Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma.

Backgrounds: The pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known. Materials and methods: In the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/obesity-associated gene (OAG) signature. The Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response. Results: Overweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment. Conclusions: Overall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC.

Formal [5+2] cycloaddition of vinylethylene carbonates to oxazol-5-(4H)-ones for the synthesis of 3,4-dihydrooxepin-2(7H)-ones.

Under the catalysis of Pd2(dba)3 (2.5 mol%), PPh3 (10.0 mol%) and TMSCl (1.0 eq.), the formal [5+2] cycloaddition of vinylethylene carbonates to oxazol-5-(4H)-ones proceeded readily in THF at 60 °C to r.t., thus furnishing 3,4-dihydrooxepin-2(7H)-ones in 67-99% chemical yields. The chemical structure of one compound was confirmed by X-ray diffraction analysis, and the others were suggested by inference.

Diastereoselective and Enantioselective Synthesis of Barbiturate-Fused Spirotetrahydroquinolines via Chiral Palladium(0)/Ligand Complex Catalyzed [4 + 2] Cycloaddition of Vinyl Benzoxazinanones with Barbiturate-Based Olefins.

Under the catalysis of chiral palladium(0)/ligand complex, the [4 + 2] cycloaddition between vinyl benzoxazinanones and barbiturate-based olefins proceeded readily and provided barbiturate-fused spirotetrahydroquinolines in up to 96% chemical yield with up to >99:1 dr and 97% ee. The absolute configuration of barbiturate-fused spirotetrahydroquinolines was clearly identified by X-ray single crystal structure analysis. The reaction mechanism was proposed to shed light on the enantioselective formation of barbiturate-fused spirotetrahydroquinolines.

[3 + 2] Cycloaddition of Oxazol-5-(4H)-ones with Nitrones for Diastereoselective Synthesis of Isoxazolidin-5-ones.

In the presence of TMSCl, the [3 + 2] cycloaddition of oxazol-5-(4H)-ones with nitrones proceeded smoothly and furnished the desired isoxazolidin-5-ones with high diastereoselectivities in reasonable chemical yields. The chemical structure of the title compounds was firmly confirmed by X-ray single-crystal structure analysis.

Design and fabrication of 3µm silicon-on-insulator waveguide integrated Ge electro-absorption modulator.

We present the design and fabrication of a waveguide-based Ge electro-absorption (EA) modulator integrated with a 3 µm silicon-on-isolator (SOI) waveguide. The proposed Ge EA modulator employs a butt-coupled horizontally-oriented p-i-n structure. The optical design achieves a low-loss transition from Ge to Si waveguides. The interaction between the optical mode of the waveguide and the bias induced electric field in the p-i-n structure was maximized to achieve high modulation efficiency. By balancing the trade-offs between the extinction ratio and the insertion loss of the device, an optimal working regime was identified. The measurement results from a fabricated device were used to verify the design. Under a -4Vpp reverse bias, the device demonstrates a total insertion loss (including the transition loss) of 2.7-5.2 dB and an extinction ratio of 4.9-8.2 dB over the wavelength range of 1610-1640 nm. Subtracting the contribution of the transition loss, the Δα/α value for the fabricated device was estimated to be between 2.2 and 3.2 with an electric field around 55 kV/cm.

36 GHz submicron silicon waveguide germanium photodetector.

We present two effective approaches to improve the responsivity of high speed waveguide-based Ge photodetectors integrated on a 0.25 µm silicon-on-insulator (SOI) platform. The main cause of poor responsivity is identified as metal absorption from the top contact to Ge. By optimizing Ge thickness and offsetting the contact window, we have demonstrated that the responsivity can be improved from 0.6A/W to 0.95 A/W at 1550 nm with 36 GHz 3 dB bandwidth. We also demonstrate that a wider device with double offset contacts can achieve 1.05 A/W responsivity at 1550 nm and 20 GHz 3 dB bandwidth.

Compact single-chip VMUX/DEMUX on the silicon-on-insulator platform.

We demonstrate a compact, single-chip 40-channel, dense wavelength division multiplexing (DWDM) variable attenuator multi/demultiplexer (VMUX/DEMUX) by monolithic integration of an echelle grating and high-speed p-i-n VOA on the silicon-on-insulator (SOI) platform. The demonstrated device has a flat-top filter shape, on chip loss of 5.0 dB, low PDL of 0.3 dB after compensation of the polarization dependent frequency (PDF) shift, a fast attenuation response speed of 3 MHz, and an area of only 25 mm by 10 mm.

30GHz Ge electro-absorption modulator integrated with 3 µm silicon-on-insulator waveguide.

We demonstrate a compact waveguide-based high-speed Ge electro-absorption (EA) modulator integrated with a single mode 3 µm silicon-on-isolator (SOI) waveguide. The Ge EA modulator is based on a horizontally-oriented p-i-n structure butt-coupled with a deep-etched silicon waveguide, which transitions adiabatically to a shallow-etched single mode large core SOI waveguide. The demonstrated device has a compact active region of 1.0 × 45 µm(2), a total insertion loss of 2.5-5 dB and an extinction ratio of 4-7.5 dB over a wavelength range of 1610-1640 nm with -4V(pp) bias. The estimated Δα/α value is in the range of 2-3.3. The 3 dB bandwidth measurements show that the device is capable of operating at more than 30 GHz. Clear eye-diagram openings at 12.5 Gbps demonstrates large signal modulation at high transmission rate.

GHz-bandwidth optical filters based on high-order silicon ring resonators.

Previously demonstrated high-order silicon ring filters typically have bandwidths larger than 100 GHz. Here we demonstrate 1-2 GHz-bandwidth filters with very high extinction ratios (~50 dB). The silicon waveguides employed to construct these filters have propagation losses of ~0.5 dB/cm. Each ring of a filter is thermally controlled by metal heaters situated on the top of the ring. With a power dissipation of ~72 mW, the ring resonance can be tuned by one free spectral range, resulting in wavelength-tunable optical filters. Both second-order and fifth-order ring resonators are presented, which can find ready application in microwave/radio frequency signal processing.

Thermally-efficient reconfigurable narrowband RF-photonic filter.

We present the design and fabrication of thermally-efficient tuning structures integrated into a narrowband reconfigurable radio-frequency (RF)-photonics filter using silicon-on-insulator waveguide optical delay lines. By introducing thermal isolation trenching, we are able to achieve IIR, FIR or arbitrary mixed response with less than 120 mW average tuning power in a single RF-photonic unit cell filter.

Low loss shallow-ridge silicon waveguides.

We demonstrate low loss shallow-ridge silicon waveguides with an average propagation loss of 0.274 + or - 0.008 dB/cm in the C-band (1530 nm - 1565 nm). These waveguides have a cross section of 0.25 microm by 2 microm and are fabricated by standard photolithography and dry etching. We also investigate a compact double-level taper which adiabatically couples light from these waveguides to silicon strip waveguides enabling tight bends.

High speed carrier-depletion modulators with 1.4V-cm V(pi)L integrated on 0.25microm silicon-on-insulator waveguides.

We demonstrate a very efficient high speed silicon modulator with an ultralow pi-phase-shift voltage-length product V(pi)L = 1.4V-cm. The device is based on a Mach-Zehnder interferometer (MZI) fabricated using 0.25microm thick silicon-on-insulator (SOI) waveguide with offset lateral PN junctions. Optimal carrier-depletion induced index change has been achieved through the optimization of the overlap region of carriers and photons. The 3dB bandwidth of a typical 1mm long device was measured to be more than 12GHz. An eye-diagram taken at a transmission rate of 12.5Gb/s confirms the high speed capability of the device.

Low power and compact reconfigurable multiplexing devices based on silicon microring resonators.

We present thermally reconfigurable multiplexing devices based on silicon microring resonators with low tuning power and low thermal crosstalk. Micro-heaters on top of the rings are employed to tune the resonant wavelengths through the thermo-optic effect of silicon. We achieve a low tuning power of 21 mW per free spectral range for a single ring by exploiting thermal isolation trenches close to the ring waveguides. Negligible thermal crosstalk is demonstrated for rings spaced by 15 microm, enabling compact multiplexing devices. The tuning time constant is demonstrated to be less than 10 micros.

Wavelength-tunable silicon microring modulator.

We present a wavelength-tunable, compact, high speed and low power silicon microring modulator. With a ring radius of 5 microm, we demonstrate a modulator with a high speed of 12.5 Gbps and a driving voltage of 3 V to achieve approximately 6 dB extinction ratio in high speed measurement. More importantly, tunability of the resonant wavelength is accomplished by means of a microheater on top of the ring, with an efficiency of 2.4 mW/nm (2.4 mW is needed to tune the resonant wavelength by 1 nm). This device aims to solve the narrow bandwidth problem of silicon microcavity modulators and increase the data bandwidth in optical interconnect systems.

Vertical p-i-n germanium photodetector with high external responsivity integrated with large core Si waveguides.

We report a vertical p-i-n thin-film germanium photodetector integrated on 3microm thick large core silicon-on-insulator (SOI) waveguides. The device demonstrates very high external responsivity due to the low fiber coupling loss to the large core waveguides. The germanium width and thickness are carefully designed to achieve high responsivity yet retain high-speed performance. Even with fiber coupling loss included, the device has demonstrated greater than 0.7A/W external responsivity at 1550nm for TM polarization and 0.5A/W for TE polarization. A low dark current of 0.2microA at -0.5V bias is reported. 3dB bandwidths of 12GHz and 8.3GHz at -2.5V bias are also reported for 100microm and 200microm long devices, respectively. The device can cover the communication wavelength spectrum up to 1620nm with a relatively flat responsivity of >0.5A/W. Further studies suggest that with a modified design the device is capable of achieving 1A/W external responsivity for both TE and TM polarizations and greater than 30GHz bandwidth.

Optical loss reduction in high-index-contrast chalcogenide glass waveguides via thermal reflow.

A thermal reflow technique is applied to high-index-contrast, sub-micron waveguides in As(2)S(3) chalcogenide glass to reduce the sidewall roughness and associated optical scattering loss. We show that the reflow process effectively decreases sidewall roughness of chalcogenide glass waveguides. A kinetic model is presented to quantitatively explain the sidewall roughness evolution during thermal reflow. Further, we develop a technique to calculate waveguide optical loss using the roughness evolution model, and predict the ultimate low loss limit in reflowed high-index-contrast glass waveguides. Up to 50% optical loss reduction after reflow treatment is experimentally observed, and the practical loss limiting factors are discussed.

Planar waveguide-coupled, high-index-contrast, high-Q resonators in chalcogenide glass for sensing.

High-index-contrast compact microdisk resonators in thermally evaporated As2S3 and Ge17Sb12S71 chalcogenide glass films are designed and fabricated using standard UV lithography and characterized. Our pulley coupler configuration demonstrates coupling of the resonators to monolithically integrated photonic wire waveguides without resorting to demanding fine-line lithography. Microdisk resonators in As2S3 support whispering-gallery-mode with cavity quality factors (Q) exceeding 2 x 10(5), the highest Q value reported in resonator structures in chalcogenide glasses to the best of our knowledge. We have successfully demonstrated a lab-on-a-chip prototype sensor device with the integration of our resonator with planar microfluidic systems. The sensor shows a refractive index sensitivity of 182 nm/RIU (refractive index unit) and a wavelength resolution of 0.1 pm through a resonant peak fit. This corresponds to a refractive index detection limit of 8 x 10(-7) RIU at 1550 nm in wavelength, which could be further improved by shifting the operating wavelength to a region where water absorption is reduced.

Photonic-plasmonic scattering resonances in deterministic aperiodic structures.

In this paper, we combine experimental dark-field scattering spectroscopy and accurate electrodynamics calculations to investigate the scattering properties of two-dimensional plasmonic lattices based on the concept of aperiodic order. In particular, by discussing visible light scattering from periodic, Fibonacci, Thue-Morse and Rudin-Shapiro lattices fabricated by electron-beam lithography on transparent quartz substrates, we demonstrate that deterministic aperiodic Au nanoparticle arrays give rise to broad plasmonic resonances spanning the entire visible spectrum. In addition, we show that far-field diffractive coupling is responsible for the formation of characteristic photonic-plasmonic scattering modes in aperiodic arrays of metal nanoparticles. Accurate scattering simulations based on the generalized Mie theory approach support our experimental results. The possibility of engineering complex metal nanoparticle arrays with distinctive plasmonic resonances extending across the entire visible spectrum can have a significant impact on the design and fabrication of novel nanodevices based on broadband plasmonic enhancement.

Plasmon mode transformation in modulated-index metal-dielectric slot waveguides.

The concept of adiabatic mode transformation between silicon waveguide and surface plasmon-polariton modes in subwavelength metal-dielectric slots is investigated. The mode transformer consists of a modulated-index slot region, which is bound by two metal slabs. Using the design scheme, we will show that the optical dispersion of a modulated-index metal slot waveguide can be engineered well above the silicon light-line on a large wavelength region, allowing direct phase-matching between surface plasmon polaritons and traditional waveguide modes. Based on full-field, finite difference simulations, we demonstrate that reversible mode conversion can be achieved within submicrometer length scales.

Low-loss compact-size slotted waveguide polarization rotator and transformer.

Two mode-evolution-based low-loss compact-size integrated polarization rotators and transformers are presented. They are designed to fulfill the tasks of rotating mode polarizations between Gaussian-like strip waveguide modes and non-Gaussian-like slotted waveguide modes, as well as the mode transforming between horizontal and vertical slotted waveguides. Consisting of several adiabatic tapers, the presented devices can achieve complete polarization rotations and transformations between different classes of waveguide modes with a device length of tens of micrometers and with a negligible insertion loss.