Identification of TAP1 as a T-cell related therapeutic target in gastric cancer by mediating oxalipliatin-related synergistic enhancement of immunotherapy.

BACKGROUND: Given the intricate molecular complexities and heterogeneity inherent in T-cell immunotherapy of gastric cancer (GC), elucidative T-cell-related biomarkers were imperative needed for facilitating the prediction of GC patient prognosis and identify potential synergistic therapeutic targets. METHODS: We conducted COX regression analysis in TISIDB, TCGA-STAD, and GEO databases to identify 19 GC T-cell-mediated sensitivity tumor killing (TTK) genes (key GCTTKs). Based on key GCTTKs, we constructed two TTK patterns and analyzed their metabolic pathways, mutation features, clinical data distribution, immune cell infiltration, and prognosis. LASSO regression was performed to develop a T-cell-mediated GC Prognosis (TGCP) model. We validated the TGCP model in GC patients. TAP1 was further selected for investigation of its biological functions and molecular mechanisms. We assessed the potential of TAP1 as a promising therapeutic target for GC using Patient-derived organoids (PDOs)-derived xenografts (PDOXs) models of GC. RESULTS: The TTK patterns display notable disparities. The TGCP model showcases its proficiency in predicting immune response efficacy, effectively distinguishes immunotherapy difference GC patients. Our findings find further confirmation in PDOX models, affirming TAP1 can enhance immunotherapy facilitated by PDL1 inhibitors. Furthermore, Oxaliplatin, by promoting TAP1 expression, augments PDL1 expression, thereby enhancing the efficacy of immunotherapy. CONCLUSIONS: We constructed a TGCP model, which demonstrates satisfactory predictive accuracy. Out of 9 prognostic genes, TAP1 was validated as a synergistic target for Oxaliplatin and PDL1 inhibitors, offering a genetic-level explanation for the synergy observed in GC treatment involving Oxaliplatin in combination with PDL1 inhibitors.

H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis.

The role of the Immunoglobulin Superfamily (IgSF) as adhesion molecules in orchestrating inflammation is pivotal, yet its specific involvement in gastric cancer (GC) remains unknown. We analyzed IgSF components and discerned conspicuously elevated VCAM1 expression in GC, correlating with a poor prognosis. Remarkably, VCAM1 enhances GC cell proliferation and migration by activating AKT-mTOR signaling. Moreover, lactate in the tumor microenvironment (TME) promotes dynamic lactylation of H3K18 (H3K18la), leading to transcriptional activation of VCAM1 in GC cells. Furthermore, VCAM1 actively mediates intercellular communication in the TME. AKT-mTOR-mediated CXCL1 expression is increased by VCAM1, facilitating the recruitment of human GC-derived mesenchymal stem cells (hGC-MSCs), thereby fostering immunesuppression and accelerating cancer progression. In summary, H3K18 lactylation upregulated VCAM1 transcription, which activated AKT-mTOR signaling, and promoted tumor cell proliferation, EMT Transition and tumor metastasis. VCAM1 upregulated CXCL1 expression by AKT-mTOR pathway, so as to facilitate hGC-MSCs and M2 macrophage recruitment and infiltration. These findings provide novel therapeutic targets for GC.

Experimental Study on the Agglomeration Behavior of Elongated Biomass Particles in a Lifting Tube.

Pneumatic conveying devices are commonly used in the fields of chemical industry, raw material transportation, and material processing. Elongated biomass particles are not evenly distributed in the lifting tube because biomass clumps during conveying. Pneumatic conveying test setup and measurement system were built in this paper in order to study the agglomeration behavior of elongated biomass particles in the lifting tube experimentally. Particle tracking velocimetry (PTV) was used to determine the area distribution and velocity distribution of particles at different apparent air velocities and mass flow rates. The results show that while keeping the mass flow rate constant at 46.50 g/s, the apparent gas velocity increased from 5.91 to 7.91 m/s and the maximum size of agglomerates decreased from 0.689 to 0.235. The apparent gas velocity was kept at 6.40 m/s, and the particle mass flow rate was adjusted from 56.50 to 16.20 g/s. The maximum size of the agglomerates was reduced to 0.115. Therefore, appropriately increasing the apparent gas velocity or decreasing the particle mass flow rate can improve the uniformity of the particle distribution in the lifting tube. The results would provide a reference for parameter adjustment of pneumatic conveying devices in industrial production.

Molecular and clonal evolution in vivo reveal a common pathway of distant relapse gliomas.

The evolutionary trajectories of genomic alterations underlying distant recurrence in glioma remain largely unknown. To elucidate glioma evolution, we analyzed the evolutionary trajectories of matched pairs of primary tumors and relapse tumors or tumor in situ fluid (TISF) based on deep whole-genome sequencing data (ctDNA). We found that MMR gene mutations occurred in the late stage in IDH-mutant glioma during gene evolution, which activates multiple signaling pathways and significantly increases distant recurrence potential. The proneural subtype characterized by PDGFRA amplification was likely prone to hypermutation and distant recurrence following treatment. The classical and mesenchymal subtypes tended to progress locally through subclonal reconstruction, trunk genes transformation, and convergence evolution. EGFR and NOTCH signaling pathways and CDNK2A mutation play an important role in promoting tumor local progression. Glioma subtypes displayed distinct preferred evolutionary patterns. ClinicalTrials.gov, NCT05512325.

Genomic alterations of oligodendrogliomas at distant recurrence.

BACKGROUND: Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses. METHODS: In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence. RESULTS: Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor. CONCLUSION: Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. CLINICALTRIALS: gov, Identifier: NCT05512325.

M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC.

N7 methylguanosine (m7G) has a crucial role the development of hepatocellular carcinoma (HCC). This study aimed to investigate the impact of the m7G methylation core genes (METTL1 and WDR4) and associated RNA risk signatures on HCC. we found m7G methylation core genes (METTL1 and WDR4) were upregulated in four HCC cell lines, and downregulation of METTL1 and WDR4 attenuated HCC cell proliferation, migration, and invasion. Moreover, METTL1 and WDR4 are upregulated in HCC tissues, and that there is a significant positive correlation between them. METTL1 and WDR4 were identified as independent prognostic markers for HCC by employing overall survival (OS), disease-specific survival (DSS), Progression Free Interval survival (PFI), and univariate/multivariate Cox analyses. We identified 1479 coding RNAs (mRNAs) and 232 long non-coding RNAs (lncRNAs) associated with METTL1 / WDR4 by using weighted coexpression network analysis (WGCNA) and co-clustering analysis. The least absolute shrinkage and selection operator (lasso) were used to constructing mRNA and lncRNA risk signatures associated with the METTL1 / WDR4. These risk were independent poor prognostic factors in HCC. Furthermore, we found that METTL1 / WDR4 expression and mRNA / lncRNA risk scores were closely associated with TP53 mutations. Clinicopathological features correlation results showed that METTL1 / WDR4 expression and mRNA / lncRNA risk score were associated with the stage and invasion depth (T) of HCC. To predict the overall survival of HCC individuals, we constructed a nomogram with METTL1/WDR4 expression, mRNA/lncRNA risk score, and clinicopathological features. In addition, we combined single-cell sequencing datasets and immune escape-related checkpoints to construct an immune escape-related protein-protein interaction(PPI) network. In conclusion, M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC.

ATF4-mediated circTDRD3 promotes gastric cancer cell proliferation and metastasis by regulating the miR-891b/ITGA2 axis and AKT signaling pathway.

BACKGROUND: Gastric cancer (GC) is a cancer of the gastrointestinal tract that is highly malignant and has poor prognosis. Circular RNAs are a class of nonclassical RNA molecules that have been determined to be involved in GC malignancy in various ways. However, the underlying function and mechanism of circTDRD3 in gastric cancer remain largely unknown. METHODS: We analyzed circTDRD3 expression in databases and verified the findings in GC cell lines and tissue specimens. A series of functional gene overexpression and knockdown assays in vivo and in vitro were carried out to investigate the role of circTDRD3 in proliferation and metastasis. Here, we revealed the role of the miR-891b/ITGA2 axis by analyzing bioinformatics datasets. Furthermore, we performed dual-luciferase, fluorescence in situ hybridization, RNA pull-down, and functional rescue experiments to examine the relationships between circTDRD3 and its interacting molecules. Western blot confirmed the positive regulatory role of circTDRD3 in the AKT signaling pathway. A promoting effect of ATF4 on circTDRD3 was determined through chromatin immunoprecipitation. RESULTS: CircTDRD3 was significantly overexpressed in GC tissues compared with adjacent benign tissue, and its expression level was positively correlated with tumor volume and lymph node metastasis. CircTDRD3 promoted GC cell proliferation and migration in vitro and in vivo. Mechanistically, circTDRD3 exerted a tumor-promoting effect by regulating the miR-891b/ITGA2 axis and AKT signaling pathway in a positive feedback manner mediated by the transcription factor ATF4. CONCLUSIONS: ATF4-mediated circTDRD3 overexpression modulates the proliferation and metastasis of GC cells through the miR-891b/ITGA2 axis in a positive feedback manner.

Ni2+-Doped Garnet Solid-Solution Phosphor-Converted Broadband Shortwave Infrared Light-Emitting Diodes toward Spectroscopy Application.

Broadband shortwave infrared (SWIR) light-emitting diodes (LEDs), capable of advancing the next-generation solid-state smart invisible lighting technology, have sparked tremendous interest and will launch ground-breaking spectroscopy and instrumental applications. Nevertheless, the device performance is still suppressed by the low quantum efficiency and limited emission bandwidth of the critical phosphor layer. Herein, we report a high-performance Ni2+-doped garnet solid-solution broadband SWIR emitter centered at ∼1450 nm with a large full-width at half-maximum of ∼300 nm, thereby fabricating, for the first time, a directly excited Ni2+-doped garnet solid-solution phosphor-converted broadband SWIR LED device. A synergetic enhancement strategy, adding a fluxing agent and a charge compensator simultaneously, is proposed to deliver a more than 20-fold increase of the SWIR emission intensity and nearly 2-fold improvement of the thermal quenching behavior. The site occupation and mechanism behind the synergetic enhancement strategy are elucidated by a combination of experimental study and theoretical calculation. A prototype of the SWIR LED with a radiation flux of 1.25 mW is fabricated and utilized as an invisible SWIR light source to demonstrate the SWIR spectroscopy applications. This work not only opens a window to explore novel broadband SWIR phosphors but also provides a synergetic strategy to remarkably improve the performance of artificial SWIR LED light sources.

Tumor DNA From Tumor In Situ Fluid Reveals Mutation Landscape of Minimal Residual Disease After Glioma Surgery and Risk of Early Recurrence.

The recurrence of glioma is a difficult problem in clinical treatment. The molecular markers of primary tumors after resection cannot fully represent the characteristics of recurrent tumors. Here, abundant tumor DNA was detected in tumor in situ fluid (TISF). We report that TISF-derived tumor DNA (TISF-DNA) can detect genomic changes in recurrent tumors and facilitate recurrence risk analysis, providing valuable information for diagnosis and prognosis. The tumor DNA in TISF is more representative and sensitive than that in cerebrospinal fluid. It reveals the mutational landscape of minimal residual disease after glioma surgery and the risk of early recurrence, contributing to the clinical management and clinical research of glioma patients.

Exploring the regulatory roles of circular RNAs in the pathogenesis of atherosclerosis.

Circular RNAs (circRNAs) are a class of noncoding RNAs with a covalently closed loop structure. Recent evidence has shown that circRNAs can regulate gene transcription, alternative splicing, microRNA (miRNA) "molecular sponges", RNA-binding proteins and protein translation. Atherosclerosis is one of the leading causes of death worldwide, and more studies have indicated that circRNAs are related to atherosclerosis pathogenesis, including vascular endothelial cells, vascular smooth muscle cells, inflammation and lipid metabolism. In this review, we systematically summarize the biogenesis, characteristics and functions of circRNAs with a focus on their roles in the pathogenesis of atherosclerosis.

Identification of a novel SPT inhibitor WXP-003 by docking-based virtual screening and investigation of its anti-fungi effect.

Serine palmitoyltransferase (SPT) plays the key role on catalysing the formation of 3-ketodihydrosphingosine, which is the first step of the de novo biosynthesis of sphingolipids. SPT is linked to many diseases including fungal infection, making it a potential therapeutic target. Thus, a logical docking-based virtual screening method was used to screen selective SPT inhibitor against fungi, not human. We used myriocin-similarity database to identify compounds with good binding with fungal SPT and poor binding with homology human SPT model. Preliminary bio-assay led to the discovery of a promising inhibitor WXP-003, which displayed good inhibitory activity against diversity fungi strains with MIC ranging from 0.78 to 12.5 µg/mL. WXP-003 could significantly reduce sphingolipids content in fungi and no effect on mouse fibroblast cell line L929. Molecular dynamics simulation depicted that SPT/WXP-003 complex formed the favoured interactions. Taken together, discovery of WXP-003 provided valuable guide for the development of novel anti-fungal agents.

Characterizing the Genomic Landscape of Brain Glioma With Circulating Tumor DNA From Tumor In Situ Fluid.

Tumor in situ fluid (TISF) refers to the fluid at the local surgical cavity. We evaluated the feasibility of TISF-derived circulating tumor DNA (ctDNA) characterizing the genomic landscape for glioma. This retrospective study included TISF and tumor samples from 10 patients with glioma, we extracted cell-free DNA (cfDNA) from the TISF and then performed deep sequencing on that. And we compared genomic alterations between TISF and tumor tissue. Results showed that the concentration of cfDNA fragments from the patients for TISF ranged from 7.2 to 1,397 ng/ml. At least one tumor-specific mutation was identified in all 10 patients (100%). Further analysis of TISF ctDNA revealed a broad spectrum of genetic mutations, which have been reported to have clinical relevance. The analysis of concordance between TISF and tumor tissue reflected the spatiotemporal heterogeneity of glioma. Collectively, TISF ctDNA was a powerfully potential source for characterizing the genomic landscape of glioma, which provided new possibilities for precision medicine in patients with glioma.

IFNAR1 signaling in NK cells promotes persistent virus infection.

Inhibition of type 1 interferon (IFN-I) signaling promotes the control of persistent virus infection, but the underlying mechanisms remain poorly understood. Here, we report that genetic ablation of Ifnar1 specifically in natural killer (NK) cells led to elevated numbers of T follicular helper cells, germinal center B cells, and plasma cells and improved antiviral T cell function, resulting in hastened virus clearance that was comparable to IFNAR1 neutralizing antibody treatment. Antigen-specific B cells and antiviral antibodies were essential for the accelerated control of LCMV Cl13 infection following IFNAR1 blockade. IFNAR1 signaling in NK cells promoted NK cell function and general killing of antigen-specific CD4 and CD8 T cells. Therefore, inhibition of IFN-I signaling in NK cells enhances CD4 and CD8 T cell responses, promotes humoral immune responses, and thereby facilitates the control of persistent virus infection.

CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism.

Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of p-RB, p-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.

WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC.

Cancer stem cells (CSCs) are a small population of stem cell-like cancer cells that can initiate tumors in vivo, and are the major source of cancer initiation, relapse, and drug resistance. We previously reported that the p38 MAPK, through its downstream effectors MK2 and HSP27, suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer (NSCLC) cells, and that despite unaltered total expression of total p38 proteins, the levels of activated p38 were reduced in NSCLC tissues. However, the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown. In this study, we identified WIP1, a p38 phosphatase frequently overexpressed in cancer, as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC. Increased WIP1 expression correlated with reduced levels of activated p38, and with increased levels of a CSC marker in NSCLC tissues. Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells. WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53. We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo. These studies have identified the WIP1-p38-MK2-HSP27 cascade as a novel signaling pathway that, when altered, promotes CSC properties in NSCLC development, and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.

Colonization of endophyte Acremonium sp. D212 in Panax notoginseng and rice mediated by auxin and jasmonic acid.

Endophytic fungi can be beneficial to plant growth. However, the molecular mechanisms underlying colonization of Acremonium spp. remain unclear. In this study, a novel endophytic Acremonium strain was isolated from the buds of Panax notoginseng and named Acremonium sp. D212. The Acremonium sp. D212 could colonize the roots of P. notoginseng, enhance the resistance of P. notoginseng to root rot disease, and promote root growth and saponin biosynthesis in P. notoginseng. Acremonium sp. D212 could secrete indole-3-acetic acid (IAA) and jasmonic acid (JA), and inoculation with the fungus increased the endogenous levels of IAA and JA in P. notoginseng. Colonization of the Acremonium sp. D212 in the roots of the rice line Nipponbare was dependent on the concentration of methyl jasmonate (MeJA) (2-15 µmol/L) and 1-naphthalenacetic acid (NAA) (10-20 µmol/L). Moreover, the roots of the JA signaling-defective coi1-18 mutant were colonized by Acremonium sp. D212 to a lesser degree than those of the wild-type Nipponbare and miR393b-overexpressing lines, and the colonization was rescued by MeJA but not by NAA. It suggests that the cross-talk between JA signaling and the auxin biosynthetic pathway plays a crucial role in the colonization of Acremonium sp. D212 in host plants.

Novel CDKs inhibitors for the treatment of solid tumour by simultaneously regulating the cell cycle and transcription control.

A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.