Interdisciplinary analysis and optimization of digital photonic devices for meta-photonics.

With the continuous integration and development of AI and natural sciences, we have been diligently exploring a computational analysis framework for digital photonic devices. Here, We have overcome the challenge of limited datasets through the use of Generative Adversarial Network networks and transfer learning, providing AI feedback that aligns with human knowledge systems. Furthermore, we have introduced knowledge from disciplines such as image denoising, multi-agent modeling of Physarum polycephalum, percolation theory, wave function collapse algorithms, and others to analyze this new design system. It represents an accomplishment unattainable within the framework of classical photonics theory and significantly improves the performance of the designed devices. Notably, we present theoretical analyses for the drastic changes in device performance and the enhancement of device robustness, which have not been reported in previous research. The proposed concept of meta-photonics transcends the conventional boundaries of disciplinary silos, demonstrating the transformative potential of interdisciplinary fusion.

TLR3 activation enhances abscopal effect of radiotherapy in HCC by promoting tumor ferroptosis.

Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8+ T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.

Proteomic Analysis Identifies GSN as a Noninvasive Circulating Serum Biomarker for Predicting Early Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is susceptible to early recurrence, but it lacks effective predictive biomarkers. In this study, we retrospectively selected 179 individuals as a discovery cohort (126 HCC patients and 53 liver cirrhosis (LC) patients) for screening candidate serum biomarkers of early recurrence based on data independent acquisition-mass spectrometry strategy. And then, the candidate biomarkers were validated in an additional independent cohort with 192 individuals (142 HCC patients and 50 LC patients) using parallel reaction monitoring targeted quantitative techniques (PXD047852). Eventually, we validated that gelsolin (GSN) concentrations were significantly lower in HCC than in LC (p < 0.0001), patients with low GSN concentrations had a poor prognosis (p < 0.0001), and GSN concentrations were significantly lower in early recurrence HCC than in late recurrence HCC (p < 0.0001). These trends were also observed in alpha-fetoprotein (AFP)-negative HCC patients. The area under the curve of machine-learning-based predictive model (GSN and microvascular invasion) for predicting early recurrence risk reached 0.803 (95% confidence interval (CI): 0.786-0.820) and maintained the same efficacy in AFP-negative patients. In conclusion, GSN is a novel serum biomarker for early recurrence of HCC. The model could provide timely warning to HCC patients at high risk of recurrence.

Investigation of unidirectional coupling of dipole emitters in valley photonic heterostructure waveguides.

Photonic heterostructure has recently become a promising platform to study topological photonics with the introduction of mode width degree of freedom (DOF). However, there is still a lack of comprehensive analysis on the coupling of dipole emitters in photonic heterostructures, which constrains the development of on-chip quantum optics based on chiral dipole sources. We systematically analyze the unidirectional coupling mechanism between dipole emitters and valley photonic heterostructure waveguides (VPHWs). With the eigenmode calculations and full-wave simulations, the Stokes parameters are obtained to compare the coupling performance of two types of valley-interface VPHWs. Simulation results show that compared to the zigzag interface with inversion symmetry, the strategy of bearded interface with glide symmetry is easier to realize high-efficiency coupling. By adjusting the position and chirality of dipole emitters in VPHWs, the transmission of light reverses with guided modes coupled to different directions. Furthermore, a topological beam modulator is realized based on VPHWs, which maintains the robustness to large-area potential barriers and sharp corners. Our work supplies a powerful guide for chiral light-matter interaction, which is expected to be applied to increasingly compact and efficient on-chip optical platforms in the future.

RNA Methyltransferase FTSJ3 Regulates the Type I Interferon Pathway to Promote Hepatocellular Carcinoma Immune Evasion.

Immunotherapies such as immune checkpoint blockade have achieved remarkable success in treating cancer. Unfortunately, response rates have been limited in multiple cancers including hepatocellular carcinoma (HCC). The critical function of epigenetics in tumor immune evasion and antitumor immunity supports harnessing epigenetic regulators as a potential strategy to enhance the efficacy of immunotherapy. Here, we discovered a tumor-promoting function of FTSJ3, an RNA 2'-O-methyltransferase, in HCC by suppressing antitumor immune responses. FTSJ3 was upregulated in hepatocellular carcinoma, and high FTSJ3 expression correlated with reduced patient survival. Deletion of FTSJ3 blocked HCC growth and induced robust antitumor immune responses. Mechanistically, FTSJ3 suppressed double-stranded RNA (dsRNA)-induced IFNß signaling in a 2'-O-methyltransferase manner. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued the in vivo tumor growth defect caused by FTSJ3 deficiency, indicating that FTSJ3 deletion suppresses tumor growth by activating the RNA sensor-mediated type I IFN pathway. Furthermore, FTSJ3 deletion significantly enhanced the efficacy of programmed cell death protein 1 (PD-1) immune checkpoint blockade. The combination of FTSJ3 deficiency and anti-PD-1 antibody treatment effectively eradicated tumors and increased the survival time. In conclusion, this study reveals an epigenetic mechanism of tumor immune evasion and, importantly, suggests FTSJ3-targeting therapies as potential approach to overcome immunotherapy resistance in patients with HCC. SIGNIFICANCE: Hepatocellular carcinoma cells use 2'-O-methylation catalyzed by FTSJ3 for immune evasion by suppressing abnormal dsRNA-mediated type I IFN responses, providing a potential target to activate antitumor immunity and enhance immunotherapy efficacy.

Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.

Patients with hepatocellular carcinoma (HCC) at the same clinical stage can have extremely different prognoses, and molecular subtyping provides an opportunity for individualized precision treatment. In this study, genomic, transcriptomic, proteomic, and phosphoproteomic profiling of primary tumor tissues and paired para-tumor tissues from HCC patients (N = 160) are integrated. Proteomic profiling identifies three HCC subtypes with different clinical prognosis, which are validated in three publicly available external validation sets. A simplified panel of nine proteins associated with metabolic reprogramming is further identified as a potential subtype-specific biomarker for clinical application. Multi-omics analysis further reveals that three proteomic subtypes have significant differences in genetic alterations, microenvironment dysregulation, kinase-substrate regulatory networks, and therapeutic responses. Patient-derived cell-based drug tests (N = 26) show personalized responses for sorafenib in three proteomic subtypes, which can be predicted by a machine-learning response prediction model. Overall, this study provides a valuable resource for better understanding of HCC subtypes for precision clinical therapy.

An all-silicon design of a high-efficiency broadband transmissive terahertz polarization convertor.

Polarization, a fundamental behavior of electromagnetic waves, holds immense potential across diverse domains such as environmental monitoring, biomedicine, and ocean exploration. However, achieving efficient modulation of terahertz waves with wide operational bandwidth poses significant challenges. Here, we introduce an all-silicon polarization converter designed specifically to operate in the terahertz range of the electromagnetic spectrum. Simulation results demonstrate that the average conversion efficiency of cross-linear waves exceeds 80% across a wide frequency range spanning from 1.00 to 2.32 THz, with the highest conversion efficiency peaking at an impressive 99.97%. Additionally, our proposed structure facilitates linear-to-circular polarization conversion with an ellipticity of 1 at 0.85 THz. Furthermore, by rotating the cross-shaped microstructure, active control over arbitrary polarization states can be achieved. To summarize, the proposed structure offers remarkable flexibility and ease of integration, providing a reliable and practical solution for achieving broadband and efficient polarization conversion of terahertz waves.

Proteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma.

Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based discovery-verification-validation proteomics workflow to explore serum proteomic biomarkers for HCC early diagnosis in 1002 individuals. Machine learning model determined as P4 panel (HABP2, CD163, AFP and PIVKA-II) clearly distinguish HCC from liver cirrhosis (LC, AUC 0.979, sensitivity 0.925, specificity 0.915) and healthy individuals (HC, AUC 0.992, sensitivity 0.975, specificity 1.000) in an independent validation cohort, outperforming existing clinical prediction strategies. Furthermore, the P4 panel can accurately predict LC to HCC conversion (AUC 0.890, sensitivity 0.909, specificity 0.877) with predicting HCC at a median of 11.4 months prior to imaging in prospective external validation cohorts (No.: Keshen 2018_005_02 and NCT03588442). These results suggest that proteomics-driven serum biomarker discovery provides a valuable reference for the liquid biopsy, and has great potential to improve early diagnosis of HCC.

Terahertz narrowband filter metasurfaces based on bound states in the continuum.

The electromagnetically induced transparency (EIT) effect realized by metasurfaces have potential for narrowband filtering due to their narrow bandwidth. In optics, bound states in the continuum (BIC) can produce strong localized resonances, which means that light can be trapped and stored for long periods of time to produce very high Q-factors. This has potential applications in designing highly efficient sensors and narrow bandpass filters. Here, we present two metal-flexible dielectric metasurfaces consisting of copper structures and polyimide substrates. Quasi BICs are obtained by breaking C2 symmetry of the metal structures. Resonance-captured quasi-BICs with ultra-high q-factor resonances satisfy the dark modes required to realize the EIT and couple to the bright modes in the structure to achieve narrowband filtering. The peak transmission rates are around 0.9 at 0.29 THz-0.32 THz and 0.23 THz-0.27 THz, respectively. Our results have practical implications for the realization of low-frequency terahertz communications.

The relationship between activity level and cognitive function in Chinese community-dwelling elderly.

To study the relationship between daily activity level and cognitive function in community-dwelling elderly. We collected demographic features, cognitive function, activity level and self-rating depression scale scores in 53 community-dwelling olderly aged 60 years or above. The activity level and moderate-to-vigorous physical activity (MVPA) time were assessed by using the accelerometer for 7 consecutive days. We compared activity level, MVPA time and depression scores between cognitive impaired and normal groups. Cognitive functions were compared in groups with different MVPA level, and the correlation between cognitive function and MVPA time was analysed. Of the 53 subjects, 27 had varying degrees of cognitive impairment. Individuals with cognitive impairment shown significantly shorter MVPA time and higher depression score compared to the cognitive normal group (P < 0.05). After controlling for confounding factors (age, BMI), MVPA time was associated with cognitive function (r = 0.358, P = 0.009). The memory factor score correlated with MVPA time (r = 0.357, P = 0.012) and mean activity level (r = 0.287, P = 0.046). Moderate-to-vigorous physical activity in the elderly was positively related to their cognitive function. Strengthening daily activities may beneficial for the elderly to maintain better cognitive function.

Multifunctional terahertz metasurfaces for polarization transformation and wavefront manipulation.

Conventionally, the realization of polarization transformation and wavefront manipulation in metasurfaces relies on the Pancharatnam-Berry (PB) phase together with the dynamic phase. However, the reported polarization transformation and wavefront manipulation were limited to spin-dependent wavefront manipulation for circular polarization (CP). To obtain more abundant functions, we propose a novel technology that relies on the dynamic phase with a spatial interleaving unit arrangement. With the functions of a quarter wave plate, the metasurfaces we designed can achieve multiple wavefront manipulations which are not only for the spin polarization transformation but also for the linear polarization transformation. Specifically, we design a bifocal metasurface, which can focus on one circularly polarized component as a point and spin-opposite component as a vortex under the linearly polarized (LP) incidence. With the further adjustment of the unit arrangement, the left-hand circularly polarized (LCP) and right-hand circularly polarized (RCP) components under the LP incidence can be refocused on the same point and then composited, resulting in a new LP exit wave. Furthermore, we prove theoretically that the desired x-LP component and y-LP component under the arbitrary CP incidence can also be manipulated independently. We believe that the versatility of this method will provide a novel platform for the development of terahertz integrated photonics.

Growing Human Hepatocellular Tumors Undergo a Global Metabolic Reprogramming.

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed by the environment of the growing tumor. In less vascularized regions of tumor, cancer cells experience hypoxia and nutrient starvation. Here, we show that HCC undergoes a global metabolic reprogramming during tumor growth. A combined proteomics and metabolomics analysis of paired peritumoral and tumor tissues from 200 HCC patients revealed liver-specific metabolic reprogramming and metabolic alterations with increasing tumor sizes. Several proteins and metabolites associated with glycolysis, the tricarboxylic acid cycle and pyrimidine synthesis were found to be differentially regulated in serum, tumor and peritumoral tissue with increased tumor sizes. Several prognostic metabolite biomarkers involved in HCC metabolic reprogramming were identified and integrated with clinical and pathological data. We built and validated this combined model to discriminate against patients with different recurrence risks. An integrated and comprehensive metabolomic analysis of HCC is provided by our present work. Metabolomic alterations associated with the advanced stage of the disease and poor clinical outcomes, were revealed. Targeting cancer metabolism may deliver effective therapies for HCC.

Quantitative Secretome Analysis Reveals Clinical Values of Carbonic Anhydrase II in Hepatocellular Carcinoma.

Early detection and intervention are key strategies to reduce mortality, increase long-term survival, and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomic strategy was used to study the secretomes in conditioned media from HCC cancerous tissues, surrounding noncancerous tissues, and distal noncancerous tissues to identify diagnostic and prognostic biomarkers for HCC. In total, 22 and 49 dysregulated secretory proteins were identified in the cancerous and surrounding noncancerous tissues, respectively, compared with the distal noncancerous tissues. Among these proteins, carbonic anhydrase II (CA2) was identified to be significantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients compared with that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after radical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence and overall survival. Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition pathway. Taken together, this study identified a novel biomarker for HCC diagnosis and prognosis, and provided a valuable resource of HCC secretome for investigating serological biomarkers.

Proteomic analyses reveal divergent ubiquitylation patterns in hepatocellula carcinoma cell lines with different metastasis potential.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours, metastasis and recurrence remain the primary reasons for poor prognosis. Ubiquitination serves as a degradation mechanism of proteins, but it is involved in additional cellular processes including metastasis. Here, by using label-free quantification, double-glycine (di-Gly) antibody affinity purification and high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS), we investigated quantitative proteome, ubiquitylome, and the crosstalk between the two datasets in HCC cell lines with different metastasis potential to identify biomarkers associated with HCC metastasis. In total, 83 ubiquitinated proteins significantly and steadily changed their abundance according to their metastatic potential, and the participated biological processes of these ubiquitinated proteins were tightly associated with tumour metastasis. Further signaling pathway analysis revealed that the ribosome and proteasome were significantly over-activated in the highly metastatic cells. Furthermore, we analyzed the crosstalk between the whole proteome and the ubiquitylome, and further discussed the mechanism that how ubiquitination events affect HCC metastasis. Eventually, the ubiquitination of Ku80 was validated to be significantly down-regulated in the high-metastatic cells comparing with the low-metastatic cells. We believe that these findings will help us better understand the underlying molecular mechanisms of the metastasis of HCC. SIGNIFICANCE: In this manuscript, we used label free based proteomics combined with diglycine antibody (di-Gly) affinity purification approach to identify biomarkers associated with HCC recurrence/metastasis in in a serial HCC cell lines with increasing invasion and metastasis potential. And then, we analyzed the crosstalk between the whole proteome and the ubiquitylome. Eventually, the ubiquitination of Ku80 was confirm to be closely associated with invasion and migration of HCC cells. As far as we know, this is the first time to use quantitative proteomic approach to study the ubiquitylomics in HCC cell lines with increasing metastasis ability.

Death-associated protein kinase 1 suppresses hepatocellular carcinoma cell migration and invasion by upregulation of DEAD-box helicase 20.

Death-associated protein kinase 1 (DAPK) is a calcium/calmodulin kinase that plays a vital role as a suppressor gene in various cancers. Yet its role and target gene independent of p53 is still unknown in hepatocellular carcinoma (HCC). In this study, we discovered that DAPK suppressed HCC cell migration and invasion instead of proliferation or colony formation. Using a proteomics approach, we identified DEAD-box helicase 20 (DDX20) as an important downstream target of DAPK in HCC cells and critical for DAPK-mediated inhibition of HCC cell migration and invasion. Using integrin inhibitor RGD and GTPase activity assays, we discovered that DDX20 suppressed HCC cell migration and invasion through the CDC42-integrin pathway, which was previously reported as an important downstream pathway of DAPK in cancer. Further research using cycloheximide found that DAPK attenuates the proteasomal degradation of DDX20 protein, which is dependent on the kinase activity of DAPK. Our results shed light on new functions and regulation for both DAPK and DDX20 in carcinogenesis and identifies new potential therapeutic targets for HCC.

4E-BP1Thr46 Phosphorylation Association with Poor Prognosis in Quantitative Phosphoproteomics of Portal Vein Tumor Thrombus Revealed that 4E-BP1Thr46 Phosphorylation is Associated with Poor Prognosis in HCC.

PURPOSE: Early formation of portal vein tumor thrombosis (PVTT) is a key characteristic of hepatocellular carcinoma (HCC) metastasis, but to date, the aetiology of PVTT in HCC metastasis is largely unknown. We aim to find highly sensitive and specific biomarkers for the prediction of HCC prognosis. PATIENTS AND METHODS: We used isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative phosphoproteomics approach to investigate the molecular signatures of the HCC with PVTT in primary HCC tissues, surrounding non-cancerous tissues and PVTT tissues. The different proteome profiles in three groups were investigated and might reveal different underlying molecular mechanisms. RESULTS: In total, we identified 1745 phosphoproteins with 2724 phosphopeptides and 4594 phosphorylation sites in three groups. Among these phosphoproteins, 80 phosphoproteins were dysregulated in PVTT/Pan group, 51 phosphoproteins were dysregulated in HCC/Pan group, and 10 phosphoproteins were dysregulated in PVTT/HCC group. Furthermore, the phosphorylation of 4E-BP1 was elevated in HCC tissues and PVTT tissues in comparison with surrounding non-cancerous tissues,  and the elevated fold change of phosphorylation level was higher than that in expression level of 4E-BP1. The further IHC analysis in acohort of 20 HCC tissues showed that the phosphorylation of 4E-BP1 on Thr46 might be closely related to HCC prognosis. CONCLUSION: The high phosphorylation level of 4E-BP1Thr46 might serve as a biomarker for the diagnosis of early recurrence and metastasis of HCC.

Moesin facilitates metastasis of hepatocellular carcinoma cells by improving invadopodia formation and activating ß-catenin/MMP9 axis.

Moesin has been proved to be implicated in invasiveness and metastasis in many other cancers, but unclear in HCC. Thus, this study was performed to investigate the clinical significance of moesin and its biological functions in HCC. The results showed that moesin was significantly up-regulated in HCC tissues and was an independent prognostic factor for predicting the recurrence of HCC patients, postoperatively. Furthermore, we also demonstrated that moesin promoted the migration and invasion of HCC cells in vitro and in vivo. And the mechanism studies indicated that moesin overexpression increased the formation of invadopodia and improved the activation of ß-catenin/MMP9 axis. Taken together, our findings revealed that moesin acted as an important onco-protein participating in the metastasis of HCC.

Ku80 negatively regulates the expression of OCT4 via competitive binding to SALL4 and promoting lysosomal degradation of OCT4.

SALL4 and OCT4, along with other pluripotency-associated transcription factors, play critical roles in maintaining embryonic stem cell pluripotency and self-renewal. Ku80 is a component of the protein complex called DNA-dependent protein kinase, which mainly involved in DNA double-strand break repair. In this study, we show evidence that Ku80 physically interacted with SALL4. The interaction competitively disrupts the SALL4-OCT4 complex and result in OCT4 lysosomal degradation. Finally, Ku80 inhibits self-renewal and metastasis of hepatocellular carcinoma cells through breaking the SALL4-OCT4 interactions and down-regulating the expression of OCT4. Our study reveal novel function of Ku80 in stemness maintaining of cancer stem cells via its interaction with SALL4 and highlight the double-sidedness of Ku80 as an anti-cancer target.

Characteristics and outcomes of Ludwig's angina in patients admitted to the intensive care unit: A 6-year retrospective study of 29 patients.

BACKGROUND/PURPOSE: Ludwig's angina (LA) still presents regularly and various characteristics are documented, but patients admitted to the Intensive Care Unit (ICU) has not been studied. The purpose of this study was to investigate the clinical characteristics and outcomes of patients with LA who were admitted to ICU. MATERIALS AND METHODS: We retrospectively reviewed all 29 patients with LA who were admitted to the ICU of a university hospital from January 2013 to October 2018. Results were evaluated via descriptive analysis. The Log-Rank test was used to analyze the hospital/ICU length of stay (LOS). RESULTS: The male: female ratio was 2.63:1. Mean age was 53.41 ±â€¯16.57 years (range 8-78 years). Concomitant conditions comprised diabetes mellitus in 10 patients (34.48%), and hypertension in six (20.69%). The main reason for ICU admission was surgical (44.83%). The mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores were 13.52 ±â€¯3.18 and 3.83 ±â€¯2.89, respectively. Twenty-eight patients (96.55%) received respiratory support. Sixteen patients (55.17%) had positive bacterial culture results. Fourteen bacterial strains were detected, most of which were gram-positive (72.72%). Mean LOS was 6.89 ±â€¯14.39 days (range 0.5-73 days), and 24.79 ±â€¯16 days in the hospital. The ICU mortality rate was 10.34%. Compared with LA patients without descending necrotizing mediastinitis (DNM), those with DNM had longer ICU and hospital LOS. The laboratory investigations were higher. CONCLUSION: LA patients in ICU were predominantly male, with a wide range age, high incidence of complications, long hospital LOS.

Terahertz metamaterial beam splitters based on untraditional coding scheme.

Terahertz waves have attracted considerable research interest in recent years because of their potential applications in diverse fields. As an important device to control terahertz waves, beam splitters with greater flexibility and higher degrees of freedom are highly desirable. In order to obtain higher degrees of freedom in beam splitting, 2-bit or higher-bit coding elements are usually introduced into metamaterial beam splitters based on the coding theory. In this work, a new "offset" coding scheme using only the 1-bit coding elements of "0" and "1" is presented, and the period of coding for beam splitting can be a non-integer multiple of the length of a single unit rather than only its integer multiples. Therefore, more beam-splitting degrees of freedom can be obtained, and the design strategy is experimentally verified. We believe that the new coding scheme will also be of significance in radar cross section reduction and flexible wave control.