UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

Multi-nodes dissemination of stable radio frequency with 10-17 instability over 2000 km optical fiber.

To meet the demand of flexible access for high-precision synchronization frequency, we demonstrate multi-node stable radio frequency (RF) dissemination over a long-distance optical fiber. Stable radio frequency signals can be extracted at any node along the optical fiber, not just at the endpoint. The differential mixing structure (DMS) is employed to avoid the frequency harmonic leakage and enhance the precision. The phase-locked loop (PLL) provides frequency reference for the DMS while improving the signal to noise ratio (SNR) of dissemination signal. We measure the frequency instability of multi-node stable frequency dissemination system (MFDS) at different locations along the 2,000 km optical fiber. The measured short-term instability with average time of 1 s are 1.90 × 10-14 @ 500 km, 2.81 × 10-14 @ 1,000 km, 3.46 × 10-14 @ 1,500 km, and 3.84 × 10-14 @ 2,000 km respectively. The long-term instability with average time of 10,000 s are basically the same at any position of the optical fiber, which is about (6.24 ± 0.05) × 10-17. The resulting instability is sufficient for the propagation of precision active hydrogen masers.

Tri-comb generation with a dual-ring structure.

By introducing a third measurement comb with different repetition frequencies (Δ f r e p ), the tri-comb spectroscopy technique overcomes the ambiguity problem of the original dual-comb spectroscopy technique and eliminates physical delay stages in multidimensional coherent spectroscopy. Nowadays, tri-comb generation based on three frequency-stabilized comb lasers is overly complicated and costly for many potential applications. Previous research on single-cavity dual-combs inspired research on single-cavity tri-combs. However, the currently reported tri-comb structures cannot achieve independently controllable pulses. This paper shows a dual-ring tri-comb seed-source structure using wavelength-based multiplexing in one of the rings. The wavelength and power of the output pulse are independently controlled by using the dual-ring structure. The Δ f r e p of wavelength multiplexing-based dual-comb output can be tuned by adjusting the intra-ring polarization controller (PC). In the case of single-wavelength mode-locking, the PC can be adjusted to achieve a wavelength tuning range of nearly 20 nm. The tri-comb source could offer an attractive alternative solution as a low-complexity light source for field-deployable multi-comb metrology applications.

Differential phase-diversity electrooptic modulator for cancellation of fiber dispersion and laser noise.

Bandwidth and noise are fundamental considerations in all communication and signal processing systems. The group-velocity dispersion of optical fibers creates nulls in their frequency response, limiting the bandwidth and hence the temporal response of communication and signal processing systems. Intensity noise is often the dominant optical noise source for semiconductor lasers in data communication. In this paper, we propose and demonstrate a class of electrooptic modulators that is capable of mitigating both of these problems. The modulator, fabricated in thin-film lithium niobate, simultaneously achieves phase diversity and differential operations. The former compensates for the fiber's dispersion penalty, while the latter overcomes intensity noise and other common mode fluctuations. Applications of the so-called four-phase electrooptic modulator in time-stretch data acquisition and in optical communication are demonstrated.

Dual-comb fiber laser for stable frequency distribution.

A passive dual-comb laser can generate two optical frequency combs with different repetition frequencies. These repetition differences have high relative stability and mutual coherence through passive common-mode noise suppression without complex tight phase locking from a single-laser cavity. The comb-based frequency distribution requires the dual-comb laser to have a high repetition frequency difference. This paper presents a high repetition frequency difference bidirectional dual-comb fiber laser based on an all-polarization-maintaining cavity configuration and a semiconductor saturable absorption mirror with single polarization output. The proposed comb laser has a standard deviation of 69 Hz and an Allan deviation of 1.17 × 10-7 at τ = 1 s under different repetition frequencies of 12.815 MHz. Moreover, a transmission experiment has been conducted. Owing to the passive common-mode noise rejection capability of dual-comb laser, after passing an 84 km fiber link, the frequency stability of the repetition frequency difference signal is improved by two orders of magnitude than the repetition frequency signal at the receiver side.

High-resolution timing jitter measurement based on the photonics time stretch technique.

High-resolution jitter measurement is essential for the next generation of electronic communications and sensor systems. However, most electrical timing jitter measurement equipment has a low resolution because of the limitations of electronic processing accuracy. Meanwhile, photonics-based jitter measurement methods have a higher resolution but cannot measure the widely used electrical signals. This work proposes a potential high-resolution jitter measurement method for electrical signals based on the photonics time stretch technique. The jitter information can be magnified in the optical domain and then measured by electrical equipment. The experimental results demonstrate that the jitter of an electrical pulse is magnified from 59.02 ps to 663.29 ps when the magnification factor is 11.24.

Mild and moderate cardioembolic stroke patients may benefit more from direct mechanical thrombectomy than bridging therapy: A subgroup analysis of a randomized clinical trial (DIRECT-MT).

Background: The benefit of intravenous alteplase before endovascular thrombectomy is unclear in patients with acute cardioembolic stroke. Methods: We collected cardioembolic (CE) stroke patient data from the multicentre randomized clinical trial of Direct Intra-arterial Thrombectomy to Revascularize Acute Ischaemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIRECT-MT). The primary outcome was the 90-day modified Rankin Scale (mRS) score. Five subgroups of cardioembolic stroke patients were analyzed. A multivariable ordinal logistic regression analysis analyzed the difference in the primary outcome between the direct mechanical thrombectomy (MT) and bridging therapy groups. An interaction term was entered into the model to test for subgroup interaction. The DIRECT-MT trial is registered with clinicaltrials.gov Identifier: NCT03469206. Results: A total of 290 CE stroke patients from the DIRECT-MT trial were enrolled in this study: 146 patients in the direct MT group and 144 patients in the bridging therapy group. No difference between the two treatment groups in the primary outcome was found (adjusted common odds ratio, 1.218; 95% confidence interval, 0.806 to 1.841; P = 0.34). In the subgroup analysis, CE stroke patients with an NIHSS ≤ 15 in the direct MT group were associated with better outcomes (47 vs. 53, acOR, 3.14 [1.497, 6.585]) and lower mortality (47 vs. 53, aOR, 0.16 [0.026, 0.986]) than those in the bridging therapy group, while there were no significant differences between the two treatment groups in the outcome and mortality of CE stroke patients with an NIHSS >15. Conclusion: Mild and moderate cardioembolic stroke patients may benefit more from direct mechanical thrombectomy than bridging therapy. This need to be confirmed by further prospective studies in a larger number of patients.

Prognostic values of B7-H3, B7-H4, and HHLA2 expression in human pancreatic cancer tissues based on mIHC and spatial distribution analysis.

BACKGROUND: Pancreatic cancer (PC) is one of the most malignant solid tumors and its 5-year survival rate remains poor. Although immunotherapy has achieved certain therapeutic efficacy in some clinical trials, such treatment still shows low responses and overall remission rate. Therefore, it is urgently necessary to dissect the tumor microenvironment and optimize the immunotherapeutic strategies against this malignancy. METHODS: Using the multi-color immunohistochemistry assay, we investigated the expressions of B7-H3, B7-H4, HHLA2, CD8, and CD68 in 63 cases of PC tissues in a tissue microarray. Moreover, we analyzed immunolocalization features, clinical associations and prognostic values of these molecules. RESULTS: The expressions of B7-H3, B7-H4, and HHLA2 could be detected in cytokeratin staining positive (CK+) cancer epithelial cells, CD68+tumor-associated macrophages (TAMs), and even other cells defined as CK-CD8-CD68-. Higher expression of B7-H3 in tumor cells could predict a better survival of the PC patients. A positive correlation was found between the expressions of B7-H3 and HHLA2 in tumor cells, while there was a negative correlation between the expressions of B7-H4 and HHLA2 in tumor cells. A positive correlation was found between the expressions of B7-H3 and B7-H4 or HHLA2 in CD68+TAMs, but not B7-H4 and HHLA2. Tumor-infiltrating CD8+T cells in combination with CD68+TAMs could serve as an important predictor for the postoperative prognosis of PC patients. Higher expression of B7-H3, or HHLA2 in CD68+TAMs could serve as an important predictor for poorer prognosis of PC patients. Patients with B7-H3lowB7-H4low, B7-H3lowHHLA2low, or B7-H4lowHHLA2low on CD68+TAMs could have a better postoperative prognosis compared with the other sub-populations in the combinational analysis. CONCLUSIONS: Taken together, our study indicated variable expressions and prognostic values of B7-H3, B7-H4, and HHLA2, in human PC tissues, and demonstrated that these co-stimulator molecules expressed by CD68+TAMs could be used as important bio-markers for the prognostic prediction of PC patients. Moreover, these results supported that the evaluation of these markers could be used as essential candidate targets for immunotherapy against PC.

Long Non-Coding RNA GRIK1-AS1 Inhibits the Proliferation and Invasion of Gastric Cancer Cells by Regulating the miR-375/IFIT2 Axis.

Long non-coding RNAs (lncRNAs) play important roles in various biological processes and human diseases, including cancer. In this study, we demonstrated a regulatory relationship between lncRNA GRIK1-AS1 and miR-375/IFIT2 axis in gastric cancer. Our results show a decreased expression of GRIK1-AS1 in gastric cancer tissues compared to adjacent normal gastric tissues. Gastric cell lines also have reduced levels of GRIK1-AS1 compared to gastric epithelial cell line GES-1. Ectopic expression of GRIK1-AS1 in gastric cancer cell lines significantly inhibits cellular viability, migration, and invasion. RNA-pull down and the luciferase activity assays show that GRIK1-AS1 mainly interacts specifically with miR-375. We further demonstrate a negatively regulatory relationship between lncRNA GRIK1-AS1 and miR-375. We discovered that IFIT2 was one of the direct key downstream target genes of miR-375, and established the important role of the GRIK1-AS1/miR-375/IFIT2 axis in the progression of gastric cancer. Taken together, our results revealed a novel mechanism of GRIK1-AS1 as a sponge to miR-375 that impacts gastric cancer progression via modulating target mRNA IFIT2 translation, and as a result, opens a new strategy to future GRIK1-AS1 based therapeutic development.

Michelson interferometer based phase demodulation for stable time transfer over 1556 km fiber links.

Time transfer based on phase modulation schemes has attracted extensive attention in recent years. We propose and experimentally demonstrate an adjustable and stable Michelson interferometer (MI) with a DC phase tracking algorithm for two-way time transfer. Time signal with one pulse per second (1 PPS) is loaded on an optical carrier modulated in phase and demodulated by a Michelson interferometer. The whole compact and cost-effective demodulator is symmetrical with a single coupler to split and recombine optical waves, flexible with one photodetector and a bias tee to separate the DC signal and recovery pulses and stable with a phase modulator to compensate for the drift-phase noise. We show the implementation of modulation and demodulation of the time signal and obtain the stability of 2.31 × 10-11 at 1000 s averaging time. We then demonstrate two-way time transfer over 1556 km lab fibers. The experimental result shows time interval stability of 1 PPS with 5.62 × 10-11 at 1000 s averaging time. It has the potential to transfer time signals in long-distance fiber optic links.

Comparative risk for intracranial hemorrhage related to new oral anticoagulants: A network meta-analysis.

BACKGROUND: The intracranial hemorrhage (ICH) risk of oral anticoagulants/non-vitamin K antagonist oral anticoagulants (NOACs) remains largely unknown. Patients who need oral anticoagulants such as aspirin or warfarin often suffer from obvious complications. METHODS: This network meta-analysis intended to assess the ICH risk in patients taking NOACs. The data from PubMed, the Cochrane database, and Embase were reviewed. All phase III randomized controlled trials of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), aspirin and warfarin were reviewed. RESULTS: Twenty-three trials involving 137,713 participants were included, involving 6 regimens. Warfarin had the first risk of ICH (surface under the cumulative ranking area: 0.82), followed by dabigatran, edoxaban, aspirin, apixaban, rivaroxaban, and placebo. Dabigatran had the lowest risk of all-cause mortality (surface under the cumulative ranking area: 0.63), followed by apixaban, edoxaban, warfarin, rivaroxaban, aspirin, and placebo. CONCLUSION: Warfarin significantly increased the risk of ICH in patients taking oral anticoagulants compared with 4 NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) and aspirin. Apixaban is least likely to induce all-cause mortality.

Abnormal increase of miR-4262 promotes cell proliferation and migration by targeting large tumor suppressor 1 in gliomas.

BACKGROUND: miRNA was recently detected as tumor suppressor or inducer in various cancers including gliomas. Due to the abnormal expression of miR-4262 in glioma cancer, we supposed that miR-4262 made efforts in proliferation and migration in glioma cancer. METHODS: CCK-8, Transwell migration Assay and Wound-healing assay were appraisal assays for cell proliferation and migration. qRT-PCR and western blot were performed to test the expression of miR-4262, MMP2, MMP13 and LATS1 in glioma cancers tissues and cancer cells. The targeting detection between miR-4262 and LATS1 was detected by luciferase reporter assay. RESULTS: miR-4262 expression was dramatically higher in glioma tumor tissues than in para-tumor control. Inhibition of miR-4262 in glioma cancer cells prominently inhibited cell proliferation and migration. Mechanically, downregulation of miR-4262 inhibited expression of matrix metalloproteinase (MMP) -2, -13. In addition, miR-4262 directly and negatively modulated expression of large tumor suppressor 1 (LATS1). Moreover, we discovered that overexpression of LATS1 could reverse the effects of miR-4262 on cell proliferation and migration, as well as the production of MMP-2, -13. CONCLUSIONS: In glioma cancer, miR-4262 regulated cell proliferation and migration mediated by LATS1. This indicated that miR-4262 is a tumor inducer in glioma cancer and may be a feasible target for glioma therapy.

Stable radio frequency transfer over fiber based on microwave photonic phase shifter.

We demonstrate a radio frequency (RF) phase-stable transmission over fiber based on microwave photonic phase shifter. In the proposed system, both assistant RF signals are applied to drive two arms of a dual-drive Mach-Zehnder modulator (DMZM), respectively. An optical bandpass filter is followed to filter out the first-order sideband of optical modulated signal. Due to the phase independence between two optical sidebands, the phase perturbation caused by fiber-length variations can be compensated automatically via controlling the direct-current bias voltage of the DMZM. We have performed RF transfer in a 155 km single-mode fiber with a frequency instability of 3.05 × 10-17 at 10,000 s averaging time.

Tera-sample-per-second single-shot device analyzer.

With the ever-increasing need for bandwidth in data centers and 5G mobile communications, technologies for rapid characterization of wide-band devices are in high demand. We report an instrument for extremely fast characterization of the electronic and optoelectronic devices with 27 ns frequency-response acquisition time at the effective sampling rate of 2.5 Tera-sample/s and an ultra-low effective timing jitter of 5.4 fs. This instrument features automated digital signal processing algorithms including time-series segmentation and frame alignment, impulse localization and Tikhonov regularized deconvolution for single-shot impulse and frequency response measurements. The system is based on the photonic time-stretch and features phase diversity to eliminate frequency fading and extend the bandwidth of the instrument.

Stable radio frequency dissemination via a 1007 km fiber link based on a high-performance phase lock loop.

In this paper, we propose an active-compensation stable radio frequency (RF) transmission scheme based on a high-performance phase lock loop (PLL). In our PLL, a new structure for phase-detection is designed with only one standard RF signal to obtain a simple structure with no interference from other signals. In addition, different optical wavelengths carrying the same RF signal are utilized in the two directions to suppress Rayleigh scattering. The low phase noise homemade bi-directional erbium doped fiber amplifier (EDFA) module is used to reduce signal-to-noise ratio (SNR) deterioration. Hence, the transmission distance is greatly improved. The effects of polarization mode dispersion and phase noise produced by the EDFA on the transmission distance are discussed. Ultimately, a stable RF signal with 2.4 GHz transmitted over a 1007 km fiber link is obtained. The experimental results demonstrate that frequency instabilities of 1.2×10- 13 at 1s and 5.1×10- 16 at 20000s. Therefore, the system can be used for atomic clocks comparisons and provides frequency standard for time transfer systems over a long-haul fiber.

Simple and efficient nonlinear polarization evolution mode-locked fiber laser by three-dimensionally manipulating a polarization beam splitter.

A simple and efficient femtosecond nonlinear polarization evolution (NPE) mode-locked laser is presented. Different from conventional NPE fiber lasers, the polarization beam splitter (PBS) is three-dimensionally manipulated to achieve polarization control and state selection in our NPE laser. The polarizer, half-wave plate, and quarter-wave plate from conventional NPE fiber lasers are replaced by this PBS. Thus, the configuration and the system gain of our proposed laser are simply and efficiently improved. As a result, transfer efficiency of 24.17% is experimentally demonstrated. In addition, measured self-started pulses with average power of 49 mW and center wavelength of 1584 nm are generated with single-pulse energy of 1.51 nJ.

Radiotherapy Upregulates Programmed Death Ligand-1 through the Pathways Downstream of Epidermal Growth Factor Receptor in Glioma.

BACKGROUND: In the present study, we aimed to investigate the role of epidermal growth factor receptor (EGFR) pathway in the up-regulation of programmed death ligand-1 (PD-L1) caused by radiotherapy (RT). MATERIALS AND METHODS: Tissue microarrays (TMA) consisting of glioma cancer specimens from 64 patients were used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed in vitro experiments to assess the role of EGFR pathway in RT-upregulated PD-L1 expression using human glioma cell lines U87 and U251. RESULTS: Our data demonstrated that the PD-L1 expression was significantly correlated with EGFR expression in glioma specimens (χ2=5.00, P=0.025). The expressions of PD-L1 at the protein and mRNA levels were both significantly up-regulated by RT (P<0.05). The expressions of phosphorylated EGFR and janus kinase 2 (JAK2) were also induced by RT (P<0.05). Besides, inhibition of EGFR pathway could abrogate the RT-triggered PD-L1 up-regulation (P>0.05). The combination of RT with EGFR inhibitor exhibited the same effect on antitumor immune response compared with the combination of RT with PD-L1 neutralizing antibody (Ab). CONCLUSIONS: RT could up-regulate the PD-L1 expression through the pathways downstream of EGFR in glioma.

Stable frequency dissemination over multi-access fiber loop link with optical comb.

An optical comb based stable frequency dissemination system is proposed and experimentally demonstrated over a multi-access optical fiber loop link. In the system, a new technique based on optical-microwave phase locking loop is designed for phase compensation. In the experiment, a mode-locked fiber laser at a repetition rate of 100 MHz is used to provide an optical source at local site, then it transmits along a 150 km fiber loop link. To testify the proposed system, two accessing nodes are measured in the loop link. The dissemination frequency instability is measured at 3.65 × 10-15/1 s and 7.8 × 10-18/1000 s at the intermediate node. The similar performance is shown at the other node. Hence, the system has the potential application in high-precision frequency transmission system via a long-haul multi-access loop link.

High expression of B7-H6 in human glioma tissues promotes tumor progression.

B7-H6, a new member of B7-family ligand, also known as NCR3LG1, plays an important role in NK cells mediated immune responses. Many studies have shown that it is highly expressed in various human cancers, and its expression levels are significantly associated with cancer patients' clinicopathological parameters and postoperative prognoses. But, still the exact role of B7-H6 expression in human glioma remains elusive. In the present study, we have characterized the B7-H6 expression in the human glioma tissues as well as glioma cell lines, U87 and U251. We observed that B7-H6 was highly expressed in the human glioma tissues, and its expression was significantly associated with cancer progression. By using the RNA interference technology, we successfully ablated B7-H6 expression in human glioma cell lines to further study its contribution towards various biological features of this malignancy. Our study identified that the B7-H6 knockdown in U87 and U251 glioma cells significantly suppressed cell proliferation, migration, invasion, and enhanced apoptosis along with induction of cell cycle arrest. It thus suggested that B7-H6 play an important role in the regulation of the biological behavior of these glioma cells. However, the detailed mechanism of B7-H6 mediated regulation of glioma cancer cell transformation and its prognostic value merits further investigation.