DDX39B protects against sorafenib-induced ferroptosis by facilitating the splicing and cytoplasmic export of GPX4 pre-mRNA in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main histological subtype of primary liver cancer and remains one of the most common solid malignancies globally. Ferroptosis was recently defined as an iron-catalyzed form of regulated necrosis. Because cancer cells exhibit higher iron requirements than noncancer cells, treatment with ferroptosis-inducing compounds may be a feasible strategy for cancer therapy. However, cancer cells develop acquired resistance to evade ferroptosis, and the mechanisms responsible for ferroptosis resistance are not fully clarified. In the current study, we reported that DDX39B was downregulated during sorafenib-induced ferroptosis in a dose- and time-dependent manner. Exogenous introduction of DDX39B ensured the survival of HCC cells upon exposure to sorafenib, while the opposite phenomenon was observed in DDX39B-silenced HCC cells. Mechanistically, we demonstrated that DDX39B increased GPX4 levels by promoting the splicing and cytoplasmic translocation of GPX4 pre-mRNA, which was sufficient to detoxify sorafenib-triggered excess lipid ROS production, lipid peroxidation accumulation, ferrous iron levels, and mitochondrial damage. Inhibition of DDX39B ATPase activity by CCT018159 repressed the splicing and cytoplasmic export of GPX4 pre-mRNA and synergistically assisted sorafenib-induced ferroptotic cell death in HCC cells. Taken together, our data uncover a novel role for DDX39B in ferroptosis resistance by modulating the maturation of GPX4 mRNA via a posttranscriptional approach and suggest that DDX39B inhibition may be a promising therapeutic strategy to enhance the sensitivity and vulnerability of HCC cells to sorafenib.

Epstein-Barr virus causes vascular abnormalities in epithelial malignancies through upregulating ANXA3-HIF-1α-VEGF pathway.

Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.

Multimode Stimuli-Responsive Room-Temperature Phosphorescence Achieved by Doping Butterfly-like Fluorogens into Crystalline Small-Molecular Hosts.

Materials with stimuli-responsive purely organic room-temperature phosphorescence (RTP) exempt from exquisite molecular design and complex preparation are highly desirable but still relatively rare. Moreover, most of them work in a single switching mode. Herein, we employ a versatile host-guest-doped strategy to facilely construct efficient RTP systems with multimode stimuli-responsiveness without ingenious molecular design. By conveniently doping butterfly-like guests, namely, N,N'-diphenyl-dihydrodibenzo[a,c]phenazines (DPACs), featured with vibration-induced emission into the small-molecular hosts via various methods, RTP systems with finely tunable photophysical properties are readily obtained. Through systematic mechanistic studies and with the aid of a series of control experiments, we unveil the critical role of the host crystallinity in achieving efficient RTP. By virtue of the inherent environmental sensitivity of both RTP and fluorescence of the DPACs, our systems exhibit multiple-stimuli-responsiveness with the luminescence not only switching between the fluorescence and phosphorescence but also continuously changing in the fluorescence color. Advanced dynamic anticounterfeiting and multilevel information encryption is thereby realized.

The yield of SNP microarray analysis for fetal ultrasound cardiac abnormalities.

BACKGROUND: Chromosomal microarray analysis (CMA) has emerged as a critical instrument in prenatal diagnostic procedures, notably in assessing congenital heart diseases (CHD). Nonetheless, current research focuses solely on CHD, overlooking the necessity for thorough comparative investigations encompassing fetuses with varied structural abnormalities or those without apparent structural anomalies. OBJECTIVE: This study sought to assess the relation of single nucleotide polymorphism-based chromosomal microarray analysis (SNP-based CMA) in identifying the underlying causes of fetal cardiac ultrasound abnormalities. METHODS: A total of 2092 pregnant women who underwent prenatal diagnosis from 2017 to 2022 were included in the study and divided into four groups based on the presence of ultrasound structural abnormalities and the specific type of abnormality. The results of the SNP-Array test conducted on amniotic fluid samples from these groups were analyzed. RESULTS: Findings from the study revealed that the non-isolated CHD group exhibited the highest incidence of aneuploidy, overall chromosomal abnormalities, and trisomy 18, demonstrating statistically significant differences from the other groups (p < 0.001). Regarding the distribution frequency of copy number variation (CNV) segment size, no statistically significant distinctions were observed between the isolated CHD group and the non-isolated CHD group (p > 0.05). The occurrence rates of 22q11.2 and 15q11.2 were also not statistically different between the isolated CHD group and the non-isolated congenital heart defect group (p > 0.05). CONCLUSION: SNP-based CMA enhances the capacity to detect abnormal CNVs in CHD fetuses, offering valuable insights for diagnosing chromosomal etiology and facilitating genetic counseling. This research contributes to the broader understanding of the utility of SNP-based CMA in the context of fetal cardiac ultrasound abnormalities.

SMG5 Inhibition Restrains Hepatocellular Carcinoma Growth and Enhances Sorafenib Sensitivity.

Hepatocellular carcinoma (HCC) has a pathogenesis that remains elusive with restricted therapeutic strategies and efficacy. This study aimed to investigate the role of SMG5, a crucial component in nonsense-mediated mRNA decay (NMD) that degrades mRNA containing a premature termination codon (PTC), in HCC pathogenesis and therapeutic resistance. We demonstrated an elevated expression of SMG5 in HCC and scrutinized its potential as a therapeutic target. Our findings revealed that SMG5 knockdown not only inhibited the migration, invasion, and proliferation of HCC cells but also influenced sorafenib resistance. Differential gene expression analysis between the control and SMG5 knockdown groups showed an upregulation of MAT1A in the latter. High expression of MAT1A, a catalyst for S-adenosylmethionine (SAM) production, as suggested by TCGA data, was indicative of a better prognosis for HCC. Further, an enzyme-linked immunosorbent assay showed a higher concentration of SAM in SMG5 knockdown cell supernatants. Furthermore, we found that exogenous SAM supplementation enhanced the sensitivity of HCC cells to sorafenib alongside changes in the expression of Bax and Bcl 2, apoptosis-related proteins. Our findings underscore the important role of SMG5 in HCC development and its involvement in sorafenib resistance, highlighting it as a potential target for HCC treatment.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

N6-methyladenosine-modified VGLL1 promotes ovarian cancer metastasis through high-mobility group AT-hook 1/Wnt/ß-catenin signaling.

The main causes of death in patients with ovarian cancer (OC) are invasive lesions and the spread of metastasis. The present study aimed to explore the mechanisms that might promote OC metastasis. Here, we identified that VGLL1 expression was remarkably increased in metastatic OC samples. The role of VGLL1 in OC metastasis and tumor growth was examined by cell function assays and mouse models. Mechanistically level, METTL3-mediated N6-methyladenosine (m6A) modification contributed to VGLL1 upregulation in an IGF2BP2 recognition-dependent manner. Furthermore, VGLL1 directly interacts with TEAD4 and co-transcriptionally activates HMGA1. HMGA1 further activates Wnt/ß-catenin signaling to enhance OC metastasis by promoting the epithelial-mesenchyme transition traits. Rescue assays indicated that the upregulation of HMGA1 was essential for VGLL1-induced metastasis. Collectively, these findings showed that the m6A-induced VGLL1/HMGA1/ß-catenin axis might play a vital role in OC metastasis and tumor growth. VGLL1 might serve as a prognostic marker and therapeutic target against the metastasis of OC.

DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8+ T-cell Immunity in Hepatocellular Carcinoma.

Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair antitumor immunity and thereby promote HCC progression. TGFß1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFß1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGFß1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression. SIGNIFICANCE: TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair.

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

Modulating the Luminescence, Photosensitizing Properties, and Mitochondria-Targeting Ability of D-π-A-Structured Dihydrodibenzo[a,c]phenazines.

Herein, pyridinium and 4-vinylpyridinium groups are introduced into the VIE-active N,N'-disubstituted-dihydrodibenzo[a,c]phenazines (DPAC) framework to afford a series of D-π-A-structured dihydrodibenzo[a,c]phenazines in consideration of the aggregation-benefited performance of the DPAC module and the potential mitochondria-targeting capability of the resultant pyridinium-decorated DPACs (DPAC-PyPF6 and DPAC-D-PyPF6). To modulate the properties and elucidate the structure-property relationship, the corresponding pyridinyl/4-vinylpyridinyl-substituted DPACs, i.e., DPAC-Py and DPAC-D-Py, are designed and studied as controls. It is found that the strong intramolecular charge transfer (ICT) effect enables the effective separation of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of DPAC-PyPF6 and DPAC-D-PyPF6, which is conducive to the generation of ROS. By adjusting the electron-accepting group and the π-bridge, the excitation, absorption, luminescence, photosensitizing properties as well as the mitochondria-targeting ability can be finely tuned. Both DPAC-PyPF6 and DPAC-D-PyPF6 display large Stokes shifts (70-222 nm), solvent-dependent absorptions and emissions, aggregation-induced emission (AIE), red fluorescence in the aggregated state (λem = 600-650 nm), aggregation-promoted photosensitizing ability with the relative singlet-oxygen quantum yields higher than 1.10, and a mitochondria-targeting ability with the Pearson coefficients larger than 0.85. DPAC-D-PyPF6 shows absorption maximum at a longer wavelength, slightly redder fluorescence and better photosensitivity as compared to DPAC-PyPF6, which consequently leads to the higher photocytotoxicity under the irradiation of white light as a result of the larger π-conjugation.

Targeted delivery of a PD-1-blocking scFv by CD133-specific CAR-T cells using nonviral Sleeping Beauty transposition shows enhanced antitumour efficacy for advanced hepatocellular carcinoma.

BACKGROUND: CD133 is considered a marker for cancer stem cells (CSCs) in several types of tumours, including hepatocellular carcinoma (HCC). Chimeric antigen receptor-specific T (CAR-T) cells targeting CD133-positive CSCs have emerged as a tool for the clinical treatment of HCC, but immunogenicity, the high cost of clinical-grade recombinant viral vectors and potential insertional mutagenesis limit their clinical application. METHODS: CD133-specific CAR-T cells secreting PD-1 blocking scFv (CD133 CAR-T and PD-1 s cells) were constructed using a sleeping beauty transposon system from minicircle technology, and the antitumour efficacy of CD133 CAR-T and PD-1 s cells was analysed in vitro and in vivo. RESULTS: A univariate analysis showed that CD133 expression in male patients at the late stage (II and III) was significantly associated with worse progression-free survival (PFS) (P = 0.0057) and overall survival (OS) (P = 0.015), and a multivariate analysis showed a trend toward worse OS (P = 0.041). Male patients with advanced HCC exhibited an approximately 20-fold higher PD-L1 combined positive score (CPS) compared with those with HCC at an early stage. We successfully generated CD133 CAR-T and PD-1 s cells that could secrete PD-1 blocking scFv based on a sleeping beauty system involving minicircle vectors. CD133 CAR-T and PD-1 s cells exhibited significant antitumour activity against HCC in vitro and in xenograft mouse models. Thus, CD133 CAR-T and PD-1 s cells may be a therapeutically tractable strategy for targeting CD133-positive CSCs in male patients with advanced HCC. CONCLUSIONS: Our study provides a nonviral strategy for constructing CAR-T cells that could also secrete checkpoint blockade inhibitors based on a Sleeping Beauty system from minicircle vectors and revealed a potential benefit of this strategy for male patients with advanced HCC and high CD133 expression (median immunohistochemistry score > 2.284).

Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRß complex in hepatocellular carcinoma.

Introduction: The limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms. Methods: The effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging. Results: There was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRß complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth. Conclusions: Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

HIF-1α dependent RhoA as a novel therapeutic target to regulate rheumatoid arthritis fibroblast-like synoviocytes migration in vitro and in vivo.

Objective: The purpose of this work is to investigate how the Rho family of GTPases A (RhoA) mediates the pathogenesis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). Methods: The expression of RhoA in the synovial tissues of RA and Healthy people (Control) was detected using immunohistochemistry methods. The expression of RhoA and hypoxia-inducible factor-1α (HIF-1α) is inhibited by small interfering RNAs (siRNAs). The inhibition effect on RA-FLS migration was further investigated. The protein expression level of HIF-1α, RhoA, focal adhesion kinase (FAK), and myosin light chain (MLC) was also analysed using western blotting (WB). DBA1 mice were immunised with the mixture of bovine type II collagen and Freund's adjuvant to establish collagen induced arthritis (CIA) mouse model. Lip-siRhoA is administered through joint injection every two days. Micro-computed tomography (micro-CT) was used to detect mouse ankle joint destruction and evaluate the bone loss of the periarticular side. Destruction of the ankle articular cartilage was tested by histology. Expressions of P-RhoA, P-FAK and P-MLC in the ankle joint was detected by immunohistochemistry assay. Results: The expression level of RhoA in the synovial tissues of RA patients was significantly higher than that in control group. Hypoxia was able to up-regulate the expression of RhoA. Whereas, HIF-1α siRNA (siHIF-1α) could down-regulate the expression of RhoA. Additionally, both of siHIF-1α and RhoA siRNA (siRhoA) delivered by liposome (Lip-siHIF-1α and Lip-siRhoA) were found to suppress FAK and MLC phosphorylation in vitro. In CIA mouse model, Lip-siRhoA was demonstrated to ameliorate the destruction of ankle joint and reduce the severity of ankle joint cartilage damage by micro-CT and histological staining, respectively. Therefore, inhibition of FLS cell migration can protect articular bone from destruction. Furthermore, the expression of P-RhoA, P-FAK and P-MLC was evaluated and found to be down-regulated by Lip-siRhoA in vivo. Conclusion: The results demonstrated that under hypoxic environment, HIF-1α dependent RhoA pathway played an important role on cytoskeleton remodelling and RA-FLS migration. Through down-regulating RhoA expression, it could effectively treat RA in vitro and in vivo. The translational potential of this article: Our study provides new evidence for the potential clinical application of RhoA as a candidate for the treatment of RA.

Estrogen-sensitive activation of SGK1 induces M2 macrophages with anti-inflammatory properties and a Th2 response at the maternal-fetal interface.

BACKGROUND: Decidual macrophages participate in immune regulation at the maternal-fetal interface. Abnormal M1/M2 polarization of decidual macrophages might predispose immune maladaptation in recurrent pregnancy loss (RPL). However, the mechanism of decidual macrophage polarization is unclear. We explored the role of Estradiol (E2)-sensitive serum-glucocorticoid regulated kinase (SGK) 1 in promoting macrophage polarization and suppressing inflammation at the maternal-fetal interface. METHODS: We assessed serum levels of E2 and progesterone during first trimester of pregnancy in women with or without threatened miscarriages (ended in live birth, n = 448; or early miscarriages, n = 68). For detection of SGK1 in decidual macrophages, we performed immunofluorescence labeling and western blot analysis applying decidual samples from RPL (n = 93) and early normal pregnancy (n = 66). Human monocytic THP-1 cells were differentiated into macrophages and treated with Toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS), E2, inhibitors or siRNA for in vitro analysis. Flow cytometry analysis were conducted to detect macrophages polarization. We also applied ovariectomized (OVX) mice with hormones exploring the mechanisms underlying the regulation of SGK1 activation by E2 in the decidual macrophages in vivo. RESULTS: SGK1 expression down regulation in the decidual macrophages of RPL was consistent with the lower concentration and slower increment of serum E2 from 4 to 12 weeks of gestation seen in these compromised pregnancies. LPS reduced SGK1 activities, but induced the pro-inflammatory M1 phenotype of THP-1 monocyte-derived macrophages and T helper (Th) 1 cytokines that favored pregnancy loss. E2 pretreatment promoted SGK1 activation in the decidual macrophages of OVX mice in vivo. E2 pretreatment amplified SGK1 activation in TLR4-stimulated THP-1 macrophages in vitro through the estrogen receptor beta (ERß) and PI3K pathway. E2-sensitive activation of SGK1 increased M2 macrophages and Th2 immune responses, which were beneficial to successful pregnancy, by inducing ARG1 and IRF4 transcription, which are implicated in normal pregnancy. The experiments on OVX mice have shown that pharmacological inhibition of E2 promoted nuclear translocation of NF-κB in the decidual macrophages. Further more, pharmacological inhibition or knockdown of SGK1 in TLR4-stimulated THP-1 macrophages activated NF-κB by promoting its nuclear translocation, leading to increased secretion of pro-inflammatory cytokines involved in pregnancy loss. CONCLUSION: Our findings highlighted the immunomodulatory roles of E2-activated SGK1 in Th2 immune responses by priming anti-inflammatory M2 macrophages at the maternal-fetal interface, resulting in a balanced immune microenvironment during pregnancy. Our results suggest new perspectives on future preventative strategies for RPL.

Integration of image preprocessing and recognition functions in an optoelectronic coupling organic ferroelectric retinomorphic neuristor.

The human visual system (HVS) has the advantages of a low power consumption and high efficiency because of the synchronous perception and early preprocessing of external image information in the retina, as well as parallel in-memory computing within the visual cortex. Realizing the biofunction simulation of the retina and visual cortex in a single device structure provides opportunities for performance improvements and machine vision system (MVS) integration. Here, we fabricate organic ferroelectric retinomorphic neuristors that integrate the retina-like preprocessing function and recognition of the visual cortex in a single device architecture. Benefiting from the electrical/optical coupling modulation of ferroelectric polarization, our devices show a bidirectional photoresponse that acts as the basis for mimicking retinal preconditioning and multi-level memory capabilities for recognition. The MVS based on the proposed retinomorphic neuristors achieves a high recognition accuracy of ∼90%, which is 20% higher than that of the incomplete system without the preprocessing function. In addition, we successfully demonstrate image encryption and optical programming logic gate functions. Our work suggests that the proposed retinomorphic neuristors offer great potential for MVS monolithic integration and functional expansion.

BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: In the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. METHODS: Paired adjacent tissue and cancerous lesions with HBV-associated HCC were subjected to RNA-seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound-targeted microbubble destruction (UTMD)-mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. RESULTS: We discovered that hepatitis B virus (HBV) infection-induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV-infected HCC cells promoted intra-tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho-ROCK-myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD-mediated BMP9 delivery restored the anti-tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. CONCLUSIONS: HBV-induced BMP9 downregulation causes vascular abnormalities that inhibit intra-tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9-based therapy to treat HBV-associated HCC.

Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer.

Rationale: Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better understanding of the detailed mechanisms underlying 5-FU resistance is needed to increase survival. Interleukin (IL)-33 is a newly discovered alarmin-like molecule that exerts pro- and anti-tumorigenic effects in various cancers. However, the precise role of IL-33 in CRC progression, as well as in the development of 5-FU resistance, remains unclear. Methods: High-quality RNA-sequencing analyses were performed on matched samples from patients with 5-FU-sensitive and 5-FU-resistant CRC. The clinical and biological significance of IL-33, including its effects on both T cells and tumor cells, as well as its relationship with 5-FU chemotherapeutic activity were examined in ex vivo, in vitro and in vivo models of CRC. The molecular mechanisms underlying these processes were explored. Results: IL-33 expressed by tumor cells was a dominant mediator of antitumoral immunity in 5-FU-sensitive patients with CRC. By binding to its ST2 receptor, IL-33 triggered CD4+ (Th1 and Th2) and CD8+ T cell responses by activating annexin A1 downstream signaling cascades. Mechanistically, IL-33 enhanced the sensitivity of CRC cells to 5-FU only in the presence of T cells, which led to the activation of both tumor cell-intrinsic apoptotic and immune killing-related signals, thereby synergizing with 5-FU to induce apoptosis of CRC cells. Moreover, injured CRC cells released more IL-33 and the T cell chemokines CXCL10 and CXCL13, forming a positive feedback loop to further augment T cell responses. Conclusions: Our results identified a previously unrecognized connection between IL-33 and enhanced sensitivity to 5-FU. IL-33 created an immune-active tumor microenvironment by orchestrating antitumoral T cell responses. Thus, IL-33 is a potential predictive biomarker for 5-FU chemosensitivity and favorable prognosis and has potential as a promising adjuvant immunotherapy to improve the clinical benefits of 5-FU-based therapies in the treatment of CRC.

DDX39B facilitates the malignant progression of hepatocellular carcinoma via activation of SREBP1-mediated de novo lipid synthesis.

PURPOSE: The detailed molecular mechanisms of aberrant lipid metabolism in HCC remain unclear. Herein, we focused on the potential role of DDX39B in aberrant lipogenesis and malignant development in HCC. METHODS: DDX39B expression in HCC and para-cancer tissues was measured by immunohistochemistry. CCK-8, colony formation and Transwell assays were utilized to detect HCC cell proliferation, migration and invasion in vitro. Oil red O and Nile red staining and triglyceride and cholesterol detection were used to measure lipogenesis. Coimmunoprecipitation was used to detect interactions between DDX39B and SREBP1. Immunofluorescence assays were performed to investigate the impact of DDX39B on SREBP1 nuclear translocation. A luciferase assay was used to explore the transcriptional activity of SREBP1. The subcutaneous and orthotopic xenograft models in nude mice were generated to verify the contribution of the DDX39B/SREBP1 axis to tumor growth, lung metastasis and lipid synthesis in vivo. RESULTS: DDX39B is upregulated in HCC tissues and predicts a worse prognosis. Upregulated DDX39B contributes to the proliferation, metastasis and lipogenesis of HCC cells. Mechanistically, DDX39B directly interacts with SREBP1, and silencing DDX39B impairs the stabilization of the SREBP1 protein through FBXW7-mediated ubiquitination and degradation of SREBP1. Furthermore, DDX39B deficiency decreases the nuclear translocation and activation of SREBP1 and transcription of SREBP1 downstream genes, resulting in reduced lipid accumulation. CONCLUSIONS: Our study reveals a novel mechanism by which DDX39B facilitates the malignant progression of HCC via activation of SREBP1-mediated de novo lipogenesis, implicating DDX39B as both a potential predictor of recurrence and prognosis and a promising therapeutic target.

ZNF32 prevents the activation of cancer-associated fibroblasts through negative regulation of TGFB1 transcription in breast cancer.

Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related deaths in women worldwide. Cancer-associated fibroblasts (CAFs) are one of the fundamental cellular components of the tumor microenvironment and play a critical role in the initiation, progression, and therapy resistance of breast cancer. However, the detailed molecular mechanisms of CAFs activation from normal fibroblasts (NFs) are still not well understood. In the present study, we reported that ZNF32 expression in breast cancer cells was negatively correlated with CAF-related markers (FSP1, α-SMA, and FAP) in stromal fibroblasts, and loss of ZNF32 promoted the activation of CAFs, as evidenced by the enhanced proliferation and contractility of CAFs. ZNF32 deficiency-mediated fibroblast activation promoted the growth and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, we demonstrated that ZNF32 inhibited TGFB1 transcription by directly binding to the -1968/-1962 region of the TGFB1 promoter, leading to the prevention of fibroblast activation. Altogether, our findings reveal an important mechanism by which ZNF32 suppression increases the transcription of the TGFB1 gene in breast cancer cells, and subsequently, elevated levels of secretory TGF-ß stimulate NFs transformation into CAFs, which in turn facilitates the malignant progression of breast cancer. Our data implicated ZNF32 as a potential therapeutic strategy against breast cancer.

DDX17 induces epithelial-mesenchymal transition and metastasis through the miR-149-3p/CYBRD1 pathway in colorectal cancer.

DEAD box helicase 17 (DDX17) has been reported to be involved in the initiation and development of several cancers. However, the functional role and mechanisms of DDX17 in colorectal cancer (CRC) malignant progression and metastasis remain unclear. Here, we reported that DDX17 expression was increased in CRC tissues compared with noncancerous mucosa tissues and further upregulated in CRC liver metastasis compared with patient-paired primary tumors. High levels of DDX17 were significantly correlated with aggressive phenotypes and worse clinical outcomes in CRC patients. Ectopic expression of DDX17 promoted cell migration and invasion in vitro and in vivo, while the opposite results were obtained in DDX17-deficient CRC cells. We identified miR-149-3p as a potential downstream miRNA of DDX17 through RNA sequencing analysis, and miR-149-3p displayed a suppressive effect on the metastatic potential of CRC cells. We demonstrated that CYBRD1 (a ferric reductase that contributes to dietary iron absorption) was a direct target of miR-149-3p and that miR-149-3p was required for DDX17-mediated regulation of CYBRD1 expression. Moreover, DDX17 contributed to the metastasis and epithelial to mesenchymal transition (EMT) of CRC cells via downregulation of miR-149-3p, which resulted in increased CYBRD1 expression. In conclusion, our findings not only highlight the significance of DDX17 in the aggressive development and prognosis of CRC patients, but also reveal a novel mechanism underlying DDX17-mediated CRC cell metastasis and EMT progression through manipulation of the miR-149-3p/CYBRD1 pathway.