Abstract Purpose: Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. Experimental Design: In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA–based high-content screening was implemented to validate the function of the deregulated genes. Results: The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. Conclusions: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.
Modern conversational agents, including anime-themed chatbots, are frequently reactive and personality-driven but fail to capture the dynamic nature of human interactions. We propose an event-driven dialogue framework to address these limitations by embedding dynamic events in conversation prompts and fine-tuning models on character-specific data. Evaluations on GPT-4 and comparisons with industry-leading baselines demonstrate that event-driven prompts significantly improve conversational engagement and naturalness while reducing hallucinations. This paper explores the application of this approach in creating lifelike chatbot interactions within the context of Honkai: Star Rail, showcasing the potential for dynamic event-based systems to transform role-playing and interactive dialogue.
Abstract Background Pancreatic cancer (PC) is still a lethal disease and has a poor prognosis, gemcitabine-based chemotherapy is now the standard regimen in the treatment of pancreatic cancer. Gemcitabine resistance is an important obstacle for effective treatment of patients and improvement in patients’ overall survival (OS) and disease free survival (DFS). Methods We collected the surgical pathological tissue of pancreatic cancer patients who received radical surgery in our hospital from September 2004 to December 2014 continuously. 375 pancreatic cancer tissues and paired adjacent non-tumor tissues were employed for the construction of 4 tissue microarrays (TMAs). The quality of 4 TMAs was reexamined by HE staining. We did immunohistochemistry analysis to test hENT1 expression. The hENT1 antibody was used to measure hENT1 expression in TMAs by IHC staining according to standard protocols. Statistical analyses were performed using SPSS 22.0. The clinical end points of patients were calculated using Kaplan-Meier analysis and differences compared by log-rank test. Cox regression (proportional hazards model) was applied to determine the prognostic values of multivariate factors on patients’ overall survival (OS) and disease free survival (DFS). Results The hENT1 protein expression in tumor tissues was much lower than in normal tissues (80.5±8.8 versus 89.5±8.9, p=0.005). A low hENT1 expression level indicated a significant poor outcome of PC patients, including shortened DFS(21.6±2.8 months versus 36.9±4.0 months, p<0.001) and OS(33.6±3.9 versus 39.6±3.9, p=0.004). A high hENT1 expression level was related to longer DFS (35.7±4.0 versus 20.6±2.7; p<0.0001). Similarly, patients with high hENT1 expression in gemcitabine-treated group showed longer overall survival OS compared with low expression group (39.4±4.0 versus 31.5±3.9, p=0.001). In contrast, no significant difference of DFS and OS was found in non-gemcitabine treated group between the expression level of hENT1 and the prognosis of patients (p=0.413 and p=0.152). A low hENT1 expression level in tumor tissues was an independent risk factor for PC recurrence or metastasis(HR 0.53; 95% CI: 0.39-0.72; p<0.001). In addition, a low expression level of hENT1 (HR 0.60; 95%CI: 0.43-0.82; p=0.001) was independent risk factors for overall survival of PC. Low hENT1 expression level predicted worse OS (HR 0.60; 95%CI: 0.43-0.82; p=0.002) and DFS (HR 0.56; 95%CI: 0.41-0.77; p<0.001) . Conclusion hENT1 was low expressed in tumor tissues and this decreased expression level indicated a worse outcome (including shortened OS and DFS) in patients who received gemcitabine treatment postoperatively.
<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. In this study, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in patients with PDAC. FRG1 deficiency promoted FBXO32 upregulation in PDAC. FBXO32 promoted cell migration and invasion <i>in vitro</i> and tumor growth and metastasis <i>in vivo</i>. Mechanistically, FBXO32 directly interacted with eEF1A1 and promoted its polyubiquitination at the K273 site, leading to enhanced activity of eEF1A1 and increased protein synthesis in PDAC cells. Moreover, FBXO32-catalyzed eEF1A1 ubiquitination boosted the translation of <i>ITGB5</i> mRNA and activated focal adhesion kinase (FAK) signaling, thereby facilitating focal adhesion assembly and driving PDAC progression. Importantly, interfering with the FBXO32–eEF1A1 axis or pharmaceutical inhibition of FAK by defactinib, an FDA-approved FAK inhibitor, substantially inhibited PDAC growth and metastasis driven by aberrantly activated FBXO32–eEF1A1 signaling. Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible patients with PDAC for treatment with defactinib.</p><p><b>Significance:</b> FBXO32 upregulation in pancreatic cancer induced by FRG1 deficiency increases eEF1A1 activity to promote ITGB5 translation and stimulate FAK signaling, driving cancer progression and sensitizing tumors to the FAK inhibitor defactinib.</p></div>
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