Predicting the effect of chemicals on fruit using graph neural networks.

The neural network method is a type of machine learning that has made significant advances over the past few years in a variety of fields, particularly text, speech, images, videos, etc. In areas where data is unstructured, traditional machine learning has not been able to surpass the 'glass ceiling'; therefore, researchers have turned to neural networks as auxiliary tools to achieve significant breakthroughs or develop new research methods. An array of computational chemistry challenges can be addressed using neural networks, including virtual screening, quantitative structure-activity relationships, protein structure prediction, materials design, quantum chemistry, and property prediction, among others. This paper proposes a strategy for predicting the chemical properties of fruits by using graph neural networks, and it aims to provide some guidance to researchers and streamline the identification process.

Tumor microenvironment reprogramming combined with immunogenic enhancement by nanoemulsions potentiates immunotherapy.

The combination of immune checkpoint inhibitors and immunogenic cell death (ICD) inducers has become a promising strategy for the treatment of various cancers. However, its efficacy remains unmet because of the dense stroma and defective vasculatures in the tumor microenvironment (TME) that restricts the intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Herein, cancer-associated fibroblasts (CAFs)-targeted nanoemulsions are tailored to combine the ICD induction and the TME reprogramming to sensitize checkpoint blockade immunotherapy. Melittin, as an ICD inducer and an antifibrotic agent, is efficiently encapsulated into the nanoemulsion accompanied by a nitric oxide donor to improve its bioavailability and tumor targeting. The nanoemulsions exhibited dual functionality by directly inducing direct cancer cell death and enhancing the tumoral immunogenicity, while also synergistically reprogramming the TME through reversing the activated CAFs, decreasing collagen deposition and restoring tumor vessels. Consequently, these nanemulsions successfully facilitated the CTLs infiltration and suppressing the recruitment of immunosuppressive cells. A combination of AE-MGNPs and anti-CTLA-4 antibody greatly elicited a striking level of antitumor T-cell response to suppress tumor growth in CAFs-rich colorectal tumor models. Our work emphasized the integration of the ICD induction with simultaneous modulation of the TME to enhance the sensitivity of patients to checkpoint blockade immunotherapy.

Sequential activation of strigolactone and salicylate biosynthesis promotes leaf senescence.

Leaf senescence is a complex process strictly regulated by various external and endogenous factors. However, the key signaling pathway mediating leaf senescence remains unknown. Here, we show that Arabidopsis SPX1/2 negatively regulate leaf senescence genetically downstream of the strigolactone (SL) pathway. We demonstrate that the SL receptor AtD14 and MAX2 mediate the age-dependent degradation of SPX1/2. Intriguingly, we uncover an age-dependent accumulation of SLs in leaves via transcriptional activation of SL biosynthetic genes by the transcription factors (TFs) SPL9/15. Furthermore, we reveal that SPX1/2 interact with the WRKY75 subclade TFs to inhibit their DNA-binding ability and thus repress transcriptional activation of salicylic acid (SA) biosynthetic gene SA Induction-Deficient 2, gating the age-dependent SA accumulation in leaves at the leaf senescence onset stage. Collectively, our new findings reveal a signaling pathway mediating sequential activation of SL and salicylate biosynthesis for the onset of leaf senescence in Arabidopsis.

Q negatively regulates wheat salt tolerance through directly repressing the expression of TaSOS1 and reactive oxygen species scavenging genes.

The Q transcription factor plays important roles in improving multiple wheat domestication traits such as spike architecture, threshability and rachis fragility. However, whether and how it regulates abiotic stress adaptation remain unclear. We found that the transcriptional expression of Q can be induced by NaCl and abscisic acid treatments. Using the q mutants generated by CRISPR/Cas9 and Q overexpression transgenic lines, we showed that the domesticated Q gene causes a penalty in wheat salt tolerance. Then, we demonstrated that Q directly represses the transcription of TaSOS1-3B and reactive oxygen species (ROS) scavenging genes to regulate Na+ and ROS homeostasis in wheat. Furthermore, we showed that wheat salt tolerance protein TaWD40 interacts with Q to competitively interfere with the interaction between Q and the transcriptional co-repressor TaTPL. Taken together, our findings reveal that Q directly represses the expression of TaSOS1 and some ROS scavenging genes, thus causing a harmful effect on wheat salt tolerance.

Enhanced direct gaseous CO2 fixation into higher bio-succinic acid production and selectivity.

Utilizing CO2 for bio-succinic acid production is an attractive approach to achieve carbon capture and recycling (CCR) with simultaneous production of a useful platform chemical. Actinobacillus succinogenes and Basfia succiniciproducens were selected and investigated as microbial catalysts. Firstly, the type and concentration of inorganic carbon concentration and glucose concentration were evaluated. 6 g C/L MgCO3 and 24 g C/L glucose were found to be the optimal basic operational conditions, with succinic acid production and carbon yield of over 30 g/L and over 40%, respectively. Then, for maximum gaseous CO2 fixation, carbonate was replaced with CO2 at different ratios. The "less carbonate more CO2" condition of the inorganic carbon source was set as carbonate: CO2 = 1:9 (based on the mass of carbon). This condition presented the highest availability of CO2 by well-balanced chemical reaction equilibrium and phase equilibrium, showing the best performance with regarding CO2 fixation (about 15 mg C/(L·hr)), with suppressed lactic acid accumulation. According to key enzymes analysis, the ratio of phosphoenolpyruvate carboxykinase to lactic dehydrogenase was enhanced at high ratios of gaseous CO2, which could promote glucose conversion through the succinic acid path. To further increase gaseous CO2 fixation and succinic acid production and selectivity, stepwise CO2 addition was evaluated. 50%-65% increase in inorganic carbon utilization was obtained coupled with 20%-30% increase in succinic acid selectivity. This was due to the promotion of the succinic acid branch of the glucose metabolism, while suppressing the pyruvate branch, along with the inhibition on the conversion from glucose to lactic acid.

A Crossover Trial Evaluating Coconut Oil as an Alternative to Commercial Ultrasound Gel in Obstetrical Ultrasounds.

OBJECTIVE: Our objective was to evaluate the quality of obstetrical ultrasound images obtained with coconut oil compared with commercial ultrasound gel and to assess patient acceptability. STUDY DESIGN: This was a randomized two-period crossover study in which 40 pregnant patients had standard biometry images obtained with both coconut oil and commercial ultrasound gel during their growth or anatomy ultrasound. All images were then rated by two blinded maternal-fetal medicine physicians on quality, resolution, and detail using a 0 to 100 scale. Contrasts obtained from linear mixed models were used to estimate the differences in image parameters between the agents. Participant experience was evaluated with an acceptability survey which included five items measured on a five-point Likert scale. RESULTS: Image quality, as rated by physicians, was found to be equivalent between commercial ultrasound gel and coconut oil. Additionally, there was not a statistically significant difference in image resolution or detail between the two coupling agents. The overall patient experience was significantly lower for commercial ultrasound gel when compared with coconut oil (mean difference = - 5.48, 95% confidence interval = [-6.89, -4.06]). CONCLUSION: Ultrasound images collected with coconut oil as the coupling agent are equivalent in quality to those collected using commercial ultrasound gel. Patients also preferred the use of coconut oil during their ultrasound, making its use a possible way to improve the patient ultrasound experience. Coconut oil has the potential as an alternative coupling agent that could significantly increase access to ultrasound use in resource-limited settings. KEY POINTS: · Coconut oil produces quality images during obstetrical ultrasounds.. · Patients prefer the use of coconut oil to standard ultrasound gel during obstetrical ultrasounds.. · Coconut oil is a coupling agent that could increase ultrasound use in resource-limited settings..

The Norepinephrine-QseC Axis Aggravates F. nucleatum-associated Colitis Through Interkingdom Signaling.

AIMS: Inflammatory bowel disease (IBD) is associated with F. nucleatum, and chronic stress can increase the risk of aggravation. However, whether norepinephrine (NE) can enhance the pathogenicity of F. nucleatum to aggravate dextran sulfate sodium salt (DSS)-induced colitis is unclear. METHODS: Transcriptome sequencing was used to identify differentially expressed genes in bacteria treated with NE. Affinity testing and molecular docking were applied to calculate and predict the binding of NE and Quorum sensing  regulators C (QseC). The pathogenicity of Fusobacterium nucleatum treated with NE and QseC inhibitors was examined in vitro and further verified using the IBD mouse model induced by DSS. RESULTS: Norepinephrine could bind to QseC directly to upregulate the quorum sensing pathway of F. nucleatum and enhance its virulence gene expression (FadA, FomA, Fap2) and invasiveness in vitro. Meanwhile, it promoted the invasion of F. nucleatum into the intestine and increased the expression of host inflammatory cytokines (IL-6, IL-1ß) to aggravate colonic inflammation in IBD mice. The QseC inhibitor LED209 inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid (SCFA)-producing bacteria (Prevotellaceae, Lactobacillaceae) to attenuate colonic inflammation in IBD mice. CONCLUSIONS: Generally, the NE-QseC axis enhanced the pathogenicity of F. nucleatum through interkingdom signaling to aggravate colonic inflammation in IBD mice. We see that QseC may be a potential target for microbiota management of IBD under chronic pressure.

Norepinephrine could bind to QseC directly to enhance the pathogenicity of F. nucleatum to aggravate colonic inflammation. The QseC inhibitor inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid­producing bacteria to attenuate colonic inflammation.

Discovery of sesquiterpenoids from an actinomycete Crossiella cryophila through genome mining and heterologous expression.

Genome mining of the Actinomycete Crossiella cryophila facilitated the discovery of a minimal terpenoid biosynthetic gene cluster of cry consisting of a class I terpene cyclase CryA and a CYP450 monooxygenase CryB. Heterologous expression of cry allowed the isolation and characterization of two new sesquiterpenoids, ent-viridiflorol (1) and cryophilain (2). Notably, cryophilain (2) possesses a 5/7/3-fused tricyclic skeleton bearing a distinctive bridgehead hydroxy group. The combined in vivo and in vitro experiments revealed that CryA, the first ent-viridiflorol terpene cyclase, catalyzes farnesyl diphosphate to form the 5/7/3 sesquiterpene core scaffold and P450 CryB serves as a tailoring enzyme responsible for installing a hydroxy group at the bridgehead carbon.

TDCPP and TiO2 NPs aggregates synergistically induce SH-SY5Y cell neurotoxicity by excessive mitochondrial fission and mitophagy inhibition.

Tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a halogen-containing phosphorus flame retardant, is widely used and has been shown to possess health risks to humans. The sustained release of artificial nanomaterials into the environment increases the toxicological risks of their coexisting pollutants. Nanomaterials may seriously change the environmental behavior and fate of pollutants. In this study, we investigated this combined toxicity and the potential mechanisms of toxicity of TDCPP and titanium dioxide nanoparticles (TiO2 NPs) aggregates on human neuroblastoma SH-SY5Y cells. TDCPP and TiO2 NPs aggregates were exposed in various concentration combinations, revealing that TDCPP (25 µg/mL) reduced cell viability, while synergistic exposure to TiO2 NPs aggregates exacerbated cytotoxicity. This combined exposure also disrupted mitochondrial function, leading to dysregulation in the expression of mitochondrial fission proteins (DRP1 and FIS1) and fusion proteins (OPA1 and MFN1). Consequently, excessive mitochondrial fission occurred, facilitating the translocation of cytochrome C from mitochondria to activate apoptotic signaling pathways. Furthermore, exposure of the combination of TDCPP and TiO2 NPs aggregates activated upstream mitochondrial autophagy but disrupted downstream Parkin recruitment to damaged mitochondria, preventing autophagosome-lysosome fusion and thereby disrupting mitochondrial autophagy. Altogether, our findings suggest that TDCPP and TiO2 NPs aggregates may stimulate apoptosis in neuronal SH-SY5Y cells by inducing mitochondrial hyperfission and inhibiting mitochondrial autophagy.

Bibliometric and visualized analysis of reporting and data systems from 2000 to 2022: research situation, global trends, and hotspots.

Background: The reporting and data system (RADS) has been researched across the world since it was first developed. This study used bibliometrics to analyze the research trends and current status of this field over the past almost 23 years and explored possible future research hotspots. Methods: We searched the Web of Science (WOS) literature on RADSs from January 1, 2000, to November 1, 2022, and evaluated the findings visually with VOSviewer (1.6.18), CiteSpace (6.1.3), and the "bibliometrix" package in R version 4.2.1. Results: We included 6,239 publications from 88 countries and regions. The number of published has shown an overall growth trend, especially since 2016. The United States was the country with the highest number of publications and citations. The top 10 most productive institutions in RADS research were mainly from South Korea and the United States. Kim EK was the most published author, and Turkbey B had the most cited publication. European Radiology had the most publications on the subject, while Radiology was the most influential journal. Magnetic resonance imaging, carcinoma, ultrasound, RADS, mammography, breast neoplasms, and diagnosis were the most common keywords. Artificial intelligence (AI) appears to be an emerging hotspot in the research of RADS. Conclusions: This study provides an overview of the development status of research into RADSs over the past 23 years. Research into RADSs has included various systems of the body, with the most studied being the breast, prostate, liver, and thyroid. In terms of auxiliary diagnosis, there is an increasing amount of research into the application of AI in RADSs, which along with the interpretability of AI, will be a hotspot of research in the following years.

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells.

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.

Trends and Hotspots in Global Radiomics Research: A Bibliometric Analysis.

Objectives: The purpose of this research is to summarize the structure of radiomics-based knowledge and to explore potential trends and priorities by using bibliometric analysis. Methods: Select radiomics-related publications from 2012 to October 2022 from the Science Core Collection Web site. Use VOSviewer (version 1.6.18), CiteSpace (version 6.1.3), Tableau (version 2022), Microsoft Excel and Rstudio's free online platforms (http://bibliometric.com) for co-writing, co-citing, and co-occurrence analysis of countries, institutions, authors, references, and keywords in the field. The visual analysis is also carried out on it. Results: The study included 6428 articles. Since 2012, there has been an increase in research papers based on radiomics. Judging by publications, China has made the largest contribution in this area. We identify the most productive institutions and authors as Fudan University and Tianjie. The top three magazines with the most publications are《FRONTIERS IN ONCOLOGY》, 《EUROPEAN RADIOLOGY》, and 《CANCERS》. According to the results of reference and keyword analysis, "deep learning, nomogram, ultrasound, f-18-fdg, machine learning, covid-19, radiogenomics" has been determined as the main research direction in the future. Conclusion: Radiomics is in a phase of vigorous development with broad prospects. Cross-border cooperation between countries and institutions should be strengthened in the future. It can be predicted that the development of deep learning-based models and multimodal fusion models will be the focus of future research. Advances in knowledge: This study explores the current state of research and hot spots in the field of radiomics from multiple perspectives, comprehensively, and objectively reflecting the evolving trends in imaging-related research and providing a reference for future research.

Enantio- and Regioselective Cascade Hydroboration of Methylenecyclopropanes for Facile Access to Chiral 1,3- and 1,4-Bis(boronates).

Chiral 1, n-bis(boronate) plays a crucial role in organic synthesis and medicinal chemistry. However, their catalytic and asymmetric synthesis has long posed a challenge in terms of operability and accessibility from readily available substrates. The recent discovery of the C═C bond formation through ß-C elimination of methylenecyclopropanes (MCP) has provided an exciting opportunity to enhance molecular complexity. In this study, the catalyzed asymmetric cascade hydroboration of MCP is developed. By employing different ligands, various homoallylic boronate intermediate are obtained through the hydroboration ring opening process. Subsequently, the cascade hydroboration with HBpin or B2 pin2 resulted in the synthesis of enantioenriched chiral 1,3- and 1,4-bis(boronates) in high yields, accompanied by excellent chemo- and enantioselectivities. The selective transformation of these two distinct C─B bonds also demonstrated their application potential in organic synthesis.

Major Depressive Disorder Prediction Based on Sleep-Wake Disorders Symptoms in US Adolescents: A Machine Learning Approach from National Sleep Research Resource.

Background: There is substantial evidence from previous studies that abnormalities in sleep parameters associated with depression are demonstrated in almost all stages of sleep architecture. Patients with symptoms of sleep-wake disorders have a much higher risk of developing major depressive disorders (MDD) compared to those without. Objective: The aim of the present study is to establish and compare the performance of different machine learning models based on sleep-wake disorder symptoms data and to select the optimal model to interpret the importance of sleep-wake disorder symptoms to predict MDD occurrence in adolescents. Methods: We derived data for this work from 2020 to 2021 Assessing Nocturnal Sleep/Wake Effects on Risk of Suicide Phase I Study from National Sleep Research Resource. Using demographic and sleep-wake disorder symptoms data as predictors and the occurrence of MDD measured base on the center for epidemiologic studies depression scale as an outcome, the following six machine learning predictive models were developed: eXtreme Gradient Boosting model (XGBoost), Light Gradient Boosting mode, AdaBoost, Gaussian Naïve Bayes, Complement Naïve Bayes, and multilayer perceptron. The models' performance was assessed using the AUC and other metrics, and the final model's predictor importance ranking was explained. Results: XGBoost is the optimal predictive model in comprehensive performance with the AUC of 0.804 in the test set. All sleep-wake disorder symptoms were significantly positively correlated with the occurrence of adolescent MDD. The insomnia severity was the most important predictor compared with the other predictors in this study. Conclusion: This machine learning predictive model based on sleep-wake disorder symptoms can help to raise the awareness of risk of symptoms between sleep-wake disorders and MDD in adolescents and improve primary care and prevention.

RhoGDIß inhibition via miR-200c/AUF1/SOX2/miR-137 axis contributed to lncRNA MEG3 downregulation-mediated malignant transformation of human bronchial epithelial cells.

Nickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIß. Notably, artificially increasing RhoGDIß levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIß contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c-Jun activity, which in turn promoted miR-200c transcription. High levels of miR-200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR-137, SP-1 protein translation, and the suppression of RhoGDIß mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co-regulation of RhoGDIß expression by long noncoding RNA MEG3, multiple microRNAs (miR-200c and miR-137), and RNA-regulated transcription factors (c-Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIß pathway.

An Enzyme-Cleavable Solubilizing-Tag Facilitates the Chemical Synthesis of Mirror-Image Proteins.

Mirror-image proteins (D-proteins) are useful in biomedical research for purposes such as mirror-image screening for D-peptide drug discovery, but the chemical synthesis of many D-proteins is often low yielding due to the poor solubility or aggregation of their constituent peptide segments. Here, we report a Lys-C protease-cleavable solubilizing tag and its use to synthesize difficult-to-obtain D-proteins. Our tag is easily installed onto multiple amino acids such as DLys, DSer, DThr, and/or the N-terminal amino acid of hydrophobic D-peptides, is impervious to various reaction conditions, such as peptide synthesis, ligation, desulfurization, and transition metal-mediated deprotection, and yet can be completely removed by Lys-C protease under denaturing conditions to give the desired D-protein. The efficacy and practicality of the new method were exemplified in the synthesis of two challenging D-proteins: D-enantiomers of programmed cell death protein 1 IgV domain and SARS-CoV-2 envelope protein, in high yield. This work demonstrates that the enzymatic cleavage of solubilizing tags under denaturing conditions is feasible, thus paving the way for the production of more D-proteins.

NONO promotes gallbladder cancer cell proliferation by enhancing oncogenic RNA splicing of DLG1 through interaction with IGF2BP3/RBM14.

Gallbladder cancer (GBC) is a highly malignant and rapidly progressing tumor of the human biliary system, and there is an urgent need to develop new therapeutic targets and modalities. Non-POU domain-containing octamer-binding protein (NONO) is an RNA-binding protein involved in the regulation of transcription, mRNA splicing, and DNA repair. NONO expression is elevated in multiple tumors and can act as an oncogene to promote tumor progression. Here, we found that NONO was highly expressed in GBC and promoted tumor cells growth. The dysregulation of RNA splicing is a molecular feature of almost all tumor types. Accordingly, mRNA-seq and RIP-seq analysis showed that NONO promoted exon6 skipping in DLG1, forming two isomers (DLG1-FL and DLG1-S). Furthermore, lower Percent-Spliced-In (PSI) values of DLG1 were detected in tumor tissue relative to the paraneoplastic tissue, and were associated with poor patient prognosis. Moreover, DLG1-S and DLG1-FL act as tumor promoters and tumor suppressors, respectively, by regulating the YAP1/JUN pathway. N6-methyladenosine (m6A) is the most common and abundant RNA modification involved in alternative splicing processes. We identified an m6A reader, IGF2BP3, which synergizes with NONO to promote exon6 skipping in DLG1 in an m6A-dependent manner. Furthermore, IP/MS results showed that RBM14 was bound to NONO and interfered with NONO-mediated exon6 skipping of DLG1. In addition, IGF2BP3 disrupted the binding of RBM14 to NONO. Overall, our data elucidate the molecular mechanism by which NONO promotes DLG1 exon skipping, providing a basis for new therapeutic targets in GBC treatment.

Insights into the impact of modification methods on the structural characteristics and health functions of pectin: A comprehensive review.

Pectin is a complex polysaccharide that is widely present in plant cells and has multiple physiological functions. However, most pectin exists in the form of protopectin, which has a large molecular weight and cannot be fully absorbed and utilized in the human gut to exert its effects. The significant differences in the structure of different sources of pectin also limited their application in the food and medical fields. In order to achieve greater development and utilization of pectin functions, this paper reviewed several commonly used methods for pectin modification from physical, chemical, and biological perspectives, and elaborated on the relationship between these modification methods and the structure and functional properties of pectin. At the same time, the functional characteristics of modified pectin and its application in medical health, such as regulating intestinal health, anticancer, anti-inflammatory, and drug transport, were reviewed, so as to provide a theoretical basis for targeted modification of pectin and the development of new modified pectin products.

Contrast-enhanced ultrasound (CEUS) and shear wave elastography (SWE) features for characterizing serous microcystic adenomas (SMAs): In comparison to pancreatic neuroendocrine tumors (pNETs).

Objectives: Serous microcystic adenoma (SMA), a primary benign pancreatic tumor which can be clinically followed-up instead of undergoing surgery, are sometimes mis-distinguished as pancreatic neuroendocrine tumor (pNET) in regular preoperative imaging examinations. This study aimed to analyze preoperative contrast-enhanced ultrasound (CEUS) and shear wave elastography (SWE) features of SMAs in comparison to pNETs. Material and methods: In this retrospective study, patients with imaging-diagnosed pancreatic lesions were screened between October 2020 to October 2022 (ethical approval No. B2020-309R). Performing by a Siemens Sequoia (Siemens Medical Solutions, Mountain View, CA, USA) equipped with a 5C-1 curved array transducer (3.0-4.5 MHz), CEUS examination was conducted to observe the microvascular perfusion patterns of pancreatic lesions in arterial phase, venous/late phases (VLP) using SonoVue® (Bracco Imaging Spa, Milan, Italy) as the contrast agent. Virtual touch tissue imaging and quantification (VTIQ) - SWE was used to measure the shear wave velocity (SWV, m/s) value to represent the quantitative stiffness of pancreatic lesions. Multivariate logistic regression was performed to analyze potential ultrasound and clinical features in discriminating SMAs and pNETs. Results: Finally, 30 SMA and 40 pNET patients were included. All pancreatic lesions were pathologically proven via biopsy or surgery. During the arterial phase of CEUS, most SMAs and pNETs showed iso- or hyperenhancement (29/30, 97 % and 31/40, 78 %), with a specific early honeycomb enhancement pattern appeared in 14/30 (47 %) SMA lesions. During the VLP, while most of the SMA lesions remained iso- or hyperenhancement (25/30, 83 %), nearly half of the pNET lesions revealed an attenuated hypoenhancement (17/40, 43 %). The proportion of hypoenhancement pattern during the VLP of CEUS differed significantly between SMAs and pNETs (P = 0.021). The measured SWV value of SMAs was significantly higher than pNETs (2.04 ± 0.70 m/s versus 1.42 ± 0.44 m/s, P = 0.002). Taking a SWV value > 1.83 m/s as a cutoff in differentiating SMAs and pNETs, the area under the receiver operating characteristic curve (AUROC) was 0.825, with sensitivity, specificity and likelihood ratio (+) of 85.71 %, 72.73 % and 3.143, respectively. Multivariate logistic regression revealed that SWV value (m/s) of the pancreatic lesion was an independent variable in discriminating SMA and pNET. Conclusion: By comprehensively evaluating CEUS patterns and SWE features, SMA and pNET may be well differentiated before the operation. While SMA typically presents as harder lesion in VTIQ-SWE, exhibiting a specific honeycomb hyperenhancement pattern during the arterial phase of CEUS, pNET is characterized by relative softness, occasionally displaying a wash-out pattern during the VLP of CEUS.

Wnt/ß-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer.

BACKGROUND: Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. METHODS: An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro. RESULTS: Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/ß-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/ß-catenin and IMPDH2. Blocking the Wnt/ß-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP. CONCLUSIONS: IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.