Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer.

Metabolic reprogramming is a hallmark of human cancer, and cancer-specific metabolism provides opportunities for cancer diagnosis, prognosis, and treatment. However, the underlying mechanisms by which metabolic pathways affect the initiation and progression of colorectal cancer (CRC) remain largely unknown. Here, we demonstrate that cysteine is highly enriched in colorectal tumors compared to adjacent non-tumor tissues, thereby promoting tumorigenesis of CRC. Synchronously importing both cysteine and cystine in colorectal cancer cells is necessary to maintain intracellular cysteine levels. Hypoxia-induced reactive oxygen species (ROS) and ER stress regulate the co-upregulation of genes encoding cystine transporters (SLC7A11, SLC3A2) and genes encoding cysteine transporters (SLC1A4, SLC1A5) through the transcription factor ATF4. Furthermore, the metabolic flux from cysteine to reduced glutathione (GSH), which is critical to support CRC growth, is increased due to overexpression of glutathione synthetase GSS in CRC. Depletion of cystine/cysteine by recombinant cyst(e)inase effectively inhibits the growth of colorectal tumors by inducing autophagy in colorectal cancer cells through mTOR-ULK signaling axis. This study demonstrates the underlying mechanisms of cysteine metabolism in tumorigenesis of CRC, and evaluates the potential of cysteine metabolism as a biomarker or a therapeutic target for CRC.

Phosphorylation at tyrosine 317 and 508 are crucial for PIK3CA/p110α to promote CRC tumorigenesis.

BACKGROUND: PI3K/AKT signaling pathway plays important role in tumorigenesis of human cancer. Protein phosphorylation is crucial for signaling transduction of this pathway. PIK3CA, encoding the catalytic subunit p110α of PI3K complex, is one of the most frequently mutated oncogenes in human cancers. However, phosphorylation sites of PIK3CA/p110α and their underlying mechanism in tumorigenesis are largely unknown. METHODS: Tyrosine phosphorylation sites of PIK3CA/p110α are identified with Mass-Spectrum. Crispr/CAS9 strategy is applied to generate Y317F and Y508F mutant knock-in cell clones. The growth and metastasis abilities of cells are evaluated in vitro and in vivo. Phospho-proteomics analysis and Western blots are used to demonstrate downstream signaling pathways of PIK3CA/p110α tyrosine phosphorylation. In vitro kinase assay is applied to identify the kinase of PIK3CA/p110α tyrosine phosphorylation. RESULTS: Tyrosine phosphorylation of PIK3CA/p110α is stimulated by growth factors such as EGF, HGF and PDGF. Two tyrosine residues, Y317 and Y508, are identified on PIK3CA/p110α. Either Y317 or Y508 phosphorylation is essential for tumorigenesis of CRC. Mutation at Y317 of p110α reduces the proliferation, migration, and invasion of cancer cells through Src-MLC2 pathway, while mutation at Y508 of p110α impairs AKT signaling. Moreover, Src interacts with and phosphorylates p110α. CONCLUSIONS: PIK3CA/p110α phosphorylation at Y317 and Y508 play important role in tumorigenesis of colorectal cancer through two independent pathways.

120-GBaud 16-QAM silicon photonics IQ modulator for data center interconnection.

We demonstrated all-silicon IQ modulators (IQMs) operating at 120-GBaud 16-QAM with suitable bandwidth, and output power. We required optical signal-to-noise-ratio (rOSNR) that have promising potential to be used in 800-Gbps small-form-factor pluggable transceivers for data center interconnection. First, we tested an IQM chip using discrete drivers and achieved a per-polarization TX output power of -18.74 dBm and an rOSNR of 23.51 dB over a 100-km standard SMF. Notably, a low BER of 1.4e-3 was obtained using our SiP IQM chip without employing nonlinear compensation, optical equalization, or an ultra-wide-bandwidth, high-ENOB OMA. Furthermore, we investigated the performance of a 3D packaged transmitter by emulating its frequency response using an IQM chip, discrete drivers, and a programmable optical filter. With a laser power of 17 dBm, we achieved a per-polarization output power of -15.64 dBm and an rOSNR of 23.35 dB.

FAK-mediated phosphorylation at Y464 regulates p85ß nuclear translocation to promote tumorigenesis of ccRCC by repressing RB1 expression.

PI3K regulatory subunit p85s normally stabilizes and regulates catalytic subunit p110s in the cytoplasm. Recent studies show that p110-free p85s in the nucleus plays important roles in biological processes. However, the mechanisms by which p85s translocate into the nucleus remain elusive. Here, we describe the mechanism by which p85ß translocates into the nucleus to promote ccRCC tumorigenesis. Phosphorylation of p85ß at the Y464 by FAK facilitates its nuclear translocation in the kidney through enhancing the binding of p85ß to KPNA1. PIK3R2/p85ß is highly expressed in ccRCC samples and associated with overall survival of ccRCC patients. Nuclear but not cytoplasmic p85ß performs oncogenic functions by repressing RB1 expression and regulating the G1/S cell cycle transition. Nuclear p85ß represses RB1 expression by stabilizing histone methyltransferase EZH1/EZH2 proteins. Last, the FAK inhibitor defactinib significantly suppresses the tumor growth of ccRCC with high p85ß Y464 levels.

Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population.

OBJECTIVE: To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA. METHODS: Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed. RESULTS: Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch. CONCLUSION: Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle.

Rationale: Skeletal muscle insulin resistance is detectable before type 2 diabetes is diagnosed. Exposure to di(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine-disrupting chemical, is a novel risk factor for insulin resistance and type 2 diabetes. This study aimed to explore insulin signaling regulatory pathway in skeletal muscle of the DEHP-induced insulin-resistant mice and to investigate potential therapeutic strategies for treating insulin resistance. Methods: C57BL/6J male mice were exposed to 2 mg/kg/day DEHP for 15 weeks. Whole-body glucose homeostasis, oxidative stress and deregulated miRNA-mediated molecular transduction in skeletal muscle were examined. microRNA (miRNA) interventions based on lentiviruses and adeno-associated viruses 9 (AAV9) were performed. Results: Dnmt3a-dependent promoter methylation and lncRNA Malat1-related sponge functions cooperatively downregulated miR-17 in DEHP-exposed skeletal muscle cells. DEHP suppressed miR-17 to disrupt the Keap1-Nrf2 redox system and to activate oxidative stress-responsive Txnip in skeletal muscle. Oxidative stress upregulated miR-200a, which directly targets the 3'UTR of Insr and Irs1, leading to hindered insulin signaling and impaired insulin-dependent glucose uptake in skeletal muscle, ultimately promoting the development of insulin resistance. AAV9-induced overexpression of miR-17 and lentivirus-mediated silencing of miR-200a in skeletal muscle ameliorated whole-body insulin resistance in DEHP-exposed mice. Conclusions: The miR-17/Keap1-Nrf2/miR-200a axis contributed to DEHP-induced insulin resistance. miR-17 is a positive regulator, whereas miR-200a is a negative regulator of insulin signaling in skeletal muscle, and both miRNAs have the potential to become therapeutic targets for preventing and treating insulin resistance or type 2 diabetes.

Plasmonic nanostructured metal-oxide-semiconductor reflection modulators.

We propose a plasmonic surface that produces an electrically controlled reflectance as a high-speed intensity modulator. The device is conceived as a metal-oxide-semiconductor capacitor on silicon with its metal structured as a thin patch bearing a contiguous nanoscale grating. The metal structure serves multiple functions as a driving electrode and as a grating coupler for perpendicularly incident p-polarized light to surface plasmons supported by the patch. Modulation is produced by charging and discharging the capacitor and exploiting the carrier refraction effect in silicon along with the high sensitivity of strongly confined surface plasmons to index perturbations. The area of the modulator is set by the area of the incident beam, leading to a very compact device for a strongly focused beam (∼2.5 µm in diameter). Theoretically, the modulator can operate over a broad electrical bandwidth (tens of gigahertz) with a modulation depth of 3 to 6%, a loss of 3 to 4 dB, and an optical bandwidth of about 50 nm. About 1000 modulators can be integrated over a 50 mm(2) area producing an aggregate electro-optic modulation rate in excess of 1 Tb/s. We demonstrate experimentally modulators operating at telecommunications wavelengths, fabricated as nanostructured Au/HfO2/p-Si capacitors. The modulators break conceptually from waveguide-based devices and belong to the same class of devices as surface photodetectors and vertical cavity surface-emitting lasers.

Thin Au surface plasmon waveguide Schottky detectors on p-Si.

Surface plasmon sub-bandgap Schottky detectors based on an asymmetric Au stripe waveguide on p-Si are investigated theoretically and experimentally at free-space wavelengths of λ(0) = 1310 and 1550 nm. Au on p-Si produces a low Schottky barrier (0.33 eV), which improves the internal quantum efficiency. Thick and thin Au stripes are compared, with the latter increasing the hot hole emission probability relative to the former, and thus also improving the internal quantum efficiency. Two excitation schemes are considered: end facet illumination which launches surface plasmons on the detector, and top illumination which does not. Both schemes are implemented using a piezoelectric positioner that is programmed to scan the detection area in steps of 100-200 nm, thus enabling the acquisition of high-resolution photocurrent maps. The surface plasmon detectors yield a responsivity of ~1 mA W(-1), ~2× larger than the same detectors under top illumination, due to the absorption of surface plasmons. We compare the measurements with theoretical results for both excitation schemes and estimate the hot hole attenuation length in our Au stripes to be ~23 nm.

Long range surface plasmons on asymmetric suspended thin film structures for biosensing applications.

We show that long-range surface plasmons (LRSPs) are supported in a physically asymmetric thin film structure, consisting of a low refractive index medium on a metal slab, supported by a high refractive index dielectric layer (membrane) over air, as a suspended waveguide. For design purposes, an analytic formulation is derived in 1D yielding a transcendental equation that ensures symmetry of the transverse fields of the LRSP within the metal slab by constraining its thicknesses and that of the membrane. Results from the formulation are in quantitative agreement with transfer matrix calculations for a candidate slab waveguide consisting of an H(2)O-Au-SiO(2)-air structure. Biosensor-relevant figures of merit are compared for the asymmetric and symmetric structures, and it is found that the asymmetric structure actually improves performance, despite higher losses. The finite difference method is also used to analyse metal stripes providing 2D confinement on the structure, and additional constraints for non-radiative LRSP guiding thereon are discussed. These results are promising for sensors that operate with an aqueous solution that would otherwise require a low refractive index-matched substrate for the LRSP.

Grating couplers for broadside input and output coupling of long-range surface plasmons.

Metal gratings for in-coupling a Gaussian beam incident from broadside to the long-range surface plasmon polariton (LRSPP) propagating in one direction along a membrane-supported Au slab bounded by air or water are proposed and modeled by the finite-difference time-domain method. Grating couplers for out-coupling the propagating LRSPP into free radiation directed along broadside are also investigated. Short grating designs consisting of a small number of Au bumps yield 15% to 20% in-coupling efficiencies, and about 60% out-coupling efficiencies. LRSPP back-reflections along the membrane waveguide caused by the out-coupling grating are also calculated and discussed.

Quasi-distributed refractometer using tilted Bragg gratings and time domain reflectometry.

Tilted fiber Bragg gratings (TFBGs) have been demonstrated to be accurate refractometers as they couple light from the fiber core to the cladding. Because they require spectral measurements on several tens of nanometers, demodulation techniques reported so far are not suited for quasi-distributed refractive index sensing using TFBGs cascaded along a single optical fiber. We demonstrate here that a commercial Optical Time Domain Reflectometer (OTDR) can be used to multiplex identical TFBGs refractometers written in the same optical fiber. Our solution is simple, relatively fast, cost-effective and is particularly interesting for the monitoring of long structures.

Sensitivity of photonic crystal fiber modes to temperature, strain and external refractive index.

Several strong narrowband resonances are observed in the transmission spectra of fiber Bragg gratings photo-written in photonic crystal fiber that has a refractive index-neutral germanium/fluorine co-doped core. Experimental results for the strain, temperature and refractive index sensitivities of these mode resonances are reported and compared to those of conventional single mode fiber. In particular, we identify three kinds of resonances whose relative sensitivities to strain, temperature and refractive index are markedly different and present numerical simulations to explain these properties. Potential multiparameter optical sensor applications of these mode resonances are briefly discussed.

Temperature-independent tilted fiber grating vibration sensor based on cladding-core recoupling.

A novel structure in which a short optical fiber stub containing a weakly tilted Bragg grating is spliced to another slightly offset fiber. The total power reflected from this structure is independent of temperature and occurs in two well-defined wavelength bands, only one of which reflects a different amount of power as the fiber stub bends or vibrates. The smart sensing structure presents an extremely high sensitivity for microbending, and its frequency response has been tested to higher than 2 kHz so far in temperature-immune vibration measurements via cost-effective power detection.

Optical fiber refractometer using narrowband cladding-mode resonance shifts.

Short-period fiber Bragg gratings with weakly tilted grating planes generate multiple strong resonances in transmission. Our experimental results show that the wavelength separation between selected resonances allows the measurement of the refractive index of the medium surrounding the fiber for values between 1.25 and 1.44 with an accuracy approaching 1x10(-4). The sensor element is 10 mm long and made from standard single-mode telecommunication grade optical fiber by ultraviolet light irradiation through a phase mask.