A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Generation of genuine entanglement up to 51 superconducting qubits.

Scalable generation of genuine multipartite entanglement with an increasing number of qubits is important for both fundamental interest and practical use in quantum-information technologies1,2. On the one hand, multipartite entanglement shows a strong contradiction between the prediction of quantum mechanics and local realization and can be used for the study of quantum-to-classical transition3,4. On the other hand, realizing large-scale entanglement is a benchmark for the quality and controllability of the quantum system and is essential for realizing universal quantum computing5-8. However, scalable generation of genuine multipartite entanglement on a state-of-the-art quantum device can be challenging, requiring accurate quantum gates and efficient verification protocols. Here we show a scalable approach for preparing and verifying intermediate-scale genuine entanglement on a 66-qubit superconducting quantum processor. We used high-fidelity parallel quantum gates and optimized the fidelitites of parallel single- and two-qubit gates to be 99.91% and 99.05%, respectively. With efficient randomized fidelity estimation9, we realized 51-qubit one-dimensional and 30-qubit two-dimensional cluster states and achieved fidelities of 0.637 ± 0.030 and 0.671 ± 0.006, respectively. On the basis of high-fidelity cluster states, we further show a proof-of-principle realization of measurement-based variational quantum eigensolver10 for perturbed planar codes. Our work provides a feasible approach for preparing and verifying entanglement with a few hundred qubits, enabling medium-scale quantum computing with superconducting quantum systems.

Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration.

Secretory fibroblast growth factors (FGFs) and their receptors are known for their regulatory function in the early stages of neural development. FGF13, a nonsecretory protein of the FGF family, is expressed in cerebral cortical neurons during development and is a candidate gene for syndromal and nonspecific forms of X-chromosome-linked mental retardation (XLMR). However, its function during development remains unclear. We show that FGF13 acts intracellularly as a microtubule-stabilizing protein required for axon and leading process development and neuronal migration in the cerebral cortex. FGF13 is enriched in axonal growth cones and interacts directly with microtubules. Furthermore, FGF13 polymerizes tubulins and stabilizes microtubules. The loss of FGF13 impairs neuronal polarization and increases the branching of axons and leading processes. Genetic deletion of FGF13 in mice results in neuronal migration defects in both the neocortex and the hippocampus. FGF13-deficient mice also exhibit weakened learning and memory, which is correlated to XLMR patients' intellectual disability.

An integrated space-to-ground quantum communication network over 4,600 kilometres.

Quantum key distribution (QKD)1,2 has the potential to enable secure communication and information transfer3. In the laboratory, the feasibility of point-to-point QKD is evident from the early proof-of-concept demonstration in the laboratory over 32 centimetres4; this distance was later extended to the 100-kilometre scale5,6 with decoy-state QKD and more recently to the 500-kilometre scale7-10 with measurement-device-independent QKD. Several small-scale QKD networks have also been tested outside the laboratory11-14. However, a global QKD network requires a practically (not just theoretically) secure and reliable QKD network that can be used by a large number of users distributed over a wide area15. Quantum repeaters16,17 could in principle provide a viable option for such a global network, but they cannot be deployed using current technology18. Here we demonstrate an integrated space-to-ground quantum communication network that combines a large-scale fibre network of more than 700 fibre QKD links and two high-speed satellite-to-ground free-space QKD links. Using a trusted relay structure, the fibre network on the ground covers more than 2,000 kilometres, provides practical security against the imperfections of realistic devices, and maintains long-term reliability and stability. The satellite-to-ground QKD achieves an average secret-key rate of 47.8 kilobits per second for a typical satellite pass-more than 40 times higher than achieved previously. Moreover, its channel loss is comparable to that between a geostationary satellite and the ground, making the construction of more versatile and ultralong quantum links via geosynchronous satellites feasible. Finally, by integrating the fibre and free-space QKD links, the QKD network is extended to a remote node more than 2,600 kilometres away, enabling any user in the network to communicate with any other, up to a total distance of 4,600 kilometres.

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Identification of SLC7A11-AS1/SLC7A11 pair as a ferroptosis-related therapeutic target for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a prevalent malignancy worldwide, poses significant challenges in terms of prognosis, necessitating innovative therapeutic approaches. Ferroptosis offers notable advantages over apoptosis, holding promise as a novel therapeutic approach for HCC complexities. Moreover, while the interaction between long non-coding RNAs (lncRNAs) and mRNAs is pivotal in various physiological and pathological processes, their involvement in ferroptosis remains relatively unexplored. In this study, we constructed a ferroptosis-related lncRNA-mRNA correlation network in HCC using Pearson correlation analysis. Notably, the SLC7A11-AS1/SLC7A11 pair, exhibiting high correlation, was identified. Bioinformatics analysis revealed a significant correlation between the expression levels of this pair and key clinical characteristics of HCC patients, including gender, pathology, Ishak scores and tumour size. And poor prognosis was associated with high expression of this pair. Functional experiments demonstrated that SLC7A11-AS1, by binding to the 3'UTR region of SLC7A11 mRNA, enhanced its stability, thereby promoting HCC cell growth and resistance to erastin- induced ferroptosis. Additionally, in vivo studies confirmed that SLC7A11-AS1 knockdown potentiated the inhibitory effects of erastin on tumour growth. Overall, our findings suggest that targeting the SLC7A11-AS1/SLC7A11 pair holds promise as a potential therapeutic strategy for HCC patients.

Continuously Tunable MOFs Enable Precise Mass Transfer for High-Performance Isomer Separation.

Modulating mass transfer is crucial for optimizing the catalytic and separation performances of porous materials. Here, we systematically developed a series of continuously tunable MOFs (CTMOFs) that exhibit incessantly increased mass transfer. This was achieved through the strategic blending of ligands with different lengths and ratios in MOFs featuring the fcu topology. By employing a proportional mixture of two ligands in the synthesis of UiO-66, the micropores expanded, facilitating faster mass transfer. The mass transfer rate was evaluated by dye adsorption, dark-field microscopy, and gas chromatography (GC). The GC performance proved that both too-fast and too-slow mass transfer led to low separation performance. The optimized mass transfer in CTMOFs resulted in an exceptionally high separation resolution (5.96) in separating p-xylene and o-xylene. Moreover, this study represents the first successful use of MOFs for high-performance separation of propylene and propane by GC. This strategy provides new inspiration in regulating mass transfer in porous materials.

Revisiting benchmark study for response to methodological critiques of 'Evaluation of phenotype-driven gene prioritization methods for Mendelian diseases'.

Evaluation of phenotype-driven gene prioritization approaches for Mendelian diseases could facilitate the software development and method selection for the workflow configuration and clinical practice. In our original article, the performance of 10 well-recognized causal-gene prioritization methods was benchmarked using 305 cases from the deciphering developmental disorders (DDD) project and 209 in-house cases via a relatively unbiased methodology. The evaluation results showed that LIRICAL and AMELIE were two of the best methods in our benchmark experiments, and the possible integrative approach of these two methods may enhance the diagnostic efficiency. However, some methodological critiques were raised by the authors of Exomiser and PhenIX, so we revisited our benchmarking studies to answer their comments in this letter.

Evaluation of phenotype-driven gene prioritization methods for Mendelian diseases.

It's challenging work to identify disease-causing genes from the next-generation sequencing (NGS) data of patients with Mendelian disorders. To improve this situation, researchers have developed many phenotype-driven gene prioritization methods using a patient's genotype and phenotype information, or phenotype information only as input to rank the candidate's pathogenic genes. Evaluations of these ranking methods provide practitioners with convenience for choosing an appropriate tool for their workflows, but retrospective benchmarks are underpowered to provide statistically significant results in their attempt to differentiate. In this research, the performance of ten recognized causal-gene prioritization methods was benchmarked using 305 cases from the Deciphering Developmental Disorders (DDD) project and 209 in-house cases via a relatively unbiased methodology. The evaluation results show that methods using Human Phenotype Ontology (HPO) terms and Variant Call Format (VCF) files as input achieved better overall performance than those using phenotypic data alone. Besides, LIRICAL and AMELIE, two of the best methods in our benchmark experiments, complement each other in cases with the causal genes ranked highly, suggesting a possible integrative approach to further enhance the diagnostic efficiency. Our benchmarking provides valuable reference information to the computer-assisted rapid diagnosis in Mendelian diseases and sheds some light on the potential direction of future improvement on disease-causing gene prioritization methods.

Virtual Quantum Resource Distillation.

Distillation, or purification, is central to the practical use of quantum resources in noisy settings often encountered in quantum communication and computation. Conventionally, distillation requires using some restricted "free" operations to convert a noisy state into one that approximates a desired pure state. Here, we propose to relax this setting by only requiring the approximation of the measurement statistics of a target pure state, which allows for additional classical postprocessing of the measurement outcomes. We show that this extended scenario, which we call "virtual resource distillation," provides considerable advantages over standard notions of distillation, allowing for the purification of noisy states from which no resources can be distilled conventionally. We show that general states can be virtually distilled with a cost (measurement overhead) that is inversely proportional to the amount of existing resource, and we develop methods to efficiently estimate such cost via convex and semidefinite programming, giving several computable bounds. We consider applications to coherence, entanglement, and magic distillation, and an explicit example in quantum teleportation (distributed quantum computing). This work opens a new avenue for investigating generalized ways to manipulate quantum resources.

Experimental Virtual Distillation of Entanglement and Coherence.

Noise is, in general, inevitable and detrimental to practical and useful quantum communication and computation. Under the resource theory framework, resource distillation serves as a generic tool to overcome the effect of noise. Yet, conventional resource distillation protocols generally require operations on multiple copies of resource states, and strong limitations exist that restrict their practical utilities. Recently, by relaxing the setting of resource distillation to only approximating the measurement statistics instead of the quantum state, a resource-frugal protocol, "virtual resource distillation," is proposed, which allows more effective distillation of noisy resources. Here, we report its experimental implementation on a photonic quantum system for the distillation of quantum coherence (up to dimension four) and bipartite entanglement. We show the virtual distillation of the maximal superposed state of dimension four from the state of dimension two, an impossible task in conventional coherence distillation. Furthermore, we demonstrate the virtual distillation of entanglement with operations acting only on a single copy of the noisy Einstein-Podolsky-Rosen (EPR) pair and showcase the quantum teleportation task using the virtually distilled EPR pair with a significantly improved fidelity of the teleported state. These results illustrate the feasibility of the virtual resource distillation method and pave the way for accurate manipulation of quantum resources with noisy quantum hardware.

Immune cell patterns before and after neoadjuvant immune checkpoint blockade combined with chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. PATIENTS AND METHODS: A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. RESULTS: In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. CONCLUSIONS: Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Mad2 promotes Cyclin B2 recruitment to the kinetochore for guiding accurate mitotic checkpoint.

Accurate mitotic progression relies on the dynamic phosphorylation of multiple substrates by key mitotic kinases. Cyclin-dependent kinase 1 is a master kinase that coordinates mitotic progression and requires its regulatory subunit Cyclin B to ensure full kinase activity and substrate specificity. The function of Cyclin B2, which is a closely related family member of Cyclin B1, remains largely elusive. Here, we show that Mad2 promotes the kinetochore localization of Cyclin B2 and that their interaction at the kinetochores guides accurate chromosome segregation. Our biochemical analyses have characterized the Mad2-Cyclin B2 interaction and delineated a novel Mad2-interacting motif (MIM) on Cyclin B2. The functional importance of the Cyclin B2-Mad2 interaction was demonstrated by real-time imaging in which MIM-deficient mutant Cyclin B2 failed to rescue the chromosomal segregation defects. Taken together, we have delineated a previously undefined function of Cyclin B2 at the kinetochore and have established, in human cells, a mechanism of action by which Mad2 contributes to the spindle checkpoint.

Ottowia cancrivicina sp. nov., isolated from human stomach.

A Gram-negative, facultative anaerobic, non-motile and rod-shaped bacterium, designated 10c7w1T, was isolated from a human gastrointestinal tract. Colonies on agar plates were small, circular, smooth and beige. The optimal growth conditions were determined to be 37 °C, pH 7.0-7.5 and 0 % (w/v) NaCl. Comparative analysis of complete 16S rRNA gene sequences revealed that strain 10c7w1T showed the highest sequence similarity of 95.8 % to Ottowia beijingensis MCCC 1A01410T, followed by Ottowia thiooxydans (95.2 %) JCM 11629T. The average amino acid identity values between 10c7w1T and O. beijingensis MCCC 1A01410T and O. thiooxydans JCM 11629T were above 60 % (71.4 and 69.5 %). The average nucleotide identity values between strain 10c7w1T and O. beijingensis MCCC 1A01410T and O. thiooxydans JCM 11629T were 76.9 and 72.5 %, respectively. The dominant fatty acids (≥10 %) were straight chain ones, with summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c), summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c) and C16 : 00 being the most abundant. Q-8 was the only respiratory quinone. The major polar lipids of strain 10c7w1T were phosphatidylethanolamine, diphosphatidylglycerol and unknown lipids. The DNA G+C content of strain 10c7w1T was 63.6 mol%. On the basis of phylogenetic, phenotypic and chemotaxonomic data, strain 10c7w1T is considered to represent a novel species within the genus Ottowia, for which the name Ottowia cancrivicina sp. nov. is proposed. The type strain is 10c7w1T (=MCCC 1H01399T=KCTC 92200T).

Activation of polyimide by oxygen plasma for atomic layer deposition of highly compact titanium oxide coating.

Titanium oxide (TiO2) coated polyimide has broad application prospects under extreme conditions. In order to obtain a high-quality ultra-thin TiO2coating on polyimide by atomic layer deposition (ALD), the polyimide was activated byin situoxygen plasma. It was found that a large number of polar oxygen functional groups, such as carboxyl, were generated on the surface of the activated polyimide, which can significantly promote the preparation of TiO2coating by ALD. The nucleation and growth of TiO2were studied by x-ray photoelectron spectroscopy monitoring and scanning electron microscopy observation. On the polyimide activated by oxygen plasma, the size of TiO2nuclei decreased and the quantity of TiO2nuclei increased, resulting in the growth of a highly uniform and dense TiO2coating. This coating exhibited excellent resistance to atomic oxygen. When exposed to 3.5 × 1021atom cm-2atomic oxygen flux, the erosion yield of the polyimide coated with 100 ALD cycles of TiO2was as low as 3.0 × 10-25cm3/atom, which is one order less than that of the standard POLYIMIDE-ref Kapton®film.

Ultrathin Al2O3film modification on waterborne epoxy coatings by atomic layer deposition for augmenting the corrosion resistance.

The polar channels formed by the curing of waterborne anticorrosive coatings compromise their water resistance, leading to coating degradation and metal corrosion. To enhance the anticorrosive performance of waterborne coatings, this study proposed a novel method of depositing ultrathin Al2O3films on the surface of waterborne epoxy coatings by atomic layer deposition, a technique that can modify the surface properties of polymer materials by depositing functional films. The Al2O3-modified coatings exhibited improved sealing and barrier properties by closing the polar channels and surface defects and cracks. The surface structure and morphology of the modified coatings were characterized by x-ray photoelectron spectroscopy and scanning electron microscopy. The hydrophilicity and corrosion resistance of the modified coatings were evaluated by water contact angle measurement, Tafel polarization curve, and electrochemical impedance spectroscopy. The results indicated that the water contact angle of the Al2O3-modified coating increased by 48° compared to the unmodified coating, and the protection efficiency of the modified coating reached 99.81%. The Al2O3-modified coating demonstrated high anticorrosive efficiency and potential applications for metal anticorrosion in harsh marine environments.

Mediating role of chiro-inositol metabolites on the effects of HLA-DR-expressing CD14 + monocytes in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD), a chronic inflammatory condition, is caused by several factors involving aberrant immune responses. Genetic factors are crucial in IBD occurrence. Mendelian randomization (MR) can offer a new perspective in understanding IBD's genetic background. METHODS: Single nucleotide polymorphisms (SNPs) were considered instrumental variables (IVs). We analyzed the relationship between 731 immunophenotypes, 1,400 metabolite phenotypes, and IBD. The total effect was decomposed into indirect and direct effects, and the ratio of the indirect effect to the total effect was calculated. RESULTS: We identified the causal effects of HLA-DR-expressing CD14 + monocytes on IBD through MR analysis. The phenotype "HLA-DR expression on CD14 + monocytes" showed the strongest association among the selected 48 immune phenotypes. Chiro-inositol metabolites mediated the effect of CD14 + monocytes expressing HLA-DR on IBD. An increase in Chiro-inositol metabolites was associated with a reduced risk of IBD occurrence, accounting for 4.97%. CONCLUSION: Our findings revealed a new pathway by which HLA-DR-expressing CD14 + monocytes indirectly reduced the risk of IBD occurrence by increasing the levels of Chiro-inositol metabolites. The results provided a new perspective on the immunoregulatory mechanisms underlying IBD, laying a theoretical foundation for developing new therapeutic targets in the future.

Device-independent quantum random-number generation.

Randomness is important for many information processing applications, including numerical modelling and cryptography1,2. Device-independent quantum random-number generation (DIQRNG)3,4 based on the loophole-free violation of a Bell inequality produces genuine, unpredictable randomness without requiring any assumptions about the inner workings of the devices, and is therefore an ultimate goal in the field of quantum information science5-7. Previously reported experimental demonstrations of DIQRNG8,9 were not provably secure against the most general adversaries or did not close the 'locality' loophole of the Bell test. Here we present DIQRNG that is secure against quantum and classical adversaries10-12. We use state-of-the-art quantum optical technology to create, modulate and detect entangled photon pairs, achieving an efficiency of more than 78 per cent from creation to detection at a distance of about 200 metres that greatly exceeds the threshold for closing the 'detection' loophole of the Bell test. By independently and randomly choosing the base settings for measuring the entangled photon pairs and by ensuring space-like separation between the measurement events, we also satisfy the no-signalling condition and close the 'locality' loophole of the Bell test, thus enabling the realization of the loophole-free violation of a Bell inequality. This, along with a high-voltage, high-repetition-rate Pockels cell modulation set-up, allows us to accumulate sufficient data in the experimental time to extract genuine quantum randomness that is secure against the most general adversaries. By applying a large (137.90 gigabits × 62.469 megabits) Toeplitz-matrix hashing technique, we obtain 6.2469 × 107 quantum-certified random bits in 96 hours with a total failure probability (of producing a random number that is not guaranteed to be perfectly secure) of less than 10-5. Our demonstration is a crucial step towards transforming DIQRNG from a concept to a key aspect of practical applications that require high levels of security and thus genuine randomness7. Our work may also help to improve our understanding of the origin of randomness from a fundamental perspective.

Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1.

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

Anchoring super-enhancer-driven oncogenic lncRNAs for anti-tumor therapy in hepatocellular carcinoma.

Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.