The current landscape of therapies for hepatocellular carcinoma.

Globally, primary liver cancer is the third leading cause of cancer-related deaths, with approximately 830 000 deaths worldwide in 2020, accounting for 8.3% of total deaths from all cancer types (1). This disease disproportionately affects those in countries with low or medium Human Development Index scores in Eastern Asia, South-Eastern Asia, and Northern and Western Africa (2). Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often develops in the background of chronic liver disease, caused by hepatitis B or C virus, non-alcoholic steatohepatitis (NASH), or other diseases that cause cirrhosis. Prognosis can vary dramatically based on number, size, and location of tumors. Hepatic synthetic dysfunction and performance status (PS) also impact survival. The Barcelona Clinic Liver Cancer (BCLC) staging system best accounts for these variations, providing a reliable prognostic stratification. Therapeutic considerations of this complex disease necessitate a multidisciplinary approach and can range from curative-intent surgical resection, liver transplantation or image-guided ablation to more complex liver-directed therapies like transarterial chemoembolization (TACE) and systemic therapy. Recent advances in the understanding of the tumor biology and microenvironment have brought new advances and approvals for systemic therapeutic agents, often utilizing immunotherapy or VEGF-targeted agents to modulate the immune response. This review will discuss the current landscape in the treatments available for early, intermediate, and advanced stage HCC.

Low-threshold lasing from bound states in the continuum with dielectric metasurfaces.

Bound states in the continuum (BICs) with extremely large quality factors (Q factors) can enhance the light-matter interaction and thus achieve low-threshold lasing. Here, we theoretically propose and experimentally demonstrate the low-threshold lasing at room temperature based on BICs. A threshold of approximately 306.7 W/cm2 (peak intensity) under a 7.5 ns-pulsed optical excitation is presented in an all-dielectric metasurface system consisting of titanium dioxide (TiO2) nanopillars with a dye film. Also, the multimode lasing can be excited by the higher pumping. Our results may find exciting applications in on-chip coherent light sources, filtering, and sensing.

A Phase II Study of Pembrolizumab in Combination with Capecitabine and Oxaliplatin with Molecular Profiling in Patients with Advanced Biliary Tract Carcinoma.

BACKGROUND: We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment. PATIENTS AND METHODS: Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder. RESULTS: Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response. CONCLUSION: Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT03111732).

Lasing action in a strongly coupled silicon nanowire pair.

High-index dielectric nanostructures are of particular interest for nanoscale lasing due to their low absorption losses. However, the relatively weak near-field restricts the isolated dielectric cavities as low-threshold integrated on-chip laser sources. Here, we demonstrate lasing action in a silicon nanowire pair with 32 nm gap coated with dye-doped shell on the silicon-on-insulator platform. It is found that the quality factor Q is dominated by the coupling of the silicon nanowire pair, which depends on the gap size, the nanowire width, and the dye thickness. A lasing peak at the wavelength of 529 nm with FWHM of 0.6 nm is experimentally realized by the Si nanowire pair width, and the corresponding pumping power threshold is ∼34 µW/cm2. The proposed strategy, based on the well-established Si planar process, lays the groundwork for practical integrated nanolasers that have potential applications in photonic circuits.

Autophagy inhibitors alleviate Japanese encephalitis virus-induced cerebral inflammation in mice.

Japanese encephalitis (JE) is a zoonotic epidemic disease caused by Japanese encephalitis virus (JEV), and currently, no medicines are available to treat this disease. Autophagy modulators play an important role in the treatment of tumors, heart disease, and some viral diseases. The aim of this study was to investigate the effects of autophagy modulators on JEV infection and the host response in mice. The experimental mice were grouped as follows: DMEM (control), JEV, JEV+rapamycin (JEV+Rapa), JEV+wortmannin (JEV+Wort), JEV+chloroquine (JEV+CQ), Rapa, Wort, and CQ. The control group was treated with DMEM. The mice in other groups were infected with 105 PFU of JEV, and Rapa, Wort, and CQ were administered 2 h prior to JEV challenge and then administered daily for 10 consecutive days. All mice were monitored for neurological signs and survival. The damage of subcellular structures in the mouse brain was evaluated by transmission electron microscopy. The distribution of virus in the mouse brain was determined by RNAScope staining and immunohistochemical staining. The neuroinflammatory responses in the brain were examined via quantitative real-time PCR, and the signal pathways involved in neuroinflammation were identified by Western blot. The mice in the JEV+Wort and JEV+CQ groups showed milder neurological symptoms, less damage to the mitochondria in the brain tissue, and a higher survival rate than those in the JEV+Rapa and JEV groups. Compared with the JEV+Rapa and JEV groups, the distribution of JEV in the brain of mice in the JEV+Wort and JEV+CQ groups was lower, and the inflammatory response was weaker. No significant difference was observed in the expression of the PI3K/AKT/NF-κB pathway in mouse brain among the different groups. Our study suggests that the autophagy inhibitors Wort and CQ reduce JEV infection and weaken the inflammatory response, which does not depend on the PI3K/AKT/NF-κB pathway in mouse brain.

Direct experimental evidence for free-space fractional optical vortex transmutation.

The emergence of vortex transmutation has opened new ways for vorticity modulation of optical vortices. Although several approaches have been proposed to realize vortex transmutation, fractional optical vortex (FOV) transmutation remains elusive owing to a lack of effective generation and detection methods. Here we report quantitative experimental evidence for a free-space FOV transmutation rule. The key idea is to combine the advantages of a single optical element, termed as fractional spiral polygonal lenses (FSPLs), with a deep learning approach. The desired wavefront is simultaneously generated and manipulated at the focal plane of the FSPL, and the fractional output vorticity is measured by analyzing a single far-field diffraction pattern. Especially, a deep learning scheme using a Bayesian optimization method is developed for output vorticity prediction with a data recovery rate up to 98.2%. The average error of recognized fractional orbital angular momentum modes is as small as 0.02. We clearly observe the intriguing phenomenon that the central vorticity of FOV is changed following a modulo-n transmutation rule in free space. Our results have important implications for fundamental understanding of FOV systems in free space, and offer a technological foundation for potential applications such as quantum information processing and particle manipulation and transportation.

Verteporfin synergizes the efficacy of anti-PD-1 in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is one of the primary hepatobiliary malignant neoplasms with only 10% of 5-year survival rate. Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA. The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis. This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1 (PD-1) in CCA mouse model. METHODS: We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro, including both intrahepatic CCA and extrahepatic CCA cells. We examined the in vitro effect of verteporfin on cell proliferation, apoptosis, and stemness. We evaluated the in vivo efficacy of verteporfin, anti-PD-1, and a combination of both in subcutaneous CCA mouse model. RESULTS: Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion. Nevertheless, verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation, decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers (all P < 0.05). The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone. CONCLUSIONS: Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.

Optimization and Validation of Dosage Regimen for Ceftiofur against Pasteurella multocida in Swine by Physiological Based Pharmacokinetic-Pharmacodynamic Model.

Model informed drug development is a valuable tool for drug development and clinical application due to its ability to integrate variability and uncertainty of data. This study aimed to determine an optimal dosage of ceftiofur against P. multocida by ex vivo pharmacokinetic/pharmacodynamic (PK/PD) model and validate the dosage regimens by Physiological based Pharmacokinetic-Pharmacodynamic (PBPK/PD) model. The pharmacokinetic profiles of ceftiofur both in plasma and bronchoalveolar lavage fluid (BALF) are determined. PD performance of ceftiofur against P. multocida was investigated. By establishing PK/PD model, PK/PD parameters and doses were determined. PBPK model and PBPK/PD model were developed to validate the dosage efficacy. The PK/PD parameters, AUC0-24 h/MIC, for bacteriostatic action, bactericidal action and elimination were determined as 44.02, 89.40, and 119.90 h and the corresponding dosages were determined as 0.22, 0.46, and 0.64 mg/kg, respectively. AUC24 h/MIC and AUC 72 h/MIC are simulated by PBPK model, compared with the PK/PD parameters, the therapeutic effect can reach probability of target attainment (PTA) of 90%. The time-courses of bacterial growth were predicted by the PBPK/PD model, which indicated the dosage of 0.46 mg/kg body weight could inhibit the bacterial growth and perform good bactericidal effect.

Toward generalized forked gratings via deep learning.

We extend the concept of forked gratings to include the ability of high diffraction orders suppression of a single pair of vortex beams. The main idea is to appropriately distribute rectangular holes over each open space of a conventional forked grating. We further introduce the deep convolutional neural network algorithm to assist us in reconstructing and obtaining the optimal parameter of generalized forked grating. The recovery rate of our neural network is 92.3%. The 3rd order diffracted light intensity can be as low as 0.067% of the desired 1st order diffracted light intensity. The verification experiment results are also presented, confirming the helical phase structures with multitopological charges. The high diffraction orders suppression properties of the generalized forked gratings hold promise for broad applications, such as imaging, microscopy, and fundamental physics observation.

Superposition of two fractional optical vortices and the orbital angular momentum measurement by a deep-learning method.

We propose a single diffractive optical element called the composite fractional spiral zone plates to generate superimposed fractional optical vortices. Such an element is composed of two fractional spiral zone plates (FSZPs) through logical AND operation, and the produced beam carries superimposed fractional orbital angular momentum (OAM) states. By controlling the topological charge of the superimposed FSZPs, denoted by l1 and l2, one can flexibly obtain the desired superimposed fractional OAM modes of the generated beam. Especially, a deep-learning model with a densely connected convolutional neural network architecture is utilized to accurately predict the superimposed fractional OAM states of SFOVs. The average recovery rate of the superimposed fractional OAM states based on the training model is over 99%, and the average error is as small as 0.02. This work may pave the way for wide-ranging applications such as smart OAM communication, particle transmission, and even quantum entanglement.

Comprehensive characterization of TSV etching performance with phase-contrast X-ray microtomography.

Comprehensive evaluation of through-silicon via (TSV) reliability often requires deterministic and 3D descriptions of local morphological and statistical features of via formation with the Bosch process. Here, a highly sensitive phase-contrast X-ray microtomography approach is presented based on recorrection of abnormal projections, which provides comprehensive and quantitative characterization of TSV etching performance. The key idea is to replace the abnormal projections at specific angles in principles of linear interpolation of neighboring projections, and to distinguish the interface between silicon and air by using phase-retrieval algorithms. It is demonstrated that such a scheme achieves high accuracy in obtaining the etch profile based on the 3D microstructure of the vias, including diameter, bottom curvature radius, depth and sidewall angle. More importantly, the 3D profile error of the via sidewall and the consistency of parameters among all the vias are achieved and analyzed statistically. The datasets in the results and the 3D microstructure can be applied directly to a reference and model for further finite element analysis. This method is general and has potentially broad applications in 3D integrated circuits.

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer.

Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8+ T cells. T-cell receptor (TCR)ß screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.

Bistable active spectral tuning of one-dimensional nanophotonic crystal by phase change.

Active spectral tuning of nanophotonic devices offers many fascinating prospects for the realization of novel optical function. Here, switchable spectral response is enabled by the architecture of one-dimensional (1D) photonic crystal (PC) integrated with phase change material of the germanium antimony telluride (GST). Active and precise tuning of the bistable passband and central resonant frequency is demonstrated in the 1D PC composed of alternate SiN and GST nanofilms. An analytical model is derived to specify the tunable spectral features, including the band gap and resonant frequencies. Both the measured and calculated results show distinct red shifts of passband and the resonant minima (or maxima), well confirming theoretical predictions. This work demonstrates a route to construct active photonic devices with the electrically or thermally tunable spectra via 1D PC and potentially extends diverse applications based on the PC platform.

Proposed a self-absorption internal standard model to detect element concentrations of complex constituent material with a single emission line of element in laser plasmas.

Laser induced plasmas (LIPs) method is a highly regarded approach to evaluate the chemical composition of materials. But the strong self-absorption of the radiation seriously affects its accuracy. Meanwhile, the model based on self-absorption phenomenon makes its application very difficult. In this work, a self-absorption internal standard (SAIS) model is proposed for detection of the multi-element concentrations of complex constituent material with a single emission line of the element in laser plasmas. A typical LIPs experiment system is set up to generate plasmas, and the soil is selected as a test sample. The average electron temperature (0.975 eV) and electron density (1.44×1018 cm-3) are determined by the Boltzmann plot and emission lines Stark broadening, respectively. The plasmas are diagnosed as in local thermodynamic equilibrium condition. The emission lines selected to calculate the concentration of sample contain a wide set of kt values (0.575×10-30∼37.2×10-30 m3). Then, the concentrations of some elements are calculated by the model using single emission line of each element. It is found that the concentrations of the five elements (Ti, Fe, Mg, Al, Si) calculated by SAIS model are relatively consistent with the results of the traditional chemical testing methods. This indicated that the SAIS model is an effective and neat method for multi-element concentrations detection of complex constituent materials.

Binary sinusoidal single-order multilayer gratings for tender x-ray region.

We propose and theoretically analyze a single-order diffractive optical element, termed binary sinusoidal multilayer grating (BSMG), to effectively suppress high-order diffractions while retaining high diffraction efficiency in the first order. The key idea is to integrate sinusoidal-shaped microstructures with high-reflectivity multilayer coatings. The dependence of the high-order diffraction property on the microstructure shape and multilayer coatings is investigated. Theoretical calculation reveals that the second-, third-, fourth-, and fifth-order diffraction efficiencies are as low as 0.01%. Strikingly, we show that first-order relative diffraction efficiency (the ratio between the intensity of the first diffraction order versus that of the reflected light) as high as 97.7% can be achieved. Thus, the proposed BSMG should be highly advantageous in future development and application of tender x-ray spectroscopy.

Proliferative ability and accumulation of cancer stem cells in oral submucous fibrosis epithelium.

OBJECTIVES: The driving force of the malignant transformation of epithelial cells during oral submucous fibrosis (OSF) is an unsettled debate. We hypothesized that the expression and accumulation of cancer stem cells (CSCs) are accompanied by epithelial atrophy in OSF. MATERIALS AND METHODS: The expression levels of Ki67 (proliferation marker), SOX2, and Bmi1 (CSC marker) in the epithelium during the early, middle, and late stages of OSF were measured by immunohistochemistry. At the same time, we focused on the expression of three proteins in OSF patients with benign hyperkeratosis and epithelial dysplasia. RESULTS: The clinical cohort study showed upregulated expression of the proliferation-associated protein Ki67 in atrophic epithelium in patients with OSF. The expression levels of SOX2 and Bmi1 showed an increasing trend in the progression of OSF. Ki67, SOX2, and Bmi1 were highly expressed in OSF tissues with dysplasia. Moreover, the three proteins were located at the epithelial and mesenchymal junctions, and their expression showed a positive correlation with each other. CONCLUSION: The results suggest that CSC accumulation could be accompanied by epithelial atrophy during OSF, which may be responsible for the driving forces for OSF carcinogenesis.

The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers.

The proliferation and metastasis ability of tumors are mediate by the "mutual dialogue" between cells in the tumor microenvironment (TME). Extracellular vesicles (EVs), mainly exosomes and microvesicles, play an important role in achieving intercellular substance transport and information transfer in the TME. Initially considered "garbage dumpsters" and later referred to as "signal boxes", EVs carry "cargo" (proteins, lipids, or nucleic acids) that can redirect the function of a recipient cell. Currently, the molecular mechanisms and clinical applications of EVs in head and neck cancers (HNCs) are still at an early stage and need to be further investigate. In this review, we provide insight into the TME of HNCs, classifying and summarizing EVs derived from different cell types and illuminating their complex signaling networks involved in mediating tumor proliferation, invasion and metastasis, vascular angiogenesis and cancer drug resistance. In addition, we highlight the application of EVs in HNCs, underlining the special pathological and physiological environment of HNCs. The application of tumor heterogeneous EVs in saliva and circulating blood diagnostics will provide a new perspective for the early screening, real-time monitoring and prognostic risk assessment of HNCs. Given the concept of precise and individual therapy, nanostructured EVs are equipped with superior characteristics of biocompatibility, low immunogenicity, loadability and modification ability, making these molecules one of the new strategies for HNCs treatment.

The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma.

BACKGROUND: Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%. METHODS: Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients. RESULTS: Tremelimumab therapy increased CD4+-HLA-DR+, CD4+PD-1+, CD8+HLA-DR+, CD8+PD-1+, CD4+ICOS+ and CD8+ICOS+ T cells in the peripheral blood of the treated patients. Patients with higher CD4+PD1+ cell frequency at baseline were more likely to respond to tremelimumab therapy. PD-1 expression was increased on alpha fetal protein (AFP) and survivin-specific CD8 T cells upon tremelimumab treatment. An increase of tumor infiltrating CD3+ T cells were also seen in these patients. Immunosequencing of longitudinal PBMC showed that one cycle of tremelimumab significantly decreased peripheral clonality, while no additional effects were seen after loco-regional therapy. CONCLUSION: In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.

Tailoring focused optical vortices by using spiral forked plates.

We propose and experimentally demonstrate a single optical element, termed as spiral forked plates (SFPs), to simultaneously generate two tightly focused optical vortices (OVs). The key idea is to combine a spiral zone plate (SZP) and a forked grating (FG) through a logic XOR operation. Both theoretical and experimental results demonstrate that SFPs not only can completely suppress the undesirable zeroth (central) order diffraction, but also can further manipulate the topological charges (TCs) of the two resultant focused OVs by varying the TCs of the SZP and FG, following the so-called TC transformation rule. Thus, SFPs show promising potential for advancing the shrinking and integrating applications of orbital angular momentum superpositions.

The mechanism and function of circular RNAs in human diseases.

Circular RNAs (circRNAs) are a recently discovered form of RNA. Initially, circRNAs were believed to result from errors during the process of gene transcription. However, after further investigation, scientists suggested that circRNAs are of great biological significance. CircRNAs show stability, conservation, abundance, and tissue and stage specificity. They can also function as miRNA sponges, regulate gene expression, and interact with proteins to affect cell behavior. Emerging evidence has also demonstrated that circRNAs participate or show abnormal expression in diseases, including central nervous system diseases, cardiovascular diseases and cancers, indicating their marked potential in the prediction and prognosis of diseases and clinical treatment.