VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation.

BACKGROUND: Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive. METHODS: Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC. FINDINGS: Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways. INTERPRETATION: Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment. FUNDING: This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).

Integrated Reconfigurable Photon-Pair Source Based on High-Q Nonlinear Chalcogenide Glass Microring Resonators.

Chalcogenide glasses (ChGs) have recently emerged as enabling materials for building reconfigurable nanophotonic devices by employing their refractive index changes associated with photosensitive effects. In particular, the availability of low-loss thin-film ChGs and the realization of high-Q microresonators provide exciting opportunities for integrated photonics. So far, the ChG photonic devices are predominately operated in the classical optics regime. In this work, we present the realization on-chip bright photon-pair quantum light sources via spontaneous four-wave mixing in a high-Q microring resonator fabricated on the newly developed ChG Ge25Sb10S65 platform. The emission wavelength of the photon-pair source can be continuously tuned across a double-free spectral range in a reconfigurable manner. Our work serves as a starting point to fully unleash the potential of exploiting ChGs for developing reconfigurable integrated quantum photonic devices.

Single-Cell Transcriptomics Reveals Immune Reconstitution in Patients with R/R T-ALL/LBL Treated with Donor-Derived CD7 CAR-T Therapy.

PURPOSE: CD7 chimeric antigen receptor T (CAR-T) therapy has potent antitumor activity against relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), however, immune reconstitution after CAR-T remains largely unknown. PATIENTS AND METHODS: An open-label phase I clinical trial (ChiCTR2200058969) was initiated to evaluate safety and efficacy of donor-derived CD7 CAR-T cells in 7 R/R T-ALL/LBL patients. CAR-T cells were detected by flow cytometry and PCR. Cytokine levels were quantified by cytometric bead arrays. Single-cell RNA sequencing (scRNA-seq) was adopted to profile immune reconstitution. RESULTS: Optimal complete remission (CR) was 100% on day 28, and median followed-up time was 4 months. Leukopenia, thrombocytopenia, and neutropenia were observed in 6 patients, and infections occurred in 5 patients. Two patients died of serious infection and one died of a brain hemorrhage. CAR-T cells expanded efficiently in all patients. CD7+ T cells were eliminated in peripheral blood on day 11 after infusion, and CD7- T cells dramatically expanded in all patients. scRNA-seq suggested that immunologic activities of CD7- T cells were stronger than those of T cells before infusion due to higher expression levels of T-cell function-related pathways, and major characters of such CD7- T cells were activation of autoimmune-related pathways. Monocyte loss was found in 2 patients who died of serious infections, indicating the main cause of the infections after infusion. S100A8 and S100A9 were identified as potential relapse markers due to their notable upregulation in leukocyte lineage in relapsed patients versus non-relapse controls. CONCLUSIONS: Our data revealed cellular level dynamics of immune homeostasis of CD7 CAR-T therapy, which is valuable for optimizing the treatment of R/R T-ALL/LBL.

Enhancement of spontaneous emission from CdSe/ZnS quantum dots through silicon nitride photonic crystal cavity based on miniaturized bound states in the continuum.

Colloidal CdSe/ZnS quantum dots (QDs) exhibit excellent optical properties for wide potential applications in light-emitting diodes, solar concentrators, and single-photon sources. However, the ultra-thin films with low concentration of QDs still encounter inefficient photoluminescence (PL) and poor directionality of radiation, which need to be enhanced using nanophotonics device designs. Here we design and experimentally demonstrate an on-substrate silicon nitride (SiN) photonic crystal (PhC) microcavity encapsulated by a layer of PMMA hosting CdSe/ZnS QDs. The miniaturized bound states in the continuum (BIC) supported by our structures, provide high-Q resonant modes with highly-directional emission patterns. Experimental results show that the BIC mode in the microcavity has a Q-factor up to 7000 owing to the symmetric refractive index distribution along the Z-direction, rendering 8.5-fold enhancement of PL intensity and 8.4-fold acceleration of radiative emission rate. Our work provides a practical way for constructing efficient on-chip surface-emitting light sources on silicon-based integrated photonic devices.

Low-threshold nanolasers based on miniaturized bound states in the continuum.

The pursuit of compact lasers with low thresholds has imposed strict requirements on tight light confinements with minimized radiation losses. Bound states in the continuum (BICs) have been recently demonstrated as an effective mechanism to trap light. However, most reported BIC lasers are still bulky due to the absence of in-plane light confinement. Here, we combine BICs and photonic bandgaps to realize three-dimensional light confinements, as referred to miniaturized BICs (mini-BICs). We demonstrate highly compact active mini-BIC resonators with a record high-quality (Q) factor of up to 32,500, which enables single-mode lasing with the lowest threshold of 80 W/cm2 among the reported BIC lasers. In addition, photon statistics measurements further confirm the occurrence of the stimulated emission in our devices. Our work reveals a path toward compact BIC lasers with ultralow power consumption and potentially boosts the applications in cavity quantum electrodynamics, nonlinear optics, and integrated photonics.

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy.

Hematological malignancies are one of the most lethal illnesses that seriously threaten human life and health. Lipids are important constituents of various biological membranes and substances for energy storage and cell signaling. Furthermore, lipids are critical in the normal physiological activities of cells. In the process of the lethal transformation of hematological malignancies, lipid metabolism reprogramming meets the material and energy requirements of rapidly proliferating and dividing tumor cells. A large number of studies have shown that dysregulated lipid metabolism, commonly occurs in hematological malignancies, mediating the proliferation, growth, migration, invasion, apoptosis, drug resistance and immune escape of tumor cells. Targeting the lipid metabolism pathway of hematological malignancies has become an effective therapeutic approach. This article reviews the oncogenic mechanisms of lipid metabolism reprogramming in hematological malignancies, including fatty acid, cholesterol and phospholipid metabolism, thereby offering an insight into targeting lipid metabolism in the treatment of hematological malignancies.

Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner.

BTK inhibitor (BTKi) Ibrutinib carries an increased bleeding risk compared to more selective BTKis Acalabrutinib and Zanubrutinib, however, its impact on vascular endothelium remains unknown. In this study, we found that Ibrutinib induced stronger cytotoxic effect on endothelial cells than Zanubrutinib, however, Acalabrutinib cytotoxicity was extremely weak. RNA-seq, followed by KEGG analysis and quantitative RT-PCR validation, was conducted to identify the differential apoptotic target genes of BTKis, leading to their distinct cytotoxic effects on endothelial cells, which showed that Ibrutinib and Zanubrutinib dramatically modulated the expression of critical apoptotic genes, GADD45B, FOS, and BCL2A1, among which FOS and GADD45B were upregulated more significantly by Ibrutinib than Zanubrutinib, however, Acalabrutinib downregulated BCL2A1 moderately and was not able to modulate the expression of FOS and GADD45B. Next, we performed in vitro angiogenesis assays and found that Ibrutinib was more able to induce endothelial dysfunction than Zanubrutinib via stimulating more BMP4 expression, however, Acalabrutinib had no such effect. Especially, the capacity of Ibrutinib to induce endothelial dysfunction can be antagonized by targeting BMP4. Accordingly, Ibrutinib, as an angiogenesis inhibitor, inhibited ovarian and breast cancer progression in vivo. Collectively, our findings addressed a novel molecular basis underlying Ibrutinib-induced endothelial cell dysfunction and suggested the potential application of Ibrutinib to treat angiogenesis-dependent cancers.

Biomarker interaction selection and disease detection based on multivariate gain ratio.

BACKGROUND: Disease detection is an important aspect of biotherapy. With the development of biotechnology and computer technology, there are many methods to detect disease based on single biomarker. However, biomarker does not influence disease alone in some cases. It's the interaction between biomarkers that determines disease status. The existing influence measure I-score is used to evaluate the importance of interaction in determining disease status, but there is a deviation about the number of variables in interaction when applying I-score. To solve the problem, we propose a new influence measure Multivariate Gain Ratio (MGR) based on Gain Ratio (GR) of single-variate, which provides us with multivariate combination called interaction. RESULTS: We propose a preprocessing verification algorithm based on partial predictor variables to select an appropriate preprocessing method. In this paper, an algorithm for selecting key interactions of biomarkers and applying key interactions to construct a disease detection model is provided. MGR is more credible than I-score in the case of interaction containing small number of variables. Our method behaves better with average accuracy [Formula: see text] than I-score of [Formula: see text] in Breast Cancer Wisconsin (Diagnostic) Dataset. Compared to the classification results [Formula: see text] based on all predictor variables, MGR identifies the true main biomarkers and realizes the dimension reduction. In Leukemia Dataset, the experiment results show the effectiveness of MGR with the accuracy of [Formula: see text] compared to I-score with accuracy [Formula: see text]. The results can be explained by the nature of MGR and I-score mentioned above because every key interaction contains a small number of variables in Leukemia Dataset. CONCLUSIONS: MGR is effective for selecting important biomarkers and biomarker interactions even in high-dimension feature space in which the interaction could contain more than two biomarkers. The prediction ability of interactions selected by MGR is better than I-score in the case of interaction containing small number of variables. MGR is generally applicable to various types of biomarker datasets including cell nuclei, gene, SNPs and protein datasets.

Observation of Ultrafast Self-Action Effects in Quasi-BIC Resonant Metasurfaces.

High-index dielectric metasurfaces can support sharp optical resonances enabled by the physics of bound states in the continuum (BICs) often manifested in experiments as quasi-BIC resonances. They provide a way to enhance light-matter interaction at the subwavelength scale bringing novel opportunities for nonlinear nanophotonics. Strong narrow-band field enhancement in quasi-BIC metasurfaces leads to an extreme sensitivity to a change of the refractive index that may limit nonlinear functionalities for the pump intensities beyond the perturbative regime. Here we study ultrafast self-action effects observed in quasi-BIC silicon metasurfaces and demonstrate how they alter the power dependence of the third-harmonic generation efficiency. We study experimentally a transition from the subcubic to supercubic regimes for the generated third-harmonic power driven by a blue-shift of the quasi-BIC in the multiphoton absorption regime. Our results suggest a way to implement ultrafast nonlinear dynamics in high-index resonant dielectric metasurfaces for nonlinear meta-optics beyond the perturbative regime.

A colloidal gold-based immunochromatographic strip for rapid detection of SARS-CoV-2 antibodies after vaccination.

Vaccination interventions is consideredan important preventive measure to block the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and protect the organism from pathogen infection effectively. However, a quick and accurate technique to evaluate the immune efficacy of the SARS-CoV-2 inactivated vaccine remains scarce. In this paper, an IgM-IgG antibody combined detection colloidal gold immunochromatography assay kit was optimized and developed, which can assess the efficacy of the inactivated SARS-CoV-2 vaccine. We collected fingertip blood samples from 3 vaccinees and 1 unvaccinated sample. The results showed that the proportion of antibody was high after the second shots immunization. The colloidal gold-based immunochromatographic strip is rapid, convenient and easy to operate. It can be used as an auxiliary method for preliminary evaluation of the antibody effect of vaccine recipients, and provide a reference index for the potential clinical application value of the vaccine.

Giant Enhancement of Continuous Wave Second Harmonic Generation from Few-Layer GaSe Coupled to High-Q Quasi Bound States in the Continuum.

Two-dimensional (2D) layered materials such as GaSe recently have emerged as novel nonlinear optical materials with exceptional properties. Although exhibiting large nonlinear susceptibilities, the nonlinear responses of 2D materials are generally limited by the short interaction lengths with light, thus further enhancement via resonant photonic nanostructures is highly desired for building high-efficiency nonlinear devices. Here, we demonstrate a giant second-harmonic generation (SHG) enhancement by coupling 2D GaSe flakes to silicon metasurfaces supporting quasi-bound states in the continuum (quasi-BICs) under continuous-wave (CW) operation. Taking advantage of both high-quality factors and large mode areas of quasi-BICs, SHG from a GaSe flake is uniformly enhanced by nearly 4 orders of magnitude, which is promising for high-power coherent light sources. Our work provides an effective approach for enhancing nonlinear optical processes in 2D materials within the framework of silicon photonics, which also brings second-order nonlinearity associated with 2D materials to silicon photonic devices.

Distinct BTK inhibitors differentially induce apoptosis but similarly suppress chemotaxis and lipid accumulation in mantle cell lymphoma.

BACKGROUND: The more selective second-generation BTK inhibitors (BTKi) Acalabrutinib and Zanubrutinib and the first-generation BTKi Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKi with distinct binding selectivity against BTK remain largely unknown. METHODS: AlamarBlue assays were performed to define cytotoxicity of BTKi against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKi on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis. RESULTS: Acalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A, and ATM, in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKi similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences. CONCLUSION: BTKi demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

Directional and Fast Photoluminescence from CsPbI3 Nanocrystals Coupled to Dielectric Circular Bragg Gratings.

Lead halide perovskite nanocrystals (NCs), especially the all-inorganic perovskite NCs, have drawn substantial attention for both fundamental research and device applications in recent years due to their unique optoelectronic properties. To build high-performance nanophotonic devices based on perovskite NCs, it is highly desirable to couple the NCs to photonic nanostructures for enhancing the radiative emission rate and improving the emission directionality of the NCs. In this work, we synthesized high-quality CsPbI3 NCs and further coupled them to dielectric circular Bragg gratings (CBGs). The efficient couplings between the perovskite NCs and the CBGs resulted in a 45.9-fold enhancement of the photoluminescence (PL) intensity and 3.2-fold acceleration of the radiative emission rate. Our work serves as an important step for building high-performance nanophotonic light emitting devices by integrating perovskite NCs with photonic nanostructures.

Antibody-Based Immunotherapeutic Strategies for the Treatment of Hematological Malignancies.

As the most common type of cancer in the world, hematological malignancies (HM) account for 10% of all annual cancer deaths and have attracted more attention. Conventional treatments, such as chemotherapy, radiotherapy, and hematopoietic stem cell transplantation (HSCT), could relieve patients suffering HM. However, serious side effects and high costs bring patients both physical complaints and mental pressure. Recently, compared with conventional therapeutic strategies for HM patients, antibody-based immunotherapies, including cancer vaccines, oncolytic virus therapies, monoclonal antibody treatments, and CAR-T cell therapies, have displayed longer survival time and fewer adverse reactions, even though specific efficacy and safety of these antibody-based immunotherapies still need to be evaluated and improved. This review summarized the advantages of antibody-based immunotherapies over conventional treatments, as well as its existing difficulties and solutions, thereby enhancing the understanding and applications of antibody-based immunotherapies in HM treatment.

Application of Chimeric Antigen Receptor T Cells in the Treatment of Hematological Malignancies.

T cell immune protection plays a pivotal role in the treatment of patients with hematological malignancies. However, T cell exhaustion might lead to the possibility of immune escape of hematological malignancies. Adoptive cell therapy (ACT) with chimeric antigen receptor T (CAR-T) cells can restore the activity of exhausted T cell through reprogramming and is widely used in the treatment of relapsed/refractory (r/r) hematological malignancies. Of note, CD19, CD20, CD30, CD33, CD123, and CD269 as ideal targets have shown extraordinary potential for CAR-T cell therapy and other targets such as CD23 and SLAMF7 have brought promising future for clinical trials. However, CAR-T cells can also produce some adverse events after treatment of hematological malignancies, such as cytokine release syndrome (CRS), neurotoxicity, and on-target/off-tumor toxicity, which may cause systemic immune stress inflammation, destruction of the blood-brain barrier, and even normal tissue damage. In this review, we aim to summarize the composition of CAR-T cell and its application in the treatment of acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), multiple myeloma (MM), and acute myeloid leukemia (AML). Moreover, we will review the disadvantages of CAR-T cell therapy and propose several comprehensive recommendations which might guide its development.

Public-Private or Master-Servant? Examining the Implementation of the Serious Disease Insurance Scheme in China.

China's Serious Disease Insurance Scheme (SDIS) was set up to relieve the financial burdens on serious disease patients. It is a crucial part of the national basic medical insurance scheme, which is regarded as one of the largest government-funded social security programs in the world. The most significant institutional innovation of the SDIS is that the approach of a public-private partnership (PPP) is applied in an attempt to facilitate the efficiency of its implementation. The objective of this paper is to evaluate the implementation of the SDIS in China through PPPs, and to identify the problems to be tackled if the Chinese government intends to make such a plan work better for the majority of urban and rural residents. With the effective support from local officials and practitioners, the authors of this paper collected copies of SDIS contracts of multiple cities in Guangdong, one of the most developed provinces of China. Guided by a research framework drawn from the PPP literature, details of contract enforcement were also examined. The authors discovered that the role of local states is rather dominant; they have manipulated contract drafting and implementation. Additionally, current mechanisms for profit sharing, risk sharing, and information exchange have placed insurance companies in a rather disadvantageous situation. To achieve the sustainable development of the SDIS, the authors suggest that a further reform on implementation of a PPP must be pushed forward.

Robust Room Temperature Valley Hall Effect of Interlayer Excitons.

The Berry curvature in the band structure of transition metal dichalcogenides (TMDs) introduces a valley-dependent effective magnetic field, which induces the valley Hall effect (VHE). Similar to the ordinary Hall effect, the VHE spatially separates carriers or excitons, depending on their valley index, and accumulates them at opposite sample edges. The VHE can play a key role in valleytronic devices, but previous observations of the VHE have been limited to cryogenic temperatures. Here, we report a demonstration of the VHE of interlayer excitons in a MoS2/WSe2 heterostructure at room temperature. We monitored the in-plane propagation of interlayer excitons through photoluminescence mapping and observed their spatial separation into two opposite transverse directions that depended on the valley index of the excitons. Our theoretical simulations reproduced the salient features of these observations. Our demonstration of the robust interlayer exciton VHE at room temperature, enabled by their intrinsically long lifetimes, will open up realistic possibilities for the development of opto-valleytronic devices based on TMD heterostructures.

Destabilization of ROR1 enhances activity of Ibrutinib against chronic lymphocytic leukemia in vivo.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-embryonic antigen presented on chronic lymphocytic leukemia (CLL), but not on normal adult tissues, which promotes CLL-cell survival. Here, ROR1 was identified as a new client of Heat Shock Protein 90 (HSP90) via a mass spectrometry-based screen for ROR1-associated partners followed by co-immunoprecipitation (co-IP) analysis. A binding motif (ELHHPNIV) on ROR1 for HSP90 was revealed, which forms a αC-ß4 loop and is necessary for HSP90-facilitated ROR1 stabilization. We also found that targeting HSP90 leads to ROR1 degradation in a ubiquitin-proteasome dependent pathway, by which pro-survival ROR1 signaling was attenuated in CLL. Based on our previous finding that a humanized monoclonal antibody against ROR1 increases the activity of Ibrutinib against CLL, which is currently undergoing evaluation in clinical trials for the treatment of B-cell lymphoid malignancies, we then provided evidence that treatment with HSP90 inhibitor (17-DMAG) enhances anti-CLL activity of Ibrutinib in vitro and in vivo, by down-modulating ROR1. iTRAQ-based quantitative proteomic analysis of other HSP90 oncogenic clients in addition to ROR1, followed by GO/KEGG enrichment analysis, showed that Bruton's Tyrosine Kinase (BTK), B-lymphoid Tyrosine Kinase (BLK), Lymphocyte-specific Protein Tyrosine Kinase (LCK), or LCK/YES-Related Novel Protein Tyrosine Kinase (LYN), as HSP90 clients, were significantly involved in 11 biological processes and 6 signaling pathways. However, immunoblotting validation confirmed that Ibrutinib treatment dramatically deprived HSP90 inhibitors, 17-DMAG, AUY922 or PU-H71, of inducing the degradation of BTK, BLK, LCK or LYN, but not ROR1. Collectively, our data suggested that depletion of ROR1 induced by targeting HSP90 might facilitate the enhancement of Ibrutinib activity against CLL.

High-Q Quasibound States in the Continuum for Nonlinear Metasurfaces.

Sharp electromagnetic resonances play an essential role in physics in general and optics in particular. The last decades have witnessed the successful developments of high-quality (Q) resonances in microcavities operating below the light line, which however is fundamentally challenging to access from free space. Alternatively, metasurface-based bound states in the continuum (BICs) offer a complementary solution of creating high-Q resonances in devices operating above the light line, yet the experimentally demonstrated Q factors under normal excitations are still limited. Here, we present the realizations of quasi-BIC under normal excitation with a record Q factor up to 18 511 by engineering the symmetry properties and the number of the unit cells in all-dielectric metasurface platforms. The high-Q quasi-BICs exhibit exceptionally high conversion efficiency for the third harmonic generation and even enable the second harmonic generation in Si metasurfaces. Such ultrasharp resonances achieved in this work may immediately boost the performances of BICs in a plethora of fundamental research and device applications, e.g., cavity QED, biosensing, nanolasing, and quantum light generations.