH4 selectivities, the estimated percentage of larger nanopores yielding non-selective effusive gas transport is less than 25 ppm .Graphene membranes were sealed in a homemade permeation cell using a metal face seal directly on top of the W support, ensuring a leak-proof measurement of the gas transport (details in the Methods). Typically, the feed side (a pure gas feed or a mixture feed) was pressurized to 1.5–7.0 bar, whereas the permeate side connected to a pre-calibrated mass spectrometer (MS) was maintained at 1 bar with an argon sweep , with H2/CH4, and H2/CO2 selectivities increasing to 7.1–23.5 and 3.6–12.2, respectively. We note that this H2/CH4 separation performance from single-layer graphene with 0.025% porosity approaches the 2008 Robeson upper bound for polymers35 3, providing an indication that the average pore in this study is close to that made from missing 10 carbon atoms, which is supported by the HRTEM images  compared to the corresponding ideal selectivities (IS). However, the separation factors were similar (He/H2 and H2/CO2) or higher (H2/CH4) compared to the corresponding ideal selectivities , while the H2 permeance (3.3 × 10−8–2.2 × 10−7 mol m−2 s−1 Pa−1 between 25 and 150 °C) in the mixture case was similar to the single-component case , the H2 permeance and the H2/CH4 selectivity in the mixture case were similar to those in the single-component case. These results indicate that the competitive adsorption of gases on the basal plane of graphene does not play a significant role in overall transport especially when the transport is in the activated regime, and when the feed pressure is moderate (up to 8 bar in this study). We expect the competitive adsorption to play a role at a higher feed pressure , while the H2/CH4 selectivity increased marginally (8.3 to 10.5). Moreover, the graphene membranes were also stable at least up to 8 bar of mixture feed at 100 °C  allowing a high degree of control is highly attractive. In this pursuit, we report a scalable ozone functionalization-based pore-etching and pore-edge-functionalization chemistry, improving the performance of the single-layer graphene membranes. We demonstrate that a controlled temperature-dependent oxidative functionalization of the graphene lattice with ozone-derived epoxy and carbonyl groups can be used to either etch molecular-sized pores in the CVD derived graphene or constrict the existing pores.The porosity of graphene lattice yielding the attractive H3-hybridized sites (epoxy and carbonyl groups) on the basal plane of graphene43. When the functionalization density is high, such as that in graphene oxide, one can introduce nanopores in the lattice by thermal annealing47. Typically, the functional groups migrate and rearrange forming larger groups (such as lactone), and finally desorb as CO or CO2 leading to a vacancy44. Ozone, in the gas phase, can be conveniently used to oxidize graphene lattice. To understand the evolution of functionalization, CVD graphene supported on a Cu foil was exposed to ozone at various temperatures  and time (1 min to 7 min). The evolution of oxidative groups on graphene was probed by micro-Raman and X-ray photoelectron spectroscopy (XPS). The relative intensity of the D peak with respect to the G peak (ID/IG), which marks the extent of disorder in graphene48, increased from 0.07 to 4.0, while the intensity of the 2D peak decreased in intensity with the increasing reaction time and temperature, indicating that the sp3-hybridized sites in graphene increased after ozone treatment  compared to that in as-synthesized graphene  and CoAactAsur decreased after the functionalization (Supplementary Table Eact-app are complex to interpret because of relative changes in Eact (higher activation energy due to the pore-shrinkage) and ΔEsur , a 20-fold decrease in CoAactAsur for CH4  on a Cu foil . Before CVD, the foil was placed in the fused quartz tube and annealed at 1000 °C in a CO2/Ar atmosphere for 1 h, forming the NPC film on top of graphene. The NPC/graphene/Cu was floated on a Na2S2O8 bath (0.2 M in water) to etch the Cu foil. After Cu etching, the floating NPC/graphene film was rinsed in deionized water to remove the residues. Finally, NPC/graphene was scooped on the porous tungsten support.To deposit the nanoporous carbon (NPC) film on graphene, 0.1 g block-copolymer (poly (styrene-b-4-vinyl pyridine), Polymer Source) and 0.2 g turanose (Sigma-Aldrich) were dissolved in DMF (Sigma-Aldrich). After a heat treatment of the solution at 180 °C, the solution was spin-coated onto the as-synthesized CVD graphene supported on the Cu foil. Pyrolysis of the polymer film was conducted at 500 °C in a H2 and O3 (21% in O3) generated by the ozone generator (Absolute Ozone® Atlas 30) was exposed to the permeate side of graphene. After a certain time, argon was used to sweep-out the residual ozone.Ozone functionalization on the suspended graphene film was conducted in-situ in the membrane module. The gas permeation module was leak-proof based on a metal–metal (Swagelok VCR fittings) seal. The membrane was sandwiched as a gasket in the VCR-based module, making a leak-tight fitting. Before, ozone functionalization, the membrane was heated to 150 °C to remove adsorbed atmospheric contaminations and to allow measurement of the gas separation performance. Then, the membrane was cooled to the functionalization temperature. Subsequently, a mixture of OThe single-component and mixture gas permeation tests were carried out in a homemade permeation cell. Permeation tests were conducted in the open-end mode.All equipment used in the permeation setup (the mass flow controllers (MFCs) and MS) were calibrated within 5% error. The gas permeation module based on the metal–metal (Swagelok VCR fittings) seal was leak-proof. The porous tungsten support was sandwiched as a gasket in the VCR-based module, making a leak-tight fitting. To ensure temperature uniformity and accuracy, the feed and the sweep lines were preheated, and the membrane module was heated inside an oven with the temperature accuracy of ±1 °C.2, He, CO2, and CH4 in Ar, similar to those in the permeate stream.A pre-calibrated MFC regulated the flow rate of feed gas, and the feed pressure was controlled by adjusting the back-pressure regulator installed at the downstream. Another pre-calibrated MFC controlled the flow rate of sweep gas (Ar), which carried the permeate gas to the pre-calibrated MS for real-time analysis of the permeate concentration. The MS was capable to read an extremely low concentration in the permeate stream. To reduce errors, MS was calibrated at low concentration of HThe transmembrane pressure difference was varied between 1.5 to 7.0 bar. Before testing, all membranes were heated to 150 °C to remove the contaminations on the graphene surface. For the mixture permeation tests, an equimolar gas mixture was used on the feed side. The gas flux was calculated once the steady-state was established . The measurements were carried out at continuously, in real-time, and only the steady-state data were reported.SEM was carried out by using FEI Teneo SEM at 0.8–2.0 kV and working distances of 2.5–9.0 mm. No conductive coating was applied on the substrates prior to SEM. TEM imaging and electron diffraction of the NPC film and the composite graphene/NPC film were conducted by FEI Tecnai G2 Spirit Twin with 120 keV incident electron beam.28. Briefly, a thin poly(methyl methacrylate) or PMMA film was spin-coated on top of graphene. Following this, Cu was etched in a sodium persulfate bath. After rinsing the floating graphene/PMMA film with deionized water, the composite film was transferred to the TEM grid. Subsequently, PMMA was removed by heating the sample to 400 °C in a reducing atmosphere of H2/Ar.For HRTEM, graphene was transferred on a quantifoil TEM grid by the traditional wet-transfer techniqueAberration-corrected (Cs) HRTEM was performed using a double-corrected Titan Themis 60-300 (FEI) equipped with a Wein-type monochromator. To reduce the electron radiation damage, an 80 keV incident electron beam was used for all experiments. The incident electron beam was monochromated (“rainbow” mode illumination) to reduce the effects of chromatic aberration, and a negative Cs of ~15–20 μm and slight over focus were used to give a “bright atom” contrast in the images. HRTEM images were post-treated using a combination of Bandpass and Gaussian filters to reduce noise and improve contrast.2/Si wafer by the wet-transfer method28. Single-point data collection and mapping were performed using Renishaw micro-Raman spectroscope . Analysis of the Raman data was carried out using MATLAB. For calculation of the D and the G peak height, the background was subtracted from the Raman data using the least-squares curve fitting tool (lsqnonlin).Raman characterization was carried on graphene transferred onto the SiOThe X-ray photoelectron spectroscopy (XPS) analysis was conducted on the graphene mounted on Cu foil using a Mg Kα X-ray source (1253.6 eV) and Phoibos 100 (SPECS) hemispherical electron analyser with multichanneltron detector. The XPS spectra were recorded in fixed analyser transmission (FAT) mode using pass energies of 90 eV for the survey and 20 eV for the narrow scans. The samples did not show electrostatic charging thus the binding energies are presented without any correction . Because carbonyl group (C=O) is part of (O–C=O), O–C=O was counted in C=O in the summation of functional group. The XPS spectra were processed with CasaXPS, with background subtraction by the Shirley method.The authors declare that all the data supporting the findings of this study are available within the article (and its Supplementary Information file), or available from the corresponding author on reasonable request.Supplementary InformationPeer Review File


We analyze the electronic properties of a hybrid graphene-BN nanoribbon system, using a Hubbard model Hamiltonian within a mean field approximation. Due to the different electronegativities of the boron and nitrogen atoms, an electric field is induced across the zigzag graphene strip, breaking the spin degeneracy of the electronic band structure. Optimal tight-binding parameters are found from first-principles calculations. Edge potentials are proposed as corrections for the on-site energies, modeling the BN-graphene nanoribbon interfaces. We show that half-metallic responses in the hybrid systems may be driven with the help of an external electric field. We also study the role of defects across the graphene nanoribbon and at the h-BN/graphene interface regions. Modulations on the spin-dependent gaps may be achieved depending on the nature and position of the defect, constituting a way towards spin-gap engineering by means of spatial doping. In nanoribbons, the opened gap depends on the edge type and the width of the strip4. Alternatively, combining the properties of large band gap semiconductors, such as hexagonal-boron nitride (h-BN), with the conductive properties of graphene, appears as a promising route for gap modulation5. In fact, h-BN has the same honeycomb lattice as graphene, but composed of alternating boron and nitrogen atoms with a lattice constant (2.50 Å) very similar to that of graphene (2.46 Å). The band gap of h-BN is [∼5–6]eV6. Hybrid graphene and h-BN materials have been synthesized using lithography patterning and sequential CVD growth steps7. Actually, efficient epitaxial growth routes of BN onto graphene edges are possible under particular experimental conditions8, allowing a good matching between both lattices.Graphene is a zero-band-gap semiconductor with valence and conduction bands touching at the corners of the Brillouin zone. However, in order to use graphene in semiconductor electronics, such as in field-effect transistors (FETs), it is very important to open a band gap. This can be achieved, for instance, by patterning graphene into quasi-one-dimensional nanoribbons or tuning its properties for its use as a two-dimensional semiconductor11. Insulator-metal transitions in BN nanoribbons have been predicted with the application of transversal electric fields12; the actual critical field depends on the width of the ribbon. Particularly, when an electric field is applied in the transversal direction of zigzag graphene nanoribbons (ZGNRs), the system behaves as a half-metallic material14. Namely, the spin-degeneracy is broken and the energy gap for electrons with spin down (spin up) decreases (increases) until a critical electric field is reached, for which there is a null gap for the spin-down channel, and the electrons in the other channel have a direct band gap. This opens the possibility of exploring spin filtering properties of carbon systems15. Interestingly, such half-metallic behavior can be achieved even in the absence of an external electric field for some systems19 as embedded ZGNRs in zigzag h-BN nanoribbons (ZBNNRs)20.Gap engineering is also possible by means of external electric fields2 -capture devices21, electronic rectifiers22, and spin-filters activated by strain23, or by edge hydrogenation effects24. Induced half-metallic responses due to spin polarization through defective interfaces of h-BN/graphene was reported in the work of Lan et al.25. Also, laterally repeating h-BN/graphene systems present a variety of electronic properties according to the geometry of the h-BN/layers, and can be potentially used in optical devices26. The electronic properties can also be modified by dihydrogenation of the edges of hybrid C/BN nanostructures27, promoting interesting semiconductor-to-half-metal-to-metal transitions.Graphene/h-BN heterostructures have been proposed for engineering applications; for example, COm-ZBNNR/n-ZGNR/m-ZBNNR  model with electronic correlation given by a Hubbard-like term is used to account for spin-dependent solutions. Simple TB calculations can reproduce quite well the electronic bands near the Fermi level for ZGNRs when compared to first-principles results28. For the case of ZBNNRs, more complex descriptions are necessary due to the large ionicity of BN.Our study focuses on hybrid systems of the form see Fig. , with m 29, mainly related to the π-bands. Alternatively, an edge potential approach was successfully proposed by Zheng et al. as an effective correction to on-site energy values in ZBNNRs30. This attempts to explain not only π-band features, but also some σ-band effects appearing in density functional theory (DFT) results. For the hybrid system m BN/n G/m BN, the presence of a ZGNR in the middle of the boron nitride nanoribbons changes the alternating electron polarization of B and N atoms. In fact, a single edge potential is unable to explain the electronic properties of the hybrid system. For this reason, we look for an electronic effective potential across the BN/graphene interfaces deriving it from DFT results31, resulting in on-site energy corrections for our TB calculations. With this parameterization, we study the band gap behavior of hybrid systems as a function of their geometry and structure. We also consider the presence of defects that are usually frequent in such nanostructured systems, mainly at the edges and interfaces, such as edge disorder and atom migration. Spontaneous magnetization in ZBNNRs doped with carbon atoms in substitutional positions in the lattices has been reported32, so understanding the effects of such lattice imperfections on the electronic properties is relevant to improve the controlled electronic responses of these nanostructured materials. Actually, atomically controlled substitutional boron doping of graphene nanoribbons has been reported to provide a route for the design of mobility gaps and novel types of graphene transistors33.Approaches to overcome this difficulty with similar systems include corrections to on-site energies and hopping integrals at the edges of nanoribbonsσ at site i, niσ is the spin-dependent occupation number operator, and εi, Ui, tij are the on-site energy, the intra-atomic Coulomb repulsion, and integral hopping energy, respectively. Using the mean-field approximation, the Coulomb term in  values for carbon  atoms along the length of the nanoribbon. For non-pristine systems, we consider periodic defects by taking a defective supercell, and following the same self-consistent renormalization procedure described above.The hybrid system is described by a TB approach involving a set of optimal parameters that properly reproduce DFT calculations. The intrasite electron-electron interaction is included via a Hubbard term, which reproduces the half-metallic characteristics related to spin polarization. The Hubbard Hamiltonian is written as term in  reduces entclass1pt{minima38. We use the Quantum ESPRESSO (QE)39 code to compute the electronic structure for the hybrid systems, followed by the WanT Package41 to obtain the on-site and hopping parameters. We call them the post-processed DFT parameter sets. Pseudopotentials from the ultrasoft Vanderbilt type, a cutoff energy of 60Ry, and a k-point sampling for the zigzag nanoribbons of 52 points are employed.In order to obtain the Hubbard and TB parameters, we follow a similar procedure used for other h-BN/graphene systems42 from which we obtain the TB parameter values. Although post-processing DFT calculations consider interactions between a large range of neighbor atoms, we are just interested in the on-site energy and first nearest-neighbor hoppings, so parameters obtained from QE and WanT are adjusted to build an optimal set of TB parameters which give the best agreement to the DFT calculations.The codes provide a procedure based on projecting the Kohn-Sham solutions into localized atomic orbitals. The corresponding Hamiltonian in the real space has a Slater-Koster-matrix shape5. For the present hybrid system, we adjust those parameter values to obtain an electronic effective potential31, affected by the presence of ZBNNR’s edges and BN/C interfaces. More detailed description on the optimized tight-binding model used is presented as a Supplementary Material.Optimal on-site energies and hopping parameter values for other BN/graphene systems are reported elsewhereet al. proposed a TB model for a ZBNNR system with on-site energy corrections in the form of effective edge potentials30. Here we follow a similar approach. In addition to the edge corrections, we also consider the effects of the zigzag interfaces (N/C and C/B), on the on-site energies of the hybrid system.Taking into account the important contribution from edge states to the electronic density of zigzag BN nanoribbons and the electronegativity difference between B and N atoms, Zheng εi, for B, N and C atoms are shown as black circles in Fig. i-sites far enough from the edges or interfaces.The results obtained from post-processing DFT calculations for the on-site energy values, V(x) is not directly obtained from post-processing DFT calculations due to the influence of a large number of neighbor interactions. Here, we are interested in an effective TB model only considering first nearest-neighbor interactions. Blue triangles in the left panel of Fig. et al. to correct the on-site energies in ZBNNRs using exponential-type edge potentials30. Furthermore, our procedure incorporates the effects from BN edges and BN/graphene interfaces, i.e., for the BN region we have the following contribution from the edges,π-electron density at xB and xN edges, while in the internal graphene strip the contributions from the interfaces are chosen as decaying exponential functions centered at the left and right interfaces, xL and xR,The envelope function 43. In order to identify the edge-localized states in a band, we compute the analogous of the inverse participation number for the tight-binding coefficients of the wavefunction, which quantifies the localization of a state45. Thus, we estimate the degree of localization in every band according toOn-site energies taken directly from post-processing DFT calculations do not reproduce some features of the band structures due to the contributions of many neighbors and the poor projection of Kohn-Sham solutions over localized atomic orbitalsThe band structures are shown in the right panel of Fig. The resulting parameters for edge and interface potentials are shown in Table It is important to remark that the same TB parameters explain the main band structure features of other hybrid systems. Actually, we have worked with a set of ;2),\; 5;...,46. The work by Zhao et al. provides TB parameters for BN quantum dots embedded in graphene5. Starting from those values, we have modified them  = , but predicts a half-metallic response for wider ribbons, with  =  and , in agreement with Ding et al.4. Similar band structures with half-metallic response are also exhibited by other h-BN/graphene configurations47. Tight-binding band structures are also calculated with our parameterization and compared with the DFT calculations. The TB results are plotted in Fig. An interesting result of the hybrid systems is their spontaneous half-metallicity without the need of an external field, which is explained by the presence of an effective electric potential generated through the graphene strip, as it can be noticed from Eq. et al.34, i.e. the on-site energies are modified by an electrostatic potential:V is an electrostatic potential produced by a transversal electric field, parallel to axis X of the figures shown in this article and perpendicular to the edgesV being antisymmetric respect to the axis of the nanoribbon. We have chosen this model since our system is electrically neutral, and our calculations follow a procedure that ensures charge neutrality for the system as a whole.In order to further explore the half-metallicity features observed in the hybrid graphene/h-BN nanoribbons we consider the case in which an extra electric field is applied in the transversal direction of the nanoribbons. To introduce the electric field into the calculations, we have followed the same procedure as in Wakabayashi 48. Such behavior can be understood due to the absence of electron-hole symmetry.In the presence of a transversal electric field, first-principle calculations on zigzag BNNRs are shown to exhibit asymmetric responses49. After this point, the system becomes a nonmagnetic semiconductor. In other words, in the hybrid system, a first critical field occurs when a nonzero external field is applied , and a second one happens for larger values, marking the occurrence of the half-metallic behavior. This second critical electric field is shifted to higher values compared to pure graphene nanoribbons, due to the intrinsic field produced by the ZBNNR edges.TB calculations show that when adding a positive external electric field on the hybrid system, the original half-metallicity disappears; with increasing electric field, the bandgap for the spin-up channel decreases rapidly, while the bandgap for the spin-down channel widens. The bandgaps for the up and down spin channels are eventually equal at a particular electric field, marked in Fig. U adopted, but the shape of the gap curve as a function of the electric field is completely preserved . TB calculations from Culchac et al. also show a fast evolution of the gap value around the critical electric field value for ZGNRs49. The rate of change is smoother according to DFT calculations on ZGNRs, but strongly depends on the functional employed50. It is important to remark that the TB calculations can reproduce the removal of half-metallicity for large values of the electric field, a common feature for ZGNRs and h-BN/graphene heterostructures. For negative values of the electric field, the different spin-dependent gaps are moved towards a non-magnetic solution, with degenerate up and down solutions. Therefore, the addition of an external electric field breaks the intrinsic half-metallic behavior that happens for certain hybrid system geometries. This response is in agreement with the DFT results by Bohwmick et al.20.According to our TB calculations, the rate of change of the spin-up gap with respect to the electric field is very high around the first critical electric field value (next to zero field for h-BN/graphene heterostructure). We have checked that the exact electric field for which this abrupt transition takes place depends on the Coulomb potential i, given in terms of the Bohr magneton, with ni,up  being the mean number of electrons with spin up (down) at site i. The results plotted in Fig. 51. A positive external field increasing also leads to a magnetization quenching, but with different field-dependence due to the internal electric field induced by the BN edges. Of course, the critical electric field which produces the magnetization suppression depends on the characteristic sizes of the hybrid system, that may be additionally engineered.We also calculate the magnetization of the hybrid system 5BN/6 G/5BN as a function of the applied electric field. We use the expression 52 and vice versa. The presence of defects at the interface has been reported elsewhere53 and could lead to an enhancement of the half-metallic behavior54. A DFT description of these hybrids would require high computational cost. Dieb et al. overcame this difficulty55 proposing a machine learning algorithm to describe B-doped graphene systems and to find the most stable configurations. Alternatively, we model hybrid systems by means of the tight-binding approximation, using our TB parameterization and fitting curves to model the hybrid system bandgaps. We first consider the possibility of boron or nitrogen atoms placed at carbon atom positions inside the graphene strip, mimicking a migration process, as shown schematically in Fig. A more realistic description of the studied hybrid nanoribbons should certainly include roughness in the zigzag interfaces as well as possible diffusion of boron or nitrogen atoms from the h-BN region into the graphene stripn-th site. We should remember that nitrogen electronegativity is higher than those of carbon and boron atoms. Usually, in an B-doped AGNR the Fermi level is shifted downward due to missing π electrons from the B atoms56. As expected, impurity substitutions with boron and nitrogen atoms induce opposite trends for the bandgap behavior as a function of the impurity position along the graphene material: averaged higher/smaller spin-up gap as the B/N atom migrates from the N-C (left) to the C-B (right) interface. N-substitutions along the graphene strip show, on average, a more robust half-metallic response compared with B-substitutions and to the pristine case. Otherwise, notice that the system enhances the half-metallic response when B and N substitutions happens at the first neighbor carbon atom in both interfaces; site 11 for the B and site 22 for the N impurity. When a B occupies the 11-th position, it follows the natural B-N sequence along the h-BN armchair chain, leading to a narrower effective ZGNR width, what makes the gap increase. The same is valid for an N impurity at site 22. Calculations for less diluted systems  reveal similar bandgap trends, but with more variations.We analyze the gap evolution shown in Fig. As we have not directly included the structural distortions in the discussion on the defects, we have explored a possible alternative approach to include effectively the lattice distortion effects, based on the linear strain theory that changes hopping energies within tight-binding descriptions. Details are presented in the Supplementary Material. We have shown that similar results are obtained, validating our approach.Using our TB parameters with edge and interface potentials, we calculate the total energy of the system when a boron (or a nitrogen) atom substitutes a carbon atom in the graphene strip. The results show (not presented here) that a boron replacing a carbon atom at the interface is the most favorable energetic configuration, where the boron is bonded with a nitrogen atom. As expected, an analogous behavior happens for the nitrogen substitution on the other edge. These results have been corroborated by DFT calculations.Na as a parameter that indicates how far the two defects are from the frontal relative position, in terms of the number of armchair chains separating the two defects. Thus, ΔNa = 0 when both impurities belong to the same armchair chain, but located at different interfaces.We also study other defect configurations. Instead of having atomic diffusion across the graphene strip, we analyze the effect of the presence of impurities located at opposite interfaces. Figure Na = 0, while for other neighboring relative positions of the defects, the gap starts decreasing as the impurities get apart from each other. In fact, the configuration with opposite impurities amounts to an effective reduction of the width of the ribbon, which yields an increased gap.Figure Na shown in Fig. N for the particular system et al. reported57 that doping graphene sheets above a certain concentration leads to a half-metallic response. Therefore, the combined effects of interface potentials and a B(N)-doping in h-BN/graphene/h-BN systems may result in an enhancement of the half-metallic behavior depending on the doping concentration.We should also keep in mind that the oscillatory gap behavior as a function of Δn BN/m C/n BN heterostructure that reproduce the main features of DFT predictions including the effect of external electric fields. The TB parameters are not only valid for a specific size of the heterostructure: they are robust enough to explain main trends of the electronic band structures for a wide range of graphene/h-BN system sizes. Due to the ionic edges of ZBNNRs and BN/C interfaces in the hybrid systems described here, we can estimate an effective potential that gives a best fit to DFT predictions. Another advantage of our TB parameters is the study of transport using Green functions in big hybrid systems and the influence of impurities in a scattering region. The coupling regions between electrodes and scattering regions are minimized, reducing the computational cost of the transport calculations. We have enlarged our discussion on the adequateness of our approach and the possibility of validating our approach with other computational methods in the Supplementary Material.In summary, we have found TB parameters for the With respect to the applied electric fields, due to the polarity of the material, boron and nitrogen edges induce an electric field that competes with the external field, that we have successfully modeled. Half-metallicity becomes intrinsic to the BN/5 C/BN even in the absence of an external electric field. Furthermore, the graphene/h-BN heterostructure can not only work as a spin filter, but also as a spin swapping device by just turning on an external electric field.Taking advantage of our approach, we aim to study larger systems that would be computationally expensive by first-principles calculations. We use our TB parameters to analyze more realistic graphene/h-BN heterostructures by considering boron and nitrogen diffusion across the graphene strip, or graphene/h-BN interface with roughness due to substitutional impurities. We have found that in general nitrogen diffusion enhances the half-metallic response. We have also found an oscillatory gap behavior that is maximum for a pair of boron and nitrogen impurities facing each other at each BN/graphene interfaces. We attributed this maximum gap value to an effective reduction of the width of the nanoribbon. Further studies are needed to analyze a possible suppression or enhancement of the half-metallic response by modulating the concentration of boron and nitrogen impurities at the interfaces.Supplementary Material


The aim of this study was to explore whether spectral computed tomography (CT) imaging parameters are associated with PD‐L1 expression of lung adenocarcinoma.Spectral CT imaging parameters  were analyzed in 34 prospectively enrolled lung adenocarcinoma patients with common molecular pathological markers including PD‐L1 expression detected with immunohistochemistry. Patients were divided into two groups: positive PD‐L1 expression and negative PD‐L1 expression groups. Two‐sample Mann‐Whitney U test was used to test the difference of spectral CT imaging parameters between the two groups.. −54.69 ± 262.04), CT40keVv (124.39 ± 34.71 vs. −45.73 ± 238.97), CT70keVa (49.56 ± 11.76 vs. −136.51 ± 237.08) and CT70keVv (46.13 ± 15.81 vs. −133.10 ± 230.72) parameters in the positive PD‐L1 expression group of lung adenocarcinoma were significantly higher than the negative PD‐L1 expression group . There was no difference detected in IC, NIC and λHU of the arterial and venous phases between both groups .The CT40keVa (127.03 ± 37.92 vsCT40keVa, CT40keVv, CT70keVa and CT70keVv were increased in positive PD‐L1 expression. These parameters may be used to distinguish the PD‐L1 expression state of lung adenocarcinoma. Primary lung cancer is the leading cause of morbidity and mortality both in China and worldwide.At present, the detection of lung cancer‐related mutant genes and PD‐L1 expression is mainly through invasive biopsy, some of which are expensive, which limits its wide clinical use.Recently, the correlation between CT signs of lung adenocarcinoma and common gene mutations of EGFR and ALK has been studied.Spectral CT imaging has been applied in several of the studies on pulmonary nodules. Most researchers believe that quantitative parameters of spectral CT imaging have certain advantages in the differential diagnosis of benign and malignant pulmonary nodules.From January 2018 to August 2018, a total of 34 patients detected with immunohistochemistry of 67 lung adenocarcinomas , were prospectively enrolled in the study. This research protocol was approved by the Medical Ethical Committee of Peking University Cancer Hospital & Institute and written informed consent was obtained from all patients in accordance with the guidelines of National Health Commission of the People's Republic of China. Patients were selected for investigation according to the following inclusion criteria: (i) presence of at least one solitary lung adenocarcinoma proved by pathology and (ii) no contraindications to the administration of iodinated contrast material. Patients without PD‐L1 testing were excluded from this study.vol) for GSI acquisition was 4.73 mGy.CT examinations were performed with two‐phase enhanced CT scanning using spectral imaging mode on a Revolution Xtream CT scanner . Patients were injected with 40/50 mL  Iopromide  at a flow rate of 5/6 mL/second , followed by the 30 mL saline solution at the same injection rate. With a scan delay of 30 and 90 seconds after the start of contrast injection, a GSI examination of the entire chest was performed during arterial phase (AP) and portal venous phase (VP), respectively. There were no serious injection complications or issues in this study. Acquisition parameters were helical tube rotation time 0.6 seconds, helical pitch 0.985, tube current of 600 mA, 512 × 512 pixel matrix, SFOV 500 mm and collimation 40 mm, slice thickness of 5 mm, slice gap of 5 mm. Contiguous axial images (2.5 and 1.25 mm thickness) at a default monochromatic energy level of 40 and 70 KeV were then reconstructed with a soft tissue kernel (standard) with GSI data file. CT dose index . Monochromatic and material decomposition images were performed to analyze the quantitative measurements by a chest radiologist with 10 years experience. During data analysis, the radiologist amplified the display field of view to 15 or 20 cm in each lesion imaged. The region of interest (ROI) was selected as large as possible at the maximum section of the lesion carefully avoiding calcification, liquefaction, or necrosis, away from pulmonary vessels and bronchi, and as large as possible to reduce noise (50 pixels). All measurements were repeated three times at three contiguous imaging levels and average values calculated to ensure consistency.Spectral curve image, iodine‐based material decomposition images, and monochromatic images obtained at the energy level of 40 and 70 keV in both arterial phase (a) and venous phase (v) were reconstructed from the spectral CT acquisition for analysis. In the iodine density image derived from the iodine/water based material decomposition image, the iodine concentration of lesions (ICLa/ ICLv) in double‐phase enhanced scan were measured. The iodine concentration in the aorta descendens or subclavian artery (ICA) were also measured in the same slice. The normalized iodine concentration (NICa and NICv), which is the ratio of iodine concentration in lesion and aorta descendens (NIC = ICL/ICA), were calculated. These iodine concentration parameters ICLa, ICLv, ICAa, ICAv, NICa and NICv were calculated in the arterial and venous phase, respectively. The slope of spectral HU curve (λHU) was assessed only 40–70 keV region by the equations λHU = (CT40 keV−CT70 keV) HU/(70–40) based on previous studies. λHUa = (CT40 keVa−CT70 keVa) HU/(70–40) and λHUv = (CT40 keVv−CT70 keVv) HU/(70–40) were calculated.Pathological specimens were routinely fixed in 10% formalin, paraffin‐embedded. Tissue sections were cut at 4 μm thickness including the largest cut surface of the tumor, and stained with hematoxylin and eosin (H&E). Pathological diagnoses were made by two experienced lung pathologists, based on the new WHO histological classification of lung tumors in 2015,Immunostaining was performed using the standard streptavidin‐perosidase (SP142) technique with the antibodies for PD‐L1. A Leica automatic staining machine was used for immunohistochemical staining. Tumor proportion score (TPS) was counted. TPS >1% was positive and TPS >50% indicated a high expression of PD‐L1.Immunohistochemical EnVision two‐step staining was used to detect antibodies P40, TTF‐1, NapsiA and ki‐67.P‐value less than 0.05 indicated significance. SPSS was used to perform the statistical analysis .Data were transformed using a Box‐Cox power transformation by Statistics 12 , to minimize the influence of extreme values or non‐normal distributions. Parameters were expressed as mean ± SD and tested for normal distribution using Kolmogorov‐Smirnov test. The two‐sample Mann‐Whitney test was used to compare the difference of spectral CT quantitative parameters between positive PD‐L1 expression and negative PD‐L1 expression groups. A A total of 34 patients with PD‐L1 test results were enrolled into the study. The results indicated that there was one patient (2.9%) with minimally invasive adenocarcinoma (MIA) (2.9%) and 33 with invasive adenocarcinomas (IACs) (97.1%). Of these, 15 were solid cases and 19 ground‐glass opacities, which presented as predominant lepidic growth in nine cases, predominant acinar growth in nine cases, solid growth in two cases, papillary growth in two cases, micropapillary growth in one case, infiltrating mucinous adenocarcinoma in one case, and mixed of two growth in 10 cases. All cases were confirmed by pathology. PD‐L1 expression was positively detected in eight cases (23.5%), and PD‐L1 expression was negative in 26 cases (76.5%).P = 0.005; CT40keVv: 124.39 ± 34.71 vs. −45.73 ± 238.97, P = 0.004; CT70keVa: 49.56 ± 11.76 vs. −136.51 ± 237.08, P = 0.002; CT70keVv: 46.13 ± 15.81 vs. −133.10 ± 230.72, P = 0.002, as seen in Figures In the positive PD‐L1 expression and negative PD‐L1 expression groups, raw variables for differentiating positive PD‐L1 expression from negative PD‐L1 expression are shown in Table P > 0.05.IC, NIC and λHU in both arterial and venous phases in the positive PD‐L1 expression group had no statistically significant differences compared to the negative PD‐L1 expression group, and all were Currently, the choice of first‐line treatment for advanced non‐small cell lung cancer (NSCLC) depends on the presence of genetic aberrations, such as mutations of epidermal growth factor receptor (EGFR) and translocations of anaplastic lymphoma kinase (ALK). However, only 10% to 20% of patients with NSCLC have these actionable mutations.At present, using immunohistochemistry (IHC) staining in formalin‐fixed paraffin‐embedded tissue samples is the most popular method to assess PD‐L1 expression. However, there is no unified standard to detect PD‐L1 staining because there are different staining techniques and antibodies. Scoring methods and cutoff values to define positive expression are also different in individual studies which make it difficult to reach a compatible consensus.Radiographic assessment as a noninvasive and quantitative method could bring practical clinical benefit in the development of predictive markers before immunotherapy. Similarly, traditional chest CT features have also been extensively studied as radiologic markers for predicting therapeutic effect and survival time of lung adenocarcinomas. In addition, several studies have been conducted on the relationship between traditional chest CT features and gene mutations of EGFR, ALK in lung adenocarcinomas.89Zr, 64Cu, 68Ga or 111InIn this study, and as seen in Table There were several limitations in this study. First, the number of patients was relatively small, and the PD‐L1‐positive cases were proportionally lower, which probably results in selection bias; however, it is epidemiologically consistent with the incidence of lung cancer with PD‐L1 expression. It means that our results should be further validated in a large number of cases. Second, the biological behavior of different subtypes of lung adenocarcinoma varies greatly, and their spectral CT imaging parameters and PD‐L1 expression may be different. Third, the majority of selected cases in this study were elderly people with a mean age of 61.5 years, and younger patients should be included in future studies. Fourth, monochromatic CT number was measured only enhanced monochromatic spectral CT imaging at the energy level 40 and 70 keV based on previous studies,In conclusion, spectral CT imaging parameters, CT40keVa, CT40keVv, CT70keVa and CT70keVv were significantly increased when PD‐L1 expression was positive. These parameters may be used to distinguish the PD‐L1 expression status of lung adenocarcinoma.The author(s) have no relevant conflicts of interest to disclose.


We propose and numerically demonstrate two novel terahertz absorbers made up of periodic single- and double-layer decussate graphene ribbon arrays. The simulated results show that the proposed absorbers have narrowband near-unity terahertz absorption with ultra-wide frequency reconfiguration and angular stability. By tuning the Fermi level of graphene ribbons, the over 90% absorbance peak frequency of the absorber with single-layer graphene structure can be flexibly adjusted from 6.85 to 9.85 THz for both the transverse magnetic (TM) and transverse electric (TE) polarizations. This absorber with single-layer graphene demonstrates excellent angular stability with the absorbance peaks of the reconfigurable absorption bands remaining over 99.8% in a wide angle of incidence ranging from 0 to 70°. The tuning frequency can be significantly enhanced by using the absorber with double-layer graphene structure from 5.50 to 11.28 THz and 5.62 to 10.65 THz, approaching two octaves under TM and TE polarizations, respectively. The absorbance peaks of the reconfigurable absorption band of this absorber for both polarizations maintain over 70%, even at a large angle of incidence up to 70°. Furthermore, an analytical fitting model is also proposed to accurately predict the absorbance peak frequencies for this variety of absorbers. Benefitting from these attractive properties, the proposed absorber may have great potential applications in tunable terahertz trapping, detecting, sensing, and various terahertz optoelectronic devices. Terahertz waves generally refer to electromagnetic waves with a frequency of 0.1–10 THz. Terahertz technology has broad applications in terahertz communication, spectroscopy, detecting, sensing, and imaging ,3,4. THzfH − fL)/fL × 100%. Li et al. demonstrated a tunable mid-infrared narrowband absorber using parallel double-layer graphene ribbons with an RFTR of 18.7% from 22.73 to 27 THz and a wide angular stability of 60° [Graphene is a monatomic carbon layer two-dimensional material that has attracted a great deal of attention in the past decade because of its unique electrical performance, low intrinsic loss, and photonic properties . Since gy of 60° . He et ay of 60° . Zhang ey of 60° . An enhay of 60° ,27. DespTo address this issue, we propose a new variety of frequency-reconfigurable narrowband near-unity terahertz absorbers with significantly enhanced RFTR and angular stability using single/double-layer decussate graphene ribbon arrays (S/DLDGRAs). To demonstrate the properties and mechanisms of the absorbers, we present the geometric configurations and study their performance, including terahertz absorbance spectra, effective impedance characteristics, field distributions, frequency reconfiguration, and angular stability of the proposed absorbers. It was found that by tuning graphene Fermi level, the RFTR for the over 90% absorbance peak frequency of the proposed absorber with SLDGRA reached 43.8%, ranging from 6.85 to 9.85 THz for both TM and TE polarizations under normal incidence. The RFRT for the over 90% absorbance peak frequency of the absorber with DLDGRA could be further extended to 105.1% (89.5%), ranging from 5.50 (5.62) to 11.28 (10.65) THz, approaching two octaves for the TM (TE) polarization under normal incidence. The absorbance peaks of the different absorption bands for both absorbers maintained over 70% in a wide range of angle of incidence from 0° to 70°. Furthermore, we propose a simple analytical fitting model to accurately predict the reconfigurable absorbance frequencies of the absorbers. Finally, we systematically draw the conclusion of the whole work.2 dielectric layer, and a gold (Au) reflection layer from the top to the bottom. The absorber with DLDGRAs can be interpreted as the transformation of the absorber with a SLDGRA by separating two graphene ribbon arrays into different layers with a distance of h1 while keeping the identical thickness of the dielectric layer. Here, we display the top views of the unit cells of the proposed absorbers with S/DLGRAs in σg = σintra + σinter (Unit: S) [σintra and interband contribution interσ are given by:ω is the radian frequency, μc is the chemical potential or Fermi level, T0 is the temperature, Γ is the phenomenological scattering rate, Γ = 2τ−1, τ is the relaxation time, e is the charge of an electron, ξ is energy, ћ is the reduced Plank’s constant, and kB is Boltzmann’s constant. The relative dielectric constant of ZrO2 was set as εr = 4.41 [Lx and Ly are the periods of the unit cell, and Wx and Wy are the widths of the graphene ribbons in x and y directions, respectively. The thickness of the upper and lower ZrO2 spacers, the Au reflecting layer, and the total thickness of the absorbers were set as h1, h2, h3, and h = h1 + h2 + h3, respectively. In this study, we assumed the parameters as Lx = Ly = 4 µm, Wx = Wy = 0.9 μm, h1 = 1 μm, h2 = 4 μm, h3 = 1 μm, T0 = 300 K, τ = 0.6 ps [g =Z 1g/σ without thickness [A = 1−T–R, where reflectance R = |S11|2, transmission T = |S21|2, and S denotes the scattering parameter, respectively [μc of graphene can be easily tuned from 0 to 1.0 eV via chemical or electrostatic doping [The schematic of the proposed frequency-reconfigurable wide-angle terahertz absorbers with S/DLDGRAs is illustrated in Unit: S) ,29, wherr = 4.41 ,31 and tr = 4.41 . In the = 0.6 ps , respecthickness ,35 and tectively . In addic doping ,37, makiIn this section, we first study terahertz absorbance spectra, frequency reconfiguration and angular stability of the proposed absorbers with SLDGRA. Then, to demonstrate a wider frequency reconfiguration, we present and investigate the properties of the absorbers with DLDGRA. Furthermore, we also proposed a simple analytical fitting model to accurately predict the reconfigurable absorbance peak frequencies of this variety of absorbers.A, transmission T, and reflectance R for both TE and TM polarizations with μc = 0.3 eV under normal terahertz incidence (θ = 0°). It is clear that excellent narrow-band terahertz absorption was achieved with the absorbance peak approaching 100% at 6.85 THz. Because of the axisymmetric unit cell, as shown in Z, respectively. We observed that for upper green point, Re(Z) = 1.0004, and for the lower green point, Im(Z) = −0.00114, at the absorbance peak frequency of 6.85 THz, implying the impedance of the absorber matched the free space well. Therefore, since the extremely low reflectance resulting from smooth impedance matching together with zero transmission enabled by the thick gold layer, the near-unity absorbance of the absorber was achieved. E|, and magnetic field distributions, |H|, for the TM and TE polarizations along the cut-plane on the top graphene layer at 6.85 THz. The localized surface plasmon polaritons (LSPPs) were excited and strongly confined on the graphene ribbons, leading to ultra-high terahertz absorption. As expected from the symmetric configuration and polarization-independent property, the |E| and |H| for TM polarization were exactly 90° shifted from that of the TE polarization. Therefore, this absorber with a SLDGRA showed a clear independence of polarization, which has a significant advantage over the polarization-sensitive absorber with single graphene ribbon array. First, we investigated the terahertz absorption performance of the proposed absorber with a SLDGRA under normal incidence. The identical geometric parameters are shown in μc and angle of incidence θ on the absorbance spectra. μc. It was found that changing the μc of the graphene ribbon had a significant influence on the absorption frequency band. As μc increased from 0.2 to 0.8 eV, the absorbance peak frequency band red-shifted accordingly from 5.58 to 11.32 THz. Especially, good frequency reconfiguration characteristics were clearly observed. As μc increased from 0.3 to 0.6 eV, the over 90% absorbance peak frequency varied from 6.85 to 9.85 THz, demonstrating a wide absolute frequency tuning range of 3 THz with the RFTR of 43.8%, which was larger than the recently reported works [μc of 0.3 and 0.6 eV, for the first and the last absorption bands with over 90% peak absorbance, respectively. The results showed that the absorber also possessed an excellent angular stability for narrowband terahertz absorption characteristics. Owing to the wide-angle localized resonance of SPPs in the SLDGRA structure, the peak absorbance remained over 99.8%, even at a large oblique incidence angle of 70° for both cases. This absorber with wide frequency reconfiguration, absolute polarization independence, and excellent angular stability may have significant potential applications in the terahertz regime.To demonstrate the properties of wide frequency reconfiguration and angular stability, we studied the dependence of Fermi level ed works ,25,26,272 separation (h1) of the double-layer decussate graphene ribbon arrays was set as 1 µm while the rest of the geometric parameters of this absorber were fixed to be the same as the absorber with a SLDGRA. The simulated absorbance spectra for TM and TE polarizations with different μc at normal terahertz incidence are displayed in μc. For TM polarizations, the reconfigurable over 90% absorbance peak frequency significantly switched from 5.50 to 11.28 THz, corresponding an enhanced RFTR of 105.1%, as the μc increased from 0.2 to 0.8 eV. For TE polarization, the reconfigurable over 90% absorbance peak frequency switched from 5.62 to 10.65 THz, corresponding to a RFTR of 89.5%, as the μc varied from 0.3 to 1.0 eV. Compared with the RFTR of the absorber with a SLDGRA, ultra-wide frequency reconfiguration with 2× more RFTR was achieved in the absorber with DLDGRAs. To further enhance the absorbance peak frequency tuning range, we propose the absorber with DLDGRAs, as shown in μc = 0.3 eV under normal incidence. For TM polarization, |E| distributions of the LSPPs at the absorbance peak frequency of 6.81 THz along upper and lower graphene plane are shown in E| were mainly confined around upper-layer graphene ribbon edges. Therefore, the terahertz absorption for the TM polarization was mainly caused by LSPPs located at the upper-layer graphene ribbons. Similarly, the electric distributions for the TE polarization at the absorbance peak frequency of 5.62 THz along upper and lower graphene plane are shown in Next, it is remarkable that this absorber was no longer polarization-independent because of the non-axisymmetric DLDGRA structure. To better understand this characteristic, we depict the simulated electric field distributions for TM and TE polarizations along the cut-planes on upper and lower graphene layers with θ and operating frequency with μc of 0.2 and 0.8 eV for TM polarization in μc of 0.3 and 1.0 eV for TE polarization in Furthermore, we also investigated the angular stability of the proposed absorber with DLDGRAs. Here, for example, we present the simulated absorbance spectra as a function of incidence angle fp and μc. According to the quasi-static analysis in References [fp and μc is given by k = 0.1 denotes a dimensionless fitting constant, W is the width of graphene ribbon, εe is the effective permittivity of the background materials surrounding the graphene ribbon array, and εo is the permittivity of vacuum, respectively. Here, we first compared the fp of the absorber with a SLDGRA obtained from this analytical fitting mode and the simulated results, as shown in εe was expressed as εe = (εZro2 + 1)/2. It was found that with μc varying from 0.2 to 0.9 eV, fp increased from 5.58 to 11.97 THz. The analytical fitting results matched well with the simulation results. Then, we verified this analytical fitting mode for the absorber with the DLDGRA case. Because it is polarization-dependent, we compared the fitting and simulation results separately for TM and TE polarizations, as shown in εe was also approximately expressed as εe = (εZro2 + 1)/2. With the same values of εe for the absorber with DLDGRAs under TM polarization and the absorber with SLDGRA, the same analytical predictions of fp are shown in both εe should be calculated by εe = εZro2 instead. Both analytical prediction and the simulation results clearly showed that fp increased from 5.50 (4.60) to 11.97 (10.09) THz for TM (TE) polarization with μc varying from 0.2 to 0.9 eV with good agreement. Therefore, this analytical fitting mode can be used for the efficient prediction of the reconfigurable absorbance peak frequencies of this variety of absorbers.To predict the reconfigurable frequencies of the proposed absorbers, we further studied the relationship between the absorbance peak frequency ferences ,40, a fiμc from 0.3 to 0.6 eV. For the absorber with DLDGRAs, the absorbance peak frequencies of each reconfigurable bands could be significantly extended from 5.50 to 11.31 THz and 5.60 to 10.61 THz under TM and TE polarizations, respectively, approaching two octaves. Good angular stability of these absorbers was achieved, with the absorbance peaks of the reconfigurable absorbance bands maintained over 70% in a wide angle of incidence ranging from 0° to 70° for both polarizations. We proposed an analytical fitting model to predict the absorbers’ reconfigurable absorbance peak frequencies. Our results demonstrated that the proposed frequency-reconfigurable absorbers offer significant potential to realize novel reconfigurable optoelectronic devices, which may have great applications in the emerging terahertz regime.We systematically demonstrated a new variety of frequency-reconfigurable absorbers using S/DLDGRAs. The absorbers had excellent properties of narrowband near-unity terahertz absorbance, ultra-wide frequency reconfiguration, and angular stability. For the absorber with a SLDGRA, the over 90% absorbance peak frequency could be flexibly adjusted from 6.85 to 9.85 THz for both polarizations under normal incidence by tuning


Integrating graphene with other nanomaterials has created a variety of graphene nanocomposites with extraordinary chemical, optical, mechanical, and electrical properties. These composites could combine the characteristics of their components to achieve structural stability and multifunctionality with proper design of the interfacial interactions. The field of graphene nanocomposites has developed rapidly over the past decade, with many applications in various fields, such as chemical/biomedical sensing, tissue engineering, and bioimaging.−1, respectively. Moreover, this sensor achieved a temperature sensitivity of 2.33 nm/5 °C. These findings can expand the range of use for a nanoscale real-time temperature sensor with resistance to electromagnetic interference. Another project fabricated a temperature sensor consisting of two metal layers and two ethanol-sealed elliptical resonators, connected to a straight waveguide using two rectangular tubes [2 for light detection (405 to 1310 nm) [This Special Issue contains six research articles and two reviews in total, covering structure-proprieties of graphene and its applications in sensing organic solvents, light and DNA, as well as in tissue engineering. Among these, four articles reported graphene nanocomposites for chemical/biomedical sensing applications. One article reported fabrication of graphene-like ZnO/graphene oxide (GO) nanosheets for acetone vapor sensing . The senIn one of the remaining two research articles, the authors fabricated chitosan/graphene oxide (CS/GO) composite scaffolds for bone regeneration . The othOne of the two review articles investigates the application of graphene nanocomposites for DNA detection. This review comprehensively summarizes recent trends in DNA detection using graphene and graphene-related nanomaterials including graphene nanopore (GNP), graphene nanoribbon (GNR), GO, reduced graphene oxide (rGO), and graphene-nanoparticle (G-NP) hybrid materials . It alsohttps://www.mdpi.com/journal/molecules/special_issues/graphene_nanocomposites


Since one source of intracellular Ca2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might be involved in the pathogenesis of POCD.Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are CaIn the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus.Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment.Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD. Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients after anesthesia and surgery, especially in the elderly . POCD reBrain-derived neurotrophic factor (BDNF) is a neurotrophin widely expressed in the central nervous system, which plays a critical role in neuronal survival and differentiation, and synaptic plasticity through activation of its full-length receptor (TrkB-FL) , 5. Dysr2+-dependent cysteine proteases that play a physiologic role by the cleavage of several substrates, including the neurotrophin receptor TrkB [2+ concentrations and one source of intracellular Ca2+ is NMDARs related. Importantly, one recent study showed that amyloid-β peptide (Aβ) induced the overactivation of NMDARs and calpain, and then triggered the formation of a truncated isoform (TrkB-T′) and an intracellular domain (ICD) fragment, and ultimately disrupted BDNF/TrkB signaling, which can be prevented by a NMDAR antagonist memantine [Calpains are intracellular Cator TrkB , cytosketor TrkB . A calpator TrkB  and epiltor TrkB . The ovetor TrkB  and alsotor TrkB . Calpainemantine . HoweverInflammation has been proved to be a potential source of reactive oxygen species for inducing NMDARs hypofunction and nonsteroidal anti-inflammatory drugs (NSAIDs) can improve impaired NMDAR-dependent synaptic plasticity and age-related cognitive dysfunction . In addiOne hundred and forty-four 16-month-old male C57BL/6 mice (26–36 g) were obtained from the Animal Center of Southeast University, Nanjing, China. Animals were housed in groups of 3–5 individuals per cage in a standard condition with access to food and water ad libitum in a colony room kept at 19–22 °C and 40–60% humidity, under a 12-h light/dark cycle (light from 07:00 to 19:00). The experiments began after all the animals acclimated to the environment for 2 weeks. The study protocol was approved by the Ethics Committee of Zhongda Hospital, Medical School, Southeast University, and all procedures were performed in accordance with the approved guidelines. The schematic timeline of the experimental procedure is summarized in Fig. Exploratory laparotomy was performed under isoflurane anesthesia described as our previous studies , 23. MicThe NMDAR antagonist memantine   was intrA white opaque plastic chamber  was used as the open-field arena. The open-field test was performed at 5 days post-surgery to assess the exploratory locomotor activity. Each mouse was placed in the center of the arena and left to explore it for 5 min while activity was automatically recorded by a video tracking system.The Y maze is a symmetrical three-arm maze  and is used to evaluate the spontaneous alternation performance at 6 days post-surgery. Each mouse was placed in the center of the Y maze and could explore freely throughout the three different arms of the maze during an 8-min session. The sequence and total number of arms entered were recorded. Arm entry was complete when the hind paws of the mouse had been completely placed in the arm. The alteration was determined from successive consecutive entries to the three different arms on overlapping triads in which all arms were represented. For example, a sequence of entries to the three arms ABC, ACBABACABA, would generate four “successful” alternations, ACB, CBA, BAC, and CAB. Percentage alternation is the number of triads containing entries into all three arms divided by the maximum possible alternations  × 100. The re-entry into the same arm was not counted for analysis .Mice were trained for fear conditioning at 7 days post-surgery. Each mouse was placed into a conditioning chamber  and allowed to explore freely for 3 min. Then a 30-s tone  was delivered followed by a 2-s foot shock (0.7 mA). After that, the mouse stayed in the chamber for another 30 s and then returned to the home cage. Contextual fear conditioning (a hippocampus-dependent task) was assessed 24 h after training. For the contextual fear conditioning, each mouse was placed back into the same chamber in which they were explored for 5 min without tone or foot shock and scored for the freezing behavior. Freezing behavior was defined as the absence of all visible movement except for respiration. Given that no difference was observed in the auditory-cued fear test (a hippocampus-independent task) between control and surgery group in our previous studies , 23, theThe entire dissected hippocampus was harvested and subjected to Western blot analysis. The samples were lysed as described previously , 23. Pro.; Sigma, St Louise, MO, USA) and transcardially perfused with saline, followed by 4% paraformaldehyde (PFA) in phosphate-buffered saline . Brains were removed and postfixed in 4% PFA for 2 h and dehydrated in 30% sucrose at 4 °C overnight and then embedded in O.C.T. compound. The brains were cut coronally into 10-μm-thick sections from bregma − 1.70 to − 2.30 by a freezing microtome and mounted on glass slides. The sections were blocked with 1% bovine serum albumin (BSA) for 1 h at room temperature. And then the sections were incubated with primary antibodies: rabbit anti-Iba1  and rabbit anti-GFAP  in 1% BSA at 4 °C overnight. Sections were washed with PBS three times and incubated with goat anti-rabbit IgG-FITC  and goat anti-rabbit IgG-Cy3  for 1 h at room temperature. After washing out the secondary antibodies, sections were incubated with 4′,6-diamidino-2-pheny-lindole (DAPI) for nuclear staining. Fluorescent images were captured by a confocal microscope . Six sections of the hippocampus per mouse were analyzed by ImageJ  for immunofluorescence analysis. Three non-overlapping fields of each section in the hippocampal Cornu Ammonis 1 (CA1) area was randomly acquired by a counting frame size of 0.4 mm2. Positively stained areas were defined that the number of pixels per image with intensity in which was above a predetermined threshold level. The immunoreactivity of a protein was quantified by percentage area with positive staining to the total area of the imaged field. All quantitative analyses were performed by an experimenter blinded to the group of each sample.Mice were deeply anesthetized with 2% sodium pentobarbital in saline . Data are presented as mean ± S.E.M. Differences between groups were assessed with one-way ANOVA followed by post hoc Tukey multiple comparisons. The dendritic intersections were analyzed by repeated-measures ANOVA followed by post hoc Tukey multiple comparisons. A significant difference was considered as F = 16.34, p < 0.0001; Fig. F = 20.06, p < 0.0001; Fig. We performed immunostaining by using antibodies of Iba1 and GFAP on day 1 post-surgery, respectively. Compared with control + vehicle (con + veh) group, the intensity of Iba1 [F3, 0 = 16.34F3, 0 = 16.34F = 14.55, p < 0.0001; Fig. F = 19.50, p < 0.0001; Fig. F = 16.02, p < 0.0001; Fig. F = 7.250, p = 0.0018; Fig. F = 0.6109, p = 0.6158; Fig. F = 10.13, p = 0.0003; Fig. F = 8.462, p = 0.0008; Fig. Next, we detected the levels of proinflammatory cytokines on days 1 and 8 post-surgery. On day 1 post-surgery, the IL-1β [F, 20 = 14F, 20 = 14F, 20 = 14F, 20 = 14F, 20 = 14F = 234.5, p < 0.0001; Fig. F = 4.599, p = 0.0132; Fig. F = 4.854, p = 0.0107; Fig. To evaluate whether NMDAR inhibition by memantine could affect anesthesia and surgery-induced activation of calpain, we detected αII-spectrin levels and the formation of calpain-specific spectrin breakdown products (SBDPs). αII-spectrin is a major substrate for calpain and caspase-3 proteases. The activation of calpain could result in the cleavage of αII-spectrin and then produce breakdown products with distinct molecular weights. The expected molecular weight of αII-spectrin is 250 kDa, whereas the SBDP is 150 kDa. Our data showed that the levels of SBDPs were significantly increased, which was accompanied by decreased levels of αII-spectrin in the sur + veh group, suggesting the activation of calpain. However, this increase was ameliorated by memantine treatment [F = 64.15, p < 0.0001; Fig. F = 4.064, p = 0.0062; Fig. F = 4.958, p = 0.0020; Fig. F = 4.325, p = 0.0044; Fig. To determine whether TrkB is truncated by calpain activation, we administrated MDL-28170, an inhibitor of calpain. The levels of SBDPs were significantly increased and the levels of αII-spectrin were decreased after anesthesia and surgery, which were reversed by memantine or MDL-28170 treatment [F = 8.311, p < 0.0001; Fig. F = 3.739, p = 0.0095; Fig. F = 5.399, p = 0.0012; Fig. F = 4.754, p = 0.0026; Fig. F = 19.98, p < 0.0001; Fig. F = 17.00, p < 0.0001; Fig. The presence of calpain-cleaved fragments occurs early in neural cell pathology and may be indicative of necrotic and excitotoxic neuronal injury and death. As reported previously, cell apoptosis plays an important role in POCD. In the current study, we showed that the levels of bax [F = 0.1977, p = 0.9609; Fig. F = 0.009950, p > 0.9999; Fig. F = 3.949, p = 0.0072; Fig. We used Sholl analysis to assess dendritic branching and spine density in the CA1 region in the hippocampus. There was no significant difference in the total number of dendritic intersections [F = 0.07516, p = 0.9957; Fig. F = 0.05177, p = 0.9982; Fig. F = 0.1552, p = 0.9776; Fig. F = 6.052, p = 0.0002; Fig. F = 5.489, p = 0.0004; Fig. The open field was used to evaluate the locomotor activity and exploratory behavior. During the 5-min test session, there was no significant difference in the total distance [In the present study, we showed that anesthesia and surgery-induced neuroinflammation overactivated NMDARs, and the abnormal activation of NMDARs triggered the overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. Of note, NMDARs antagonist memantine or calpain inhibitor MDL-28170 attenuated these abnormalities, suggesting tackling abnormal activation of NMDARs or truncation of TrkB-FL may be a therapeutic strategy for POCD Fig. .Fig. 10Patients suffering from cognitive impairments after anesthesia and surgery have been recognized for more than 60 years. Recently, a multi-specialty working group recommended “perioperative neurocognitive disorders” (PND) as an overarching term for cognitive impairments diagnosed in the preoperative or postoperative period –33. PND Although various mechanisms have been proposed to be involved in the development of POCD, neuroinflammation is believed to play an initial and central role. In the present study, we showed that IL-1β and IL-6 levels were significantly increased and lasted for 8 days post-surgery. Our results were consistent with the previous studies , 22, 34,There is accumulating evidence suggesting a strong correlation between neuroinflammation and NMDAR dysfunction, eventually resulting in deficits of synaptic plasticity and cognitive impairments. It has been showed that microglia is activated initially and become a major cellular source of a variety of proinflammatory cytokines in a rat model of chronic neuroinflammation, which has negative effect on long-term potentiation requiring NMDAR activation . In addi2+/calpain is mechanistically involved in neuroprotective effects of memantine in anesthesia and surgery-induced cognitive impairments in aging mice. In a rat model of postoperative pain-induced cognitive impairments, memantine treatment could improve memory deficits without any effect on NMDAR expression [We previously demonstrated that NMDARs calcium/calmodulin-dependent kinase II pathway was involved in the pathogenesis of POCD . Therefopression . Interespression . Thus, tBDNF plays an important role in neuronal plasticity, learning, and memory through the activation of TrkB-FL receptors , 5. It hTrkB is expressed as a full-length, catalytically active isoform (TrkB-FL), as well as several alternatively spliced truncated isoforms lacking the intracellular kinase domain, including TrkB.T1, TrkB.T2, and TrkB.T-Shc , 52. BotThere are some limitations in this study. Firstly, we mainly observed relatively short-term cognitive performance by Y maze and fear conditioning tests after anesthesia and surgery. Using Morris water maze to measure spatial cognition are needed in our future studies. Secondly, memantine is a partial antagonist of NMDAR receptor that block the pathological activation of NMDARs, while not interfering with normal synaptic transmission . ClinicaIn summary, our study demonstrated that neuroinflammation overactivated NMDARs, at least in part, plays a key role in overactivation of calpain, cleavage of TrkB-FL receptor, BDNF/TrkB signaling dysfunction, dendritic spine loss, cell apoptosis, and consequent cognitive impairments. Hence, identifying viable therapeutic strategies to tackle abnormal activation of NMDARs or calpain may provide effective interventions for POCD.


P = 0.015). Multivariate analysis identified sPD-L1 and the neutrophil-to-lymphocyte ratio as independent prognostic factors for OS. During chemotherapy, more patients achieved complete response (CR)/partial response (PR) as their best response when sPD-L1 was decreased at the first response assessment (P = 0.038). In the patients who achieved CR/PR as their best response, sPD-L1 was significantly higher at the time of disease progression than at the first response assessment (P = 0.025). In conclusion, the sPD-L1 level at diagnosis exhibits a prognostic value in pancreatic cancer. Furthermore, sPD-L1 dynamics correlate with disease course and could be used to understand various changes in the tumor microenvironment during chemotherapy.In pancreatic cancer, acquiring a sufficient amount of tumor tissue is an obstacle. The soluble form of PD-L1 (sPD-L1) may have immunosuppressive activity. Here, we evaluated the prognostic implications of sPD-L1 in unresectable pancreatic cancer. We prospectively enrolled 60 patients treated with first-line FOLFIRINOX chemotherapy. We collected blood samples at diagnosis, first response assessment and disease progression. Serum sPD-L1 levels were measured using enzyme-linked immunosorbent assays. The median sPD-L1 level was 1.7 ng/mL . Patients with low sPD-L1 level (<4.6 ng/mL) at diagnosis showed better overall survival (OS) than those with high sPD-L1 level ( In particular, PD-L1 is the most promising immune checkpoint molecule used as a potential target for immunotherapy.With recent advances in immuno-oncology, many biomarkers of immune checkpoints have received increasing attention due to their roles as prognostic factors and therapeutic targets. Biomarkers such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) ligands, interleukin-10, transforming growth factor β (TGF-β), and programmed death-ligand 1 (PD-L1) are well-known molecules involved in escape from host immune surveillance and are associated with cancer cell proliferation1. Tumor cells are then able to escape immune recognition and the host immune response. In various cancers, such as lung cancer, breast cancer, and renal cell carcinoma, overexpression of PD-L1 in tumor cells results in aggressive behavior and is associated with a poor prognosis5. Additionally, PD-L1 expression can predict treatment response in anti-PD-1/PD-L1 agent-treated patients6. Therefore, an evaluation of PD-L1 expression could predict patient prognosis and treatment response in certain types of cancer.PD-L1, a B7 superfamily member, is expressed in tumor cells and binds to programmed death-1 (PD-1) on T cells. After the PD-L1/PD-1 interaction occurs, inhibitory signals are transmitted to T cells, thereby suppressing T cell proliferation and reducing cytokine secretion8. Therefore, the use of soluble markers could help in understanding the dynamics of the interaction between host immune responses and tumor cells or the tumor microenvironment.A biopsy is needed to evaluate PD-L1 expression in tumor tissue and the tumor microenvironment, which is the primary limitation of this method. However, soluble serum biomarkers have been regarded as promising surrogates because they can reflect the tumor status and predict survival outcomes through a minimally invasive modality9. In addition, a few studies have recently reported the dynamics of sPD-L1 in cancer patients during chemotherapy treatment8.The soluble form of PD-L1 (sPD-L1) has been reported to have prognostic value in various cancers, including lymphoma, gastric cancer, and lung cancer12. However, the results of an early trial of a monotherapy checkpoint blockade approach were disappointing and suggested that evaluating the immune checkpoint alone may be insufficient to explain the poor prognosis of pancreatic cancer13. Therefore, the role of PD-L1/PD-1 in pancreatic cancer requires further investigation, especially because in many cases, it is difficult to acquire a sufficient amount of tumor tissue to evaluate PD-L1 expression, and the value of sPD-L1 has not yet been studied.Despite previous study results, in pancreatic cancer, the prognostic role of the PD-L1/PD-1 signaling axis remains uncertain. Some studies confirmed the prognostic importance of the PD-L1/PD-1 signaling axis in pancreatic cancerThe aims of this study were to measure serum sPD-L1 levels in unresectable pancreatic cancer patients who were treated with palliative first-line chemotherapy and to evaluate the prognostic role of sPD-L1 as well as its dynamics during chemotherapy.2 on day 1), irinotecan (180 mg/m2 on day 1), leucovorin (400 mg/m2 on day 1), fluorouracil , and a continuous infusion of 5-FU . Clinical data were collected by reviewing medical records that included demographic information and the results of laboratory exams, including total bilirubin, albumin, and cancer antigen 19-9 (CA 19-9) levels and blood cell counts . The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) were calculated by dividing the neutrophil or platelet count, respectively, by the lymphocyte count. The results of a laboratory test performed at the time of diagnosis with unresectable pancreatic cancer were used in the analysis. We evaluated the disease state during FOLFIRINOX chemotherapy by computed tomography examination every three chemotherapy cycles. Response assessment was performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.114. The best overall response rate (ORR) was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) as their overall response during chemotherapy15.We prospectively recruited pathologically confirmed unresectable pancreatic cancer patients who were treated with FOLFIRINOX as their first-line palliative chemotherapy regimen. Between 2013 and 2015, 60 patients who provided informed consent for the biomarker analysis study at Seoul National University Hospital were enrolled; all were ethnically Korean. FOLFIRINOX chemotherapy consisted of oxaliplatin  according to the manufacturer’s instructions16. Each sample was analyzed in duplicate.We prospectively collected blood samples from patients at the time of diagnosis (prechemotherapy), at the first response assessment , and at the time of disease progression. Serum sPD-L1 levels were measured using an enzyme-linked immunosorbent assay t-test or one-way ANOVA, as appropriate. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. PFS was defined as the time from the date of initiation of FOLFIRINOX chemotherapy to the date of disease progression. OS was defined as the time from the date of initiation of FOLFIRINOX chemotherapy to the date of either death or last follow-up. A receiver operating characteristics (ROC) curve was used to determine the cut-off values of the NLR, the PLR, and sPD-L1 levels to best predict survival. The cut-off values used for albumin, total bilirubin, and CA 19-9 levels were the corresponding normal values. Clinical variables with univariate P-values < 0.2 were considered for inclusion in multivariate analyses, which were performed using the logistic regression model or Cox proportional hazard model, as appropriate. All statistical tests were two-sided, and a statistically significant difference was defined as P < 0.05. Statistical analyses were performed using IBM SPSS version 23.0 .Fisher’s exact test or Pearson’s chi-squared test was used to compare categorical variables. The comparison of continuous variables was performed using an independent or paired This study was approved by the institutional review board at Seoul National University Hospital  and was conducted in accordance with the guidelines of the Declaration of Helsinki for biomedical research. Informed consent was obtained from all participants.The mean and median values of the sPD-L1 level at initial diagnosis (prechemotherapy) (n = 60) were 2.2 and 1.7 ng/mL , respectively. ROC curve analysis was used to determine the cut-off value of sPD-L1, and the cut-off value of 4.6 ng/mL achieved the highest combination of sensitivity and specificity for the prediction of OS.P > 0.05).Baseline characteristics of the patients are summarized in Table Patient responses to FOLFIRINOX chemotherapy during the follow-up period were as follows: 2/60 (3.3%) patients achieved a CR; 20/60 (33.3%) patients achieved a PR; 30/60 (50%) patients achieved stable disease (SD); and 8/60 (13.3%) patients exhibited progressive disease (PD). Twenty-two (36.7%) patients achieved a CR or PR as their overall response during chemotherapy.The median follow-up duration of the 60 patients was 11.4 months , and the median PFS and OS were 6.5  and 10.3  months, respectively.P = 0.061) and high sPD-L1 level  showed a trend toward worse PFS.In a univariate analysis for PFS, older age (≥60 years), a low sPD-L1 level (<4.6 ng/mL), a low NLR (<1.83), and a low PLR (<109.6) were associated with prolonged PFS Table ; Fig. 1AP = 0.015) and low NLR  were independent prognostic factors for prolonged OS.In a univariate analysis for OS, the prognostic factors indicative of improved OS were older age (≥60 years), a low sPD-L1 level (<4.6 ng/mL), and a low NLR <1.83) .In patients diagnosed with metastatic pancreatic cancer, only a low sPD-L1 level was an independent factor for prolonged OS in univariate and multivariate analyses  were obtained from 25 patients.P = 1.000; Table vs. 9/35 [25.7%] for younger age, P = 0.037; HR, 4.858, 95% CI, 1.344–17.563, P = 0.016) and a decreased sPD-L1 level at the first response assessment time point (postchemotherapy) compared with the initial diagnosis time point (prechemotherapy)  were predictive factors for the achievement of a best overall response (CR + PR) during FOLFIRINOX chemotherapy.When we evaluated the role of sPD-L1 in predicting treatment response during FOLFIRINOX chemotherapy, the sPD-L1 levels at diagnosis (prechemotherapy) could not predict the best ORR in a univariate analysis  and decreased sPD-L1 after chemotherapy  were predictive factors for the achievement of a best overall response.Similar results were observed in patients with metastatic pancreatic cancer. Older age  during FOLFIRINOX chemotherapy, sPD-L1 levels were decreased at the first response assessment time point compared to the time of diagnosis. However, this change was not statistically significant  and the first response assessment time point showed better responses to FOLFIRINOX than those whose sPD-L1 levels increased after chemotherapy.18. Although recent palliative chemotherapies have improved the median OS of metastatic pancreatic cancer patients up to 8.5–11.1 months, the efficacy of current treatment options is still very limited20. In the era of immunotherapy, large randomized clinical trials have reported promising outcomes in patients with various cancers, such as lung cancer, melanoma, and renal cell carcinoma23. However, in pancreatic cancer, clinical trials of anti-PD-L1 monotherapies have shown disappointing outcomes24. The reason for this failure could be partly explained by the nonimmunogenic tumor microenvironment of pancreatic cancer25. The efficacy of immune checkpoint blockade has been related to the expression of PD-L1 by tumor cells and PD-1 by activated T cells. However, a previous study revealed that pancreatic cancer had low expression of both PD-1 and PD-L126. In addition, although patients have high levels of PD-L1 expression, highly immunosuppressive microenvironment elements, such as regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages, might affect the unsuccessful treatment response to immunotherapy25.Pancreatic cancer is a highly lethal malignancy worldwide27. However, several studies have reported a prognostic role for PD-L1. Tessier-Cloutier et al. demonstrated that increased PD-L1 expression (>10%) detected by immunohistochemistry was associated with poor disease-specific survival in resected pancreatic cancer patients 11. Yamaki et al. revealed that PD-L1-positive patients showed worse OS than PD-L1-negative patients who underwent surgical resection 12. However, in an analysis using sPD-L1, Kruger et al. reported that sPD-L1 did not predict adverse outcomes in patients with advanced pancreatic cancer . They found that the levels of sPD-L1 were increased in patients with elevated C-reactive protein levels (P < 0.001), suggesting that sPD-L1 could be a marker of systemic inflammation in advanced pancreatic cancer28.Due to its nonimmunogenic nature, pancreatic cancer has not yet been evaluated in a way that fully elucidates the prognostic role of PD-L1. It has been suggested that an immune checkpoint might not entirely represent the histopathological hallmarks of this malignancyIn this study, we also demonstrated the dynamics of sPD-L1 during homogenous FOLFIRINOX chemotherapy. sPD-L1 levels at the first response assessment time points were lower than those at the time of diagnosis. sPD-L1 levels were also higher at the disease progression time point than at the first response assessment time point. Although this study did not achieve statistical significance due to the small sample size, the observed changes in the sPD-L1 levels according to disease status were clinically important. In patients who achieved a CR or PR as their overall response, the sPDL1 levels were significantly increased at the disease progression time point compared to the first response assessment time point. Therefore, dynamic changes in sPD-L1 levels during chemotherapy correlated with disease progression.30.Although inflammatory markers such as the NLR and PLR did not correlate with sPD-L1 levels in our study, elevated NLR levels were associated with poor OS. This finding was in accordance with the results of previous studies that showed a relationship between increased systemic inflammation and poor outcomes in pancreatic cancerThe present study has several limitations. It was a single-center study, and the sample size was small. Therefore, further large-scale studies are needed to confirm our results. We enrolled only advanced-stage pancreatic cancer patients who were treated with FOLFIRINOX chemotherapy as a palliative first-line treatment to focus on a relatively homogeneous population. Patients who received other standard of care treatments, such as gemcitabine/nab-paclitaxel combination therapy or gemcitabine monotherapy, were excluded. A study of pancreatic cancer patients treated with these standard regimens is warranted to further support our conclusion for advanced pancreatic cancer. Despite these limitations, to the best of our knowledge, this is the first study to show the dynamics of sPD-L1 levels in unresectable pancreatic cancer patients treated with homogenous FOLFIRINOX chemotherapy. This study provides evidence that the prechemotherapy sPD-L1 level could be a prognostic factor for OS and that the dynamics of sPD-L1 levels during chemotherapy could predict treatment responses. In routine clinical practice, sPD-L1 measurement in patient blood samples could be easily incorporated. However, the standardization of this measurement should be further validated beforehand.In conclusion, pretreatment sPD-L1 levels play a significant role in predicting survival outcomes in advanced pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Additionally, the dynamics of sPD-L1 levels during chemotherapy could be used to predict the best treatment response during chemotherapy.