Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress.

BACKGROUND: Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells. METHODS: A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage. RESULTS: We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression. CONCLUSIONS: Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Correlated self-heterodyne method for ultra-low-noise laser linewidth measurements.

Narrow-linewidth lasers are important to many applications spanning precision metrology to sensing systems. Characterization of these lasers requires precise measurements of their frequency noise spectra. Here we demonstrate a correlated self-heterodyne (COSH) method capable of measuring frequency noise as low as 0.01 Hz2/Hz at 1 MHz offset frequency. The measurement setup is characterized by both commercial and lab-built lasers, and features low optical power requirements, fast acquisition time and high intensity noise rejection.

Flattening laser frequency comb spectra with a high dynamic range, broadband spectral shaper on-a-chip.

Spectral shaping is critical to many fields of science. In astronomy for example, the detection of exoplanets via the Doppler effect hinges on the ability to calibrate a high resolution spectrograph. Laser frequency combs can be used for this, but the wildly varying intensity across the spectrum can make it impossible to optimally utilize the entire comb, leading to a reduced overall precision of calibration. To circumvent this, astronomical applications of laser frequency combs rely on a bulk optic setup which can flatten the output spectrum before sending it to the spectrograph. Such flatteners require complex and expensive optical elements like spatial light modulators and have non-negligible bench top footprints. Here we present an alternative in the form of an all-photonic spectral shaper that can be used to flatten the spectrum of a laser frequency comb. The device consists of a circuit etched into a silicon nitride wafer that supports an arrayed-waveguide grating to disperse the light over hundreds of nanometers in wavelength, followed by Mach-Zehnder interferometers to control the amplitude of each channel, thermo-optic phase modulators to phase the channels and a second arrayed-waveguide grating to recombine the spectrum. The demonstrator device operates from 1400 to 1800 nm (covering the astronomical H band), with twenty 20 nm wide channels. The device allows for nearly 40 dBs of dynamic modulation of the spectrum via the Mach-Zehnders , which is greater than that offered by most spatial light modulators. With a smooth spectrum light source (superluminescent diode), we reduced the static spectral variation to ∼3 dB, limited by the properties of the components used in the circuit. On a laser frequency comb which had strong spectral modulations, and some at high spatial frequencies, we nevertheless managed to reduce the modulation to ∼5 dBs, sufficient for astronomical applications. The size of the device is of the order of a US quarter, significantly cheaper than their bulk optic counter parts and will be beneficial to any area of science that requires spectral shaping over a broad range, with high dynamic range, including exoplanet detection.

Integrated Pockels laser.

The development of integrated semiconductor lasers has miniaturized traditional bulky laser systems, enabling a wide range of photonic applications. A progression from pure III-V based lasers to III-V/external cavity structures has harnessed low-loss waveguides in different material systems, leading to significant improvements in laser coherence and stability. Despite these successes, however, key functions remain absent. In this work, we address a critical missing function by integrating the Pockels effect into a semiconductor laser. Using a hybrid integrated III-V/Lithium Niobate structure, we demonstrate several essential capabilities that have not existed in previous integrated lasers. These include a record-high frequency modulation speed of 2 exahertz/s (2.0 × 1018 Hz/s) and fast switching at 50 MHz, both of which are made possible by integration of the electro-optic effect. Moreover, the device co-lases at infrared and visible frequencies via the second-harmonic frequency conversion process, the first such integrated multi-color laser. Combined with its narrow linewidth and wide tunability, this new type of integrated laser holds promise for many applications including LiDAR, microwave photonics, atomic physics, and AR/VR.

Extending the spectrum of fully integrated photonics to submicrometre wavelengths.

Integrated photonics has profoundly affected a wide range of technologies underpinning modern society1-4. The ability to fabricate a complete optical system on a chip offers unrivalled scalability, weight, cost and power efficiency5,6. Over the last decade, the progression from pure III-V materials platforms to silicon photonics has significantly broadened the scope of integrated photonics, by combining integrated lasers with the high-volume, advanced fabrication capabilities of the commercial electronics industry7,8. Yet, despite remarkable manufacturing advantages, reliance on silicon-based waveguides currently limits the spectral window available to photonic integrated circuits (PICs). Here, we present a new generation of integrated photonics by directly uniting III-V materials with silicon nitride waveguides on Si wafers. Using this technology, we present a fully integrated PIC at photon energies greater than the bandgap of silicon, demonstrating essential photonic building blocks, including lasers, amplifiers, photodetectors, modulators and passives, all operating at submicrometre wavelengths. Using this platform, we achieve unprecedented coherence and tunability in an integrated laser at short wavelength. Furthermore, by making use of this higher photon energy, we demonstrate superb high-temperature performance and kHz-level fundamental linewidths at elevated temperatures. Given the many potential applications at short wavelengths, the success of this integration strategy unlocks a broad range of new integrated photonics applications.

Probing material absorption and optical nonlinearity of integrated photonic materials.

Optical microresonators with high quality (Q) factors are essential to a wide range of integrated photonic devices. Steady efforts have been directed towards increasing microresonator Q factors across a variety of platforms. With success in reducing microfabrication process-related optical loss as a limitation of Q, the ultimate attainable Q, as determined solely by the constituent microresonator material absorption, has come into focus. Here, we report measurements of the material-limited Q factors in several photonic material platforms. High-Q microresonators are fabricated from thin films of SiO2, Si3N4, Al0.2Ga0.8As, and Ta2O5. By using cavity-enhanced photothermal spectroscopy, the material-limited Q is determined. The method simultaneously measures the Kerr nonlinearity in each material and reveals how material nonlinearity and ultimate Q vary in a complementary fashion across photonic materials. Besides guiding microresonator design and material development in four material platforms, the results help establish performance limits in future photonic integrated systems.

Estrogen-Induced Extracellular Calcium Influx Promotes Endometrial Cancer Progress by Regulating Lysosomal Activity and Mitochondrial ROS.

OBJECTIVE: Calcium is present in serum mainly in filterable and bound forms, and Ca2+ is a major key to modulate signaling pathways that control oncogenesis and oncochannels associated with several types of cancer. However, the biological significance of serum calcium and its related mechanism with estrogen in endometrial cancer (EC) still remains elusive. This study aims to ascertain the relationship between serum calcium and clinicopathology in EC. METHODS: Retrospective assessment of a total of 502 patients diagnosed with EC after surgery in Peking University People's Hospital from 2010 to 2018. Preoperative serum ionized calcium and the albumin corrected calcium was calculated in quartiles for various postoperative clinicopathological characteristics, logistic regression adjusted for potential confounders. Intracellular calcium homeostasis change induced by estrogen was detected by confocal analysis. Downstream pathways were analyzed by transcriptome and proteomics. Mitochondrial Ca2+ and ROS (reactive oxygen species) level was detected by confocal and flow cytometry. Lysosomal morphological and membrane changes were verified by confocal or Western blot assays. RESULTS: High level of albumin-corrected serum calcium was significantly correlated with EC clinicopathological characteristics progression include lymph vascular space invasion, lymph nodes metastasis, myometrial invasion, and cervical invasion. Calcium homeostasis regulated by estrogen in EC cells derived from extracellular calcium influx but not the release of the endoplasmic reticulum. Proteomic and bioinformatic analysis revealed the calcium influx might be involved in the regulation of autophagy and mitochondrial-related pathways. Mechanistic investigation demonstrated that calcium influx acted on the function of mitochondrial ROS and lysosomal activity. CONCLUSION: Our findings revealed that serum calcium level was significantly related to poor outcomes. The extracellular calcium influx induced by estrogen was targeted to mitochondrial ROS and lysosome activity, which should be oriented to improve EC therapeutic strategies.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG ) mimicking hyperglycemia in patientEC+/dia+ . Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of IshikawaHG as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (miceEC+/dia+ ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+ . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+ .

High-performance lasers for fully integrated silicon nitride photonics.

Silicon nitride (SiN) waveguides with ultra-low optical loss enable integrated photonic applications including low noise, narrow linewidth lasers, chip-scale nonlinear photonics, and microwave photonics. Lasers are key components to SiN photonic integrated circuits (PICs), but are difficult to fully integrate with low-index SiN waveguides due to their large mismatch with the high-index III-V gain materials. The recent demonstration of multilayer heterogeneous integration provides a practical solution and enabled the first-generation of lasers fully integrated with SiN waveguides. However, a laser with high device yield and high output power at telecommunication wavelengths, where photonics applications are clustered, is still missing, hindered by large mode transition loss, non-optimized cavity design, and a complicated fabrication process. Here, we report high-performance lasers on SiN with tens of milliwatts output power through the SiN waveguide and sub-kHz fundamental linewidth, addressing all the aforementioned issues. We also show Hertz-level fundamental linewidth lasers are achievable with the developed integration techniques. These lasers, together with high-Q SiN resonators, mark a milestone towards a fully integrated low-noise silicon nitride photonics platform. This laser should find potential applications in LIDAR, microwave photonics and coherent optical communications.

Reaching fiber-laser coherence in integrated photonics.

We self-injection-lock a diode laser to a 1.41 m long, ultra-high Q integrated resonator. The hybrid integrated laser reaches a frequency noise floor of 0.006Hz2/Hz at 4 MHz offset, corresponding to a Lorentzian linewidth below 40 mHz-a record among semiconductor lasers. It also exhibits exceptional stability at low-offset frequencies, with frequency noise of 200Hz2/Hz at 100 Hz offset. Such performance, realized in a system comprised entirely of integrated photonic chips, marks a milestone in the development of integrated photonics; and, for the first time, to the best of our knowledge, exceeds the frequency noise performance of commercially available, high-performance fiber lasers.

A Novel Transcription Factor-Based Prognostic Signature in Endometrial Cancer: Establishment and Validation.

BACKGROUND: Endometrial cancer (EC) is a common malignancy of the female reproductive system worldwide. Increasing evidence has suggested that many transcription factors are aberrantly expressed in various cancers. This study aimed to develop a transcription factor-based prognostic signature for EC. METHODS: Gene expression data and clinical data of EC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression and Multivariate Cox regression analysis was used to construct a prognostic signature. Then, the efficacy of the prognostic signature was validated in a training cohort, testing cohort and then the entire cohort. Correlations between clinical features and the model were also analyzed, and a nomogram based on the multivariate Cox analysis was developed. Furthermore, we verified the effect of a key transcription factor, E2F1, on biological functions of EC in vitro. RESULTS: We developed a nine-transcription factor (MSX1, HOXB9, E2F1, DLX4, BNC2, DLX2, PDX1, POU3F2, and FOXP3) prognostic signature. Compared with those in the low-risk group, patients in the high-risk group had worse clinical outcomes. The area under the curve (AUC) of this prognostic signature for 5-year survival was 0.806 in the training cohort, 0.710 in the testing cohort and 0.761 in the entire cohort. Gene set enrichment analysis (GSEA) revealed a correlation between the prognostic signature and various cancer signaling pathways, and a hub transcription factor regulatory network was constructed. The prognostic signature was confirmed to have independent predictive value. Finally, a nomogram based on the prognostic signature and clinical independent prognostic factors was also established and performed well according to the calibration curves. Further, knockdown of E2F1 inhibited invasion and metastasis of EC cells. CONCLUSION: Our study developed and validated a transcription factor-based prognostic signature that accurately predicts prognosis of EC patients. Moreover, E2F1 may represent a potential target for the treatment of EC.

Low-Frequency Intravesical Electrical Stimulation for the Treatment of Acute Urinary Retention: A Promising Therapeutic Approach.

Acute urinary retention (AUR) is a troublesome urological disease, which causes various lower urinary tract symptoms. However, only few studies explored and evaluated the effective treatments to improve AUR. We aimed to find an effective approach to cure AUR through comparing the efficacy of existing classical low-frequency transcutaneous electrical nerve stimulation (TENS) and novel intravesical electrical stimulation (IVES). A total of 24 AUR female rats were divided into 3 groups as follows: control, TENS, and IVES groups. Rats in the control group had no fake stimulation. Rats in the TENS and IVES groups underwent transcutaneous or intravesical stimulation of a symmetrical biphasic rectangular current pulse with a frequency of 35 Hz, 30 min per day, for seven consecutive days. IVES significantly reduced the actin expression in the submucosal layer but increased its expression in the detrusor layer (p = 0.035, p = 0.001). The neovascularization in the submucosal layer in the IVES group was significantly increased than in the other 2 groups (p = 0.006). Low-frequency IVES performed better than TENS in terms of simultaneously relieving bladder hyperactivity, accelerating epithelial recovery, and strengthening detrusor muscle. IVES may be a promising therapeutic approach for bladder dysfunction, specifically for AUR and overactive bladder in clinical practice.

Dispersive-wave induced noise limits in miniature soliton microwave sources.

Compact, low-noise microwave sources are required throughout a wide range of application areas including frequency metrology, wireless-communications and airborne radar systems. And the photonic generation of microwaves using soliton microcombs offers a path towards integrated, low noise microwave signal sources. In these devices, a so called quiet-point of operation has been shown to reduce microwave frequency noise. Such operation decouples pump frequency noise from the soliton's motion by balancing the Raman self-frequency shift with dispersive-wave recoil. Here, we explore the limit of this noise suppression approach and reveal a fundamental noise mechanism associated with fluctuations of the dispersive wave frequency. At the same time, pump noise reduction by as much as 36 dB is demonstrated. This fundamental noise mechanism is expected to impact microwave noise (and pulse timing jitter) whenever solitons radiate into dispersive waves belonging to different spatial mode families.

Comprehensive Analysis of the Glycolysis-Related Gene Prognostic Signature and Immune Infiltration in Endometrial Cancer.

Glucose metabolic reprogramming and immune imbalance play important roles in the progression of cancers. The purpose of this study is to develop a glycolysis-related prognostic signature for endometrial cancer (EC) and analyze its relationship with immune function. The mRNA expression profiling of the glycolysis-related genes and clinical data of EC patients were downloaded from The Cancer Genome Atlas (TCGA). We identified a glycolysis-related gene prognostic signature for predicting the prognosis of EC by using The Least Absolute Shrinkage and Selection Operator (LASSO) regression and found the patients in the high-risk group had worse survival prognosis. Multivariate Cox regression analysis showed that the gene signature was an independent prognostic factor for EC. The ROC curve confirmed the accuracy of the prognostic signature (AUC = 0.730). Then, we constructed a nomogram to predict the 1-5 years survival rate of EC patients. The association between the gene signature and immune function was analyzed based on the "ESTIMATE" and "CIBERSORT" algorithm, which showed the immune and ESTIMATE scores of patients in the high-risk group were lower, while the low immune and ESTIMATE scores were associated with a worse prognosis of patients. The imbalance of immune cells was also found in the high-risk group. Further, the protein of CDK1, a gene in the signature, was found to be closely related to prognosis of EC and inhibition of CDK1 could inhibit migration and promote apoptosis of EC cells. This study reveals a link between glycolysis-related gene signature and immunity, and provides personalized therapeutic targets for EC.

Dirac solitons in optical microresonators.

Mode-coupling-induced dispersion has been used to engineer microresonators for soliton generation at the edge of the visible band. Here, we show that the optical soliton formed in this way is analogous to optical Bragg solitons and, more generally, to the Dirac soliton in quantum field theory. This optical Dirac soliton is studied theoretically, and a closed-form solution is derived in the corresponding conservative system. Both analytical and numerical solutions show unusual properties, such as polarization twisting and asymmetrical optical spectra. The closed-form solution is also used to study the repetition rate shift in the soliton. An observation of the asymmetrical spectrum is analysed using theory. The properties of Dirac optical solitons in microresonators are important at a fundamental level and provide a road map for soliton microcomb generation in the visible band.

Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer.

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

Greater than one billion Q factor for on-chip microresonators.

High optical quality (Q) factors are critically important in optical microcavities, where performance in applications spanning nonlinear optics to cavity quantum electrodynamics is determined. Here, a record Q factor of over 1.1 billion is demonstrated for on-chip optical resonators. Using silica whispering-gallery resonators on silicon, Q-factor data is measured over wavelengths spanning the C/L bands (100 nm) and for a range of resonator sizes and mode families. A record low sub-milliwatt parametric oscillation threshold is also measured in 9 GHz free-spectral-range devices. The results show the potential for thermal silica on silicon as a resonator material.

Decreased expression of TRPM4 is associated with unfavorable prognosis and aggressive progression of endometrial carcinoma.

Transient Receptor Potential Melastatin 4 (TRPM4) is a nonselective channel conducting monovalent ions and indirectly regulates intracellular Ca2+. Aberrant expression has been reported in a number of cancers. However, the biological function of TRPM4 in endometrial carcinoma (EC) is still unknown. We find that decreased TRPM4 expression is significantly correlated with a poor prognosis, overall survival (OS, P<0.001) and recurrence-free survival (P=0.002) through The Cancer Genome Atlas (TCGA) datasets in mRNA level. Multivariate Cox regression analysis suggests that TRPM4 is an independent prognostic factor for OS in EC patients. In vitro assays show that TRPM4-deletion results in significant promotion of proliferation and migration in EC cells. We then conducted a gene set enrichment analysis (GSEA) and according to the results, the expression of TRPM4 is modulated by estrogen, which is inhibited by ER antagonist. Furthermore, the silencing of TRPM4 causes a decreased p53 and hyper-activation of EMT, PI3K/AKT/mTOR signaling pathway in EC, as demonstrated in vitro. Overall, these results indicate that TRPM4 is clinically useful in predicting EC prognosis and represent a potential candidate as a new therapeutic target.

Increased Serum Calcium Level Promotes the Risk of Lymph Node Metastasis in Endometrial Cancer.

PURPOSE: The early predictive values of diagnostic markers for lymph node metastasis (LNM) in endometrial cancer (EC) are still unclear at present. The purpose of this study is to explore the relationship between serum calcium and LNM in EC. METHODS: We identified all patients with EC who underwent surgery between January 2012 and December 2016. Patient characteristics and various preoperative clinicopathologic data were obtained from medical records and were reviewed retrospectively. These patients were divided into two groups according to the pathology of their lymph node. Logistic regression models analyzed the relationship between the ionized calcium and LNM of EC patients, while adjusting for the potential confounders. RESULTS: A total of 448 patients were assessed. Univariate analysis showed that ionized calcium, CA125 level, tumor grade, peritoneal cytology, FIGO stage, histological type, LVSI, and myometrial invasion were positively correlated with LNM (all P<0.05). The risk of LNM increased with the promotion of serum ionized calcium (P for trend <0.01). Ionized calcium level was significant before and after the adjustment of cofounders (unadjusted: OR=11.9, 95% CI: 4.8-29.6, P< 0.01; model I: OR=11.3, 95% CI: 4.5-28.8, P< 0.01; model II: OR=5.2, 95% CI: 1.6-17.2, P< 0.05). Additionally, the risk of ionized calcium was especially evident in patients whose age was older than 60, BMI<28 kg/m2, grade 3, negative peritoneal cytology and endometrioid endometrial adenocarcinoma. CONCLUSION: Ionized calcium level was highly associated with LNM in EC and acted as a potential biomarker in predicting the risk of LNM in EC.