[This corrects the article DOI: 10.34133/research.0838.].

Although glycolysis is a metabolic hallmark of pancreatic ductal adenocarcinoma (PDAC), it remains unclear whether the excessive lactate produced regulates CAF lactylation to promote extracellular matrix (ECM) deposition. The multi-omics and spontaneous model findings indicate that lactate accumulation in the tumor microenvironment (TME) promotes histone H3 lysine 18 lactylation (H3K18la) and activation of cancer-associated fibroblasts (CAFs), leading to both ECM densification and impaired immunotherapy efficacy in PDAC. Mechanistically, ubiquitin-conjugating enzyme E2T (UBE2T) acts as an initiating factor that promotes p53 positive feedback degradation through modulation of ribosome biogenesis, thereby enhancing lactate metabolic crosstalk via glycolytic reprogramming. Genetic ablation or pharmacological inhibition of UBE2T using the selective inhibitor pentagalloylglucose (PGG) disrupts lactate metabolic crosstalk, suppresses stromal deposition, and promotes intratumoral CD8+ T cells infiltration. Furthermore, the combination of PGG and anti-PD-1 therapy exhibits synergistic effects and survival benefits in spontaneous PDAC mice and immune-reconstituted patient-derived xenografts. Collectively, these findings reveal that UBE2T drives p53 positive feedback degradation to enhance glycolysis of PDAC, leading to excessive lactate production, which promotes H3K18la in CAFs and subsequent ECM deposition. Targeting UBE2T represents a potential strategy to improve the efficacy of immunotherapy in PDAC.

Inflammatory signaling, metabolic reprogramming, and stromal complexity have emerged as core hallmarks of pancreatic ductal adenocarcinoma (PDAC). Cross-talk between these programs could represent potential targets to concurrently perturb multiple tumor-promoting processes. By integrating multiomics data from clinical cohorts, patient-derived organoids, and autochthonous models, we uncovered tumor-intrinsic inflammatory cascades in PDAC as master regulators of mevalonate pathway hijacking, which drove both malignant progression and stromal coevolution. TNFSF13B+ tumor-associated macrophages activated STAT3 signaling in neoplastic epithelia, leading to the transcriptional upregulation of USP20. This deubiquitinase stabilized HMGCR to potentiate mevalonate flux, resulting in cholesterol and geranylgeranyl pyrophosphate overproduction. Stimulation of YAP/TAZ signaling induced by the USP20-mediated metabolic alterations promoted tumor cell proliferation and triggered the activation of cancer-associated fibroblasts. Genetic ablation or pharmacologic inhibition of USP20 using a selective inhibitor reversed tumor metabolic dysregulation, suppressing both tumor growth and stromal desmoplasia. Furthermore, the combination of USP20 inhibition and anti-PD-1/anti-CTLA4 immunotherapy resulted in enhanced antitumor efficacy. These findings reveal the STAT3-USP20-HMGCR axis as a central coordinator of PDAC malignancy and position USP20 inhibition as a strategy to suppress oncogenic signaling, perturb metabolic reprogramming, and reverse microenvironmental remodeling.Significance: Targeting USP20 disrupts coevolution of pancreatic ductal adenocarcinoma and the tumor microenvironment and enhances immune checkpoint inhibitor efficacy by blocking mevalonate metabolism rewiring, providing a dual-action therapeutic approach for pancreatic cancer.

The ubiquitin-proteasome system is a fundamental regulatory mechanism that governs protein stability and intracellular signaling in eukaryotic cells. This system relies on a coordinated cascade of enzymatic activities involving activating enzymes, conjugating enzymes, and ligases to assemble distinct ubiquitin signals. These signals are subsequently edited, removed, or interpreted by deubiquitinases and ubiquitin-binding proteins. While E3 ligases have traditionally been recognized as the primary determinants of substrate specificity in the ubiquitination process, recent studies have revealed that the dysregulation of E2 enzymes can also lead to significant pathological outcomes, including chromatin instability, immune dysregulation, metabolic dysfunction, and an elevated risk of cancer. Consequently, E2 enzymes have emerged as promising therapeutic targets for the treatment of various dis-eases. This review provides a comprehensive examination of the roles and mechanisms of the ubiquitin-conjugating enzyme E2T (UBE2T) in cancer initiation, progression, and therapy resistance, highlighting its potential as a compelling target for cancer therapeutics.

CP organoids exhibit more proliferation ability, ECM-like characteristics and activation of inflammatory signaling

BACKGROUND:The application of the novel KRASG12D inhibitor in pancreatic ductal adenocarcinoma (PDAC) is currently hindered by adaptive resistance. Metabolic reprogramming is a hallmark of KRASG12D signalling, yet the mechanisms linking these alterations to immunosuppression and low therapeutic response are poorly defined. OBJECTIVE:To identify the key regulatory nodes connecting KRASG12D-driven metabolic adaptations to tumour microenvironment and develop a mechanistic-based combinatorial strategy. DESIGN:We integrated whole-exome sequencing, untargeted metabolomics and single-cell RNA sequencing of human PDAC specimens to analyse the metabolic-immune landscape. We evaluated therapeutic efficacy using the autochthonous mouse and patient-derived xenograft models. RESULTS:We found that KRASG12D enhanced cholesterol metabolism and promoted CD8+ T cell exhaustion, whereas KRASG12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy. Cotargeting cholesterol metabolism and autophagy potentiated the antitumour efficacy of the KRASG12D inhibitor MRTX1133 and alleviated CD8+ T cell exhaustion. Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival. Genetic depletion or pharmacological inhibition of USP20 with GSK2643943A suppressed these pathways and restored CD8+ T cell function, improving responses to MRTX1133 and anti-programmed cell death protein-1 (anti-PD-1). In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression. CONCLUSION:USP20 acts as a critical metabolic checkpoint that orchestrates CD8+ T cell exhaustion and therapeutic response. Targeting the USP20-cholesterol-autophagy axis represents a promising strategy to reverse immune suppression and unlock the full potential of KRASG12D inhibitors in PDAC.

Recent global data show that cancers of the digestive system are responsible for approximately one-third of all cancer-related deaths worldwide, underscoring the urgent need for innovative therapeutic strategies. In this context, emerging findings from neuroscience may unveil new avenues for tackling this pressing clinical problem. Over the past few years, rapid progress in cancer neuroscience has increasingly underscored the contribution of the nervous system to the development and progression of digestive tract tumors. Research has shown that the specialized neural network of the gastrointestinal tract establishes a framework for reciprocal interactions with digestive tract tumors. On this anatomical foundation, our review delves into the functional significance of these interactions, emphasizing the bidirectional regulatory pathways between the nervous system and tumor cells during disease progression and highlighting their intricate crosstalk with the immune microenvironment. In particular, it maps the molecular pathways by which both the central and peripheral nervous systems (PNS) modulate tumor initiation and progression. Moreover, it explains how neurotransmitters and neuroendocrine mediators drive tumor expansion through the activation of canonical oncogenic signaling cascades and the remodeling of the immunosuppressive microenvironment. This review seeks to elucidate the molecular underpinnings of neuro-immune-tumor crosstalk and to synthesize the latest neural-targeted therapeutic approaches. It also examines the principal obstacles that are impeding the clinical implementation of these interventions. By presenting an integrated overview, this work serves as a robust resource to inform future studies on neurobiological mechanisms and the development of novel therapies for gastrointestinal malignancies.

Diffuse-type gastric cancer (DGC) is an aggressive tumor type characterized by a dense extracellular matrix (ECM). Metabolic reprogramming, a key oncogenic factor driving tumor progression, is closely linked to ECM deposition, although the regulatory mechanisms remain poorly understood. In this study, we integrated single-cell sequencing, proteomics, metabolomics, and large-scale clinical data to identify the metabolic signature of DGC. We found that the tricarboxylic acid (TCA) cycle is suppressed in DGC, which correlates with the formation of a dense ECM. Annexin A8 (ANXA8) was identified as a critical regulator that inhibits the TCA cycle in DGC and is positively associated with matrix formation. Mechanistically, ANXA8 interacts with SP1 to promote the transcription of pyrophosphatase 1, thereby suppressing the TCA cycle, activating cancer-associated fibroblasts, and facilitating aberrant ECM deposition. Deletion of ANXA8 suppresses malignant phenotypes and shows synergistic effects with the chemotherapeutic agent 5-fluorouracil (5-FU). Large-scale clinical data further confirmed the correlation between ANXA8 expression and both gastric cancer progression and 5-FU therapeutic efficacy. High-throughput organoid screening identified UNC2025 as a selective ANXA8 inhibitor. Targeting ANXA8 with UNC2025 restores TCA cycle activity and inhibits ECM deposition in DGC, enhancing the therapeutic effects of 5-FU in patient-derived xenografts and organoids. Furthermore, a polyphenol-based UNC2025 nanodelivery system improved the efficacy of this combination therapy. In summary, this study elucidates how ANXA8-mediated suppression of the TCA cycle promotes dense ECM formation and malignant progression in DGC, highlighting the therapeutic potential of targeting ANXA8 in DGC treatment.

The KRASG12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRASG12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRASG12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRASG12D-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRASG12D-mutated PDAC.

The stromal microenvironment of tumors, comprised of diverse stromal cells and extracellular matrix (ECM), is intricately influenced by multiple signaling pathways, metabolic regulation, and the cell cycle, significantly contributing to tumor malignancy and therapy resistance. Posttranslational modifications (PTMs), crucial mechanisms for regulating protein function in organisms, engage in tumor initiation, progression, metastasis, and therapy resistance by modulating stromal cell behavior, stromal signal transduction, ECM deposition, and remodeling within the tumor stromal microenvironment. This article explores the regulatory role of PTMs within the tumor stromal microenvironment and reviews recent advancements in cancer therapy focused on PTMs. Targeting PTMs within the tumor stromal microenvironment shows promising potential as a novel approach and direction in cancer treatment.

Breast cancer stem cells (BCSCs) are the main cause of breast cancer recurrence and metastasis. While the ubiquitin-proteasome system contributes to the regulation of BCSC stemness, the underlying mechanisms remain unclear. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a pivotal ubiquitin enzyme regulating BCSC stemness through systemic screening assays, including single-cell RNA sequencing (scRNA-seq) and stemness-index analysis. We found that patients with high UBE2T expression exhibited worse prognosis than those with low expression (10-year PFS: 55.95% vs. 85.08%), which are consistent across various subtypes of breast cancers. Genetic ablation of UBE2T suppresses BCSC stemness and tumor progression in organoids and spontaneous MMTV-PyMT mice, dependent on the transcriptional inactivation of pluripotency genes SOX2 and NANOG. Mechanically, UBE2T collaborates with the E3 ligase TRIM25 to perform K48-linked polyubiquitination and degradation of CBX6 at K214, which deficiency helps to promote the transcription of SOX2 and NANOG and enhances BCSC stemness. The pharmacological inhibitor of UBE2T significantly reduced the expression of NANOG and SOX2, suppressed tumor progression, and demonstrated synergistic effects when combined with chemotherapeutics, but not with other treatments. Collectively, our study revealed that the UBE2T-TRIM25-CBX6 axis can regulate BCSC stemness and offers a potentially therapeutic strategy to combat breast cancer in a clinical translation setting.

The induction of replication stress has emerged as a potent strategy for cancer therapy, with alkylating agents, nucleoside analogs, and inhibitors of cyclin and cyclin-dependent kinase remaining prominent drugs. As mechanistic insights into responses to replication stress are evolving, novel therapeutic agents targeting replication stress response pathways have been progressively developed. Despite the demonstrated pharmacological and clinical efficacy of certain agents, the therapeutic landscape remains characterized by suboptimal patient prognoses. Mounting evidence implicates cancer cell metabolic reprogramming as a critical determinant in both modulating replication stress and attenuating genotoxic drug efficacy. In addition, some metabolic enzymes demonstrate non-canonical functions that potentiate DNA damage response, while some metabolic pathways contribute vulnerability to replication stress in malignant cells. Therefore, this review seeks to elucidate the mechanisms by which metabolic reprogramming modulates replication stress in cancer cells and to provide an overview of the latest advancements in therapeutic regimens development.

BACKGROUND & AIMS: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is wide-spread and compromises long-term survival. Here, we iden-tified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. METHODS: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/ thorn , LSL-Trp53R172H/ thorn , Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. RESULTS: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcita-bine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiq-uitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglu-cose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG dimin-ished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. CONCLUSIONS: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and allevi-ating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

目的:探讨紧密连接蛋白claudin-7(CLDN-7)在胰腺癌中的表达情况,以及其与患者临床病理特征和预后的相关性.方法:应用Oncomine、GEPIA和GEO数据库综合分析CLDN-7 mRNA在胰腺癌中的表达水平,应用Kaplan-Meier Plotter数据库分析胰腺癌中CLDN-7的表达水平与生存预后的关系;选取兰州大学第二医院普外科2015年至2018年手术切除的44例胰腺癌患者的癌组织及31例癌旁组织标本,采用免疫组织化学染色法检测CLDN-7蛋白的表达水平,并分析其与临床病理特征以及预后的关系;GO分析和KEGG通路富集分析CLDN-7可能参与的信号通路及发挥的主要功能,并且在TCGA和GEPIA数据库中进行验证.结果:数据库及收取的临床样本分析均显示,CLDN-7在胰腺癌组织中显著高表达,其高表达与胰腺癌患者临床预后有关联,并且CLDN-7的表达水平是影响胰腺癌患者术后总体生存时间的独立因素(均P<0.05);GO分析和KEGG通路富集分析证实,CLDN-7参与胰腺癌患者DNA损伤修复、糖代谢等;TCGA和GEPIA数据库验证显示,胰腺癌中CLDN-7的表达与DNA损伤修复相关基因POLD4、SMUG1、NTHL1及糖代谢的相关基因ALDOA、TALDO1、PGLS的表达呈现出明显的正相关性(均P<0.01).结论:CLDN-7在胰腺癌中高表达且标志着更差的临床预后,并与胰腺癌的DNA损伤修复及肿瘤内糖代谢相关.

The front-end readout ASIC based on Si CMOS technology is primarily designed according to the output signal characteristics of the 3D Si PIN array thermal neutron detector.The key circuit modules of the designed readout ASIC include the charge sensitive amplifier (CSA),the analog switch design,an automatic gain control module (AGC) with three-level charge sensitivity automatic switching,the correlation dual sampling (CDS) and reference current source circuit.The simulation results show that the input dynamic range of the front-end circuit is 10 fC-8.0 pC.The three gain coefficients of the designed ASIC according to the thermal neutron detector output signal characteristics are set as 1.9 V/pC,0.39 V/pC and 94 mV/pC,respectively.The inte-gral nonlinearity of the designed ASIC is less than 1％.The single channel static power consumption is about 5.36 mW.The equivalent noise charge at zero input detector capacitance is 241.6e-.The counting rate can arrive to the level of 1 MHz.

目的:探讨环指蛋白144B(ring finger protein 144B,RNF144B)在胃癌组织中的表达水平及其与胃癌患者临床预后的关系.方法:回顾性分析2013年1月-2014年1月在兰州大学第二医院确诊并行根治性手术治疗的胃癌患者的临床资料;我们的研究一共纳入了105名患者,记录患者的TNM分期、肿瘤大小、分化水平、癌胚抗原(carcino-embryonic antigen,CEA)等指标并记录患者的总体生存时间(overall survival,OS);利用免疫组织化学染色(immunohistochemistry,IHC)检测RNF144B在胃癌及癌旁组织中的表达,并分析其与患者一般临床病理特征的联系;应用Cox回归模型评估患者术后总体生存时间的影响因素;使用Kaplan-Meier Plotter数据库对RNF144B进行生存相关性分析,随后利用临床数据进行验证.结果:RNF144B在胃癌组织中显著高表达(P=0.0039),RNF144B高表达组的患者CEA水平、Ki67阳性率、临床病理分期、T分期均显著高于低表达组,而分化程度差于低表达组(P<0.05);多因素分析显示RNF144B高表达、肿瘤分化程度低、临床病理分期高均是影响胃癌患者术后总体生存时间的独立因素(P<0.05);Kaplan-Meier法分析得RNF144B高表达组术后5年生存率(6.06％)低于低表达组(29.69％)(P<0.01).结论:RNF144B在胃癌中高表达并标志着更差的临床预后.

Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were analyzed by using the Drugbank database. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC ( n = 10) were lower compared with normal tissue ( n = 184) ( P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

For locating and grasping the lost gamma ray source with a robot in a nuclear accident,a gamma ray dosimeter based on double GM (Geiger-Müller) counters(ZP1321,ZP1301) was primarily designed with wide-dynamic range.The front-end analogue circuits for detector signal processing and the microcontroller-based detector data processing and transmission programs were designed and tested primarily with 137 Cs gamma ray source.The main influence factors on the designed dosimeter output signal were measured and analyzed.The primary experimental results show that the designed gamma ray dosimeter without shielding case can detect gamma ray radiation sources on-line successfully.

Iron overload has recently been connected with bone mineral density in osteoporosis. However, to date, the effect of iron overload on osteoblasts remains poorly understood. The purpose of this study is to examine osteoblast biological activity under iron overload. The osteoblast cells (hFOB1.19) were cultured in a medium supplemented with different concentrations (50, 100, and 200 μM) of ferric ammonium citrate as a donor of ferric ion. Intracellular iron was measured with a confocal laser scanning microscope. Reactive oxygen species (ROS) were detected by 2,7-dichlorofluorescin diacetate fluorophotometry. Osteoblast biological activities were evaluated by measuring the activity of alkaline phosphatase (ALP) and mineralization function. Results indicated that iron overload could consequently increase intracellular iron concentration and intracellular ROS levels in a concentration-dependent manner. Additionally, ALP activity was suppressed, and a decline in the number of mineralized nodules was observed in in vitro cultured osteoblast cells. According to these results, it seems that iron overload probably inhibits osteoblast function through higher oxidative stress following increased intracellular iron concentrations.

Objective To explore the relationship between osteoporosis and iron overload in elder women with hip fragile fracture.Methods Serum ferritin(FER) was examined and T value of hip and spine BMD was calculated in 30 elder women(≥70 years old,group A) with hip fragile fracture and 30 younger women(25～45 years old,group B) with traumatic fracture.Results The average FER was higher in group A than that in group B(269.97ng/ml vs.59.78ng/ml)(P0.01).T values of hip and spine in group A were-2.35 and-2.51,which were 0.08 and 0.32 in group B(P0.01).Conclusion Iron overload in the elder women with osteoporos is a strong factor correlated to osteoporosis.