Giant magnetocaloric effect in spin supersolid candidate Na2BaCo(PO4)2.

Supersolid, an exotic quantum state of matter that consists of particles forming an incompressible solid structure while simultaneously showing superfluidity of zero viscosity1, is one of the long-standing pursuits in fundamental research2,3. Although the initial report of 4He supersolid turned out to be an artefact4, this intriguing quantum matter has inspired enthusiastic investigations into ultracold quantum gases5-8. Nevertheless, the realization of supersolidity in condensed matter remains elusive. Here we find evidence for a quantum magnetic analogue of supersolid-the spin supersolid-in the recently synthesized triangular-lattice antiferromagnet Na2BaCo(PO4)2 (ref. 9). Notably, a giant magnetocaloric effect related to the spin supersolidity is observed in the demagnetization cooling process, manifesting itself as two prominent valley-like regimes, with the lowest temperature attaining below 100 mK. Not only is there an experimentally determined series of critical fields but the demagnetization cooling profile also shows excellent agreement with the theoretical simulations with an easy-axis Heisenberg model. Neutron diffractions also successfully locate the proposed spin supersolid phases by revealing the coexistence of three-sublattice spin solid order and interlayer incommensurability indicative of the spin superfluidity. Thus, our results reveal a strong entropic effect of the spin supersolid phase in a frustrated quantum magnet and open up a viable and promising avenue for applications in sub-kelvin refrigeration, especially in the context of persistent concerns about helium shortages10,11.

MYC expression and fatty acid oxidation in EGFR-TKI acquired resistance.

This report expands on our previous research, highlighting a unique inverse correlation between MYC expression in tumor cells and immune cells during the development of EGFR-TKI resistance. It is observed that MYC expression and fatty acid oxidation (FAO) metabolism in tissue-resident memory (TRM) CD8 + T cells are significantly impaired. These findings offer new insights into the mechanisms of TKI resistance. Although the study is preliminary, it suggests caution when interpreting the effectiveness of MYC inhibitors in reversing TKI resistance, especially when immune factors are not considered.

Construction of a three-dimensional inflammation model of human bronchial epithelial cells BEAS-2B by using the self-assembling D-form peptide Sciobio-â ¢.

Human bronchial epithelial cells in the airway system, as the primary barrier between humans and the surrounding environment, assume a crucial function in orchestrating the processes of airway inflammation. Target to develop a new three-dimensional (3D) inflammatory model to airway system, and here we report a strategy by using self-assembling D-form peptide to cover the process. By testing physicochemical properties and biocompatibility of Sciobio-Ⅲ, we confirmed that it can rapidly self-assembles under the trigger of ions to form a 3D nanonetwork-like scaffold, which supports 3D cell culture including the cell strains like BEAS-2B cells. Subsequently, inflammation model was established by lipopolysaccharide (LPS), the expression of some markers of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8), the levels of relevant inflammatory factors were measured by RT-qPCR and the secretion profile of inflammatory cytokines by ELISA, are obtained the quite difference effects in 2D and 3D microenvironment, which suggested Sciobio-Ⅲ hydrogel is an ideal scaffold that create the microenvironment for 3D cell culture. Here we are success to establish a 3D inflammation model for airway system. This innovative model allows for rapid and accurate evaluation of drug metabolism and toxicological side effects, hope to use in drug screening for airway inflammatory diseases and beyond.

Engineering Self-Assembling Peptide Hydrogel to Enhance the Capacity of Dendritic Cells to Activate In Vivo T-Cell Immunity.

The efficacy of the dendritic cell (DC) has failed to meet expectations thus far, and crucial problems such as the immature state of DCs, low targeting efficiency, insufficient number of dendritic cells, and microenvironment are still the current focus. To address these problems, we developed two self-assembling peptides, RLDI and RQDT, that mimic extracellular matrix (ECM). These peptides can be self-assembled into highly ordered three-dimensional nanofiber scaffold structures, where RLDI can form gelation immediately. In addition, we found that RLDI and RQDT enhance the biological function of DCs, including releasing antigens sustainably, adhering to DCs, promoting the maturation of DCs, and increasing the ability of DC antigen presentation. Moreover, peptide hydrogel-based DC treatment significantly achieved prophylactic and treatment effects on colon cancer. These results have certain implications for the design of new broad-spectrum vaccines in the future.

Single-cell transcriptional profiling uncovers the association between EOMES+CD8+ T cells and acquired EGFR-TKI resistance.

Acquired resistance to tyrosine kinase inhibitors (TKIs) is reportedly inevitable in lung cancers harboring epidermal growth factor receptor (EGFR) mutations, emphasizing the need for novel approaches to predict EGFR-TKI resistance for clinical monitoring and patient management. This study identified a significant increase in eomesodermin (EOMES)+CD8+ T cells in the TKI-resistant patients, which was correlated with poor survival. The increase in EOMES+CD8+ T cells was further confirmed in both tissue samples and peripheral blood of patients with TKIs resistance. The integrated analysis of pseudotime and Gene set variation showed that the increase in EOMES+CD8+ T cells may be attributed to TRM T cell conversion and metabolic reprogramming. Overall, this work suggested an association between the increased number of EOMES+CD8+ T cells and acquired TKI drug resistance, supporting the utility of EOMES+CD8+ T cells as a biomarker for TKI treatment response.

Transcriptomic analysis reveals the inhibitory effect of beta-sitosterol on proliferation of bovine preadipocytes.

Fat deposition affects beef quantity and quality via preadipocyte proliferation. Beta-sitosterol, a natural small molecular compound, has various functions, such as anti-inflammation, antibacterial, and anticancer properties. The mechanism of action of Beta-sitosterol on bovine preadipocytes remains unclear. This study, based on RNA-seq, reveals the impact of Beta -sitosterol on the proliferation of bovine preadipocytes. Compared to the control group, Beta-sitosterol demonstrated a more pronounced inhibitory effect on cell proliferation after 48 hours of treatment than after 24 hours, as evidenced by the results of EdU staining and flow cytometry. RNA-seq and Western Blot analyses further substantiated these findings. Our results suggest that the impact of Beta-sitosterol on the proliferation of bovine preadipocytes is not significant after a 24-hour treatment. It is only after extending the treatment time to 48 hours that Beta-sitosterol may induce cell cycle arrest at the G2/M phase by suppressing the expression of CCNB1, thereby inhibiting the proliferation of bovine preadipocytes.

Ferritinophagy: A new idea for liver diseases regulated by ferroptosis.

BACKGROUND: The discovery of regulatory cell death has led to a breakthrough in the therapeutic field. Various forms of cell death, such as necrosis, apoptosis, pyroptosis, autophagy, and ferroptosis, play an important role in the development of liver diseases. In general, more than one form of cell death pathways is responsible for the disease state. Therefore, it is particularly important to study the regulation and interaction of various cell death forms in liver diseases. DATA SOURCES: We performed a PubMed search up to November 2022 with the following keywords: ferritinophagy, ferroptosis, and liver disease. We also used terms such as signal path, inducer, and inhibitor to supplement the query results. RESULTS: This review summarized the basic characteristics of ferritinophagy and ferroptosis and the regulation of ferroptosis by ferritinophagy and reviewed the key targets and treatment strategies of ferroptosis in different liver diseases. CONCLUSIONS: Ferritinophagy is a potential therapeutic target in ferroptosis-related liver diseases.

An inflammation-associated ferroptosis signature optimizes the diagnosis, prognosis evaluation and immunotherapy options in hepatocellular carcinoma.

Inflammation and ferroptosis crosstalk complexly with immune microenvironment of hepatocellular carcinoma (HCC), thus affecting the efficacy of immunotherapy. Herein, our aim was to identify the inflammation-associated ferroptosis (IAF) biomarkers for contributing HCC. A total of 224 intersecting DEGs identified from different inflammation- and ferroptosis-subtypes were set as IAF genes. Seven of them including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 were used for construction of a risk model which classified HCC patients into two groups (high and low risk). HCC patients in the high-risk group exhibited shorter survival rate and higher immune score, and were predicted to have higher respond rate in immune checkpoint inhibition (ICI) therapy. Levels of the seven genes were significantly changed in HCC tissues in comparison to adjacent tissues. After inserting the gene expression into the risk model, we found that the risk model exhibited the higher diagnostic value for distinguish HCC tissues compared each single gene. Furthermore, HCC tissues from our research group with high-risk score exhibited more cases of microsatellite instability (MSI), heavier tumour mutational burden (TMB), higher expression level of PDL1 and cells with CD8. Knockdown of APOA5 reduced HCC cell proliferation combining with elevating inflammation and ferroptosis levels. In conclusion, we considered APOA5 maybe a novel target for suppressing HCC via simultaneously elevating inflammation and ferroptosis levels, and signature constructed by seven IAF genes including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 can act as a biomarker for optimising the diagnosis, prognosis evaluation and immunotherapy options in HCC patients.

N6-methyladenosine regulators are potential prognostic biomarkers for multiple myeloma.

N6-methyladenosine (m6A) regulators play an important role in tumorigenesis; however, their role in multiple myeloma (MM) remains unknown. This study aimed to create an m6A RNA regulators prognostic signature for MM patients. We integrated data from the Multiple Myeloma Research Foundation CoMMpass Study and the Genotype-Tissue Expression database to analyze gene expression profiles of 21 m6A regulators. Consistent clustering analysis was used to identify the clusters of patients with MM having different clinical outcomes. Gene distribution was analyzed using principal component analysis. Next, we generated an mRNA gene signature of m6A regulators using a multivariate logistic regression model with least absolute shrinkage and selection operator. The expressions of m6A regulators, except FMR1, were significantly different in MM samples compared with those in normal samples. The KIAA1429, HNRNPC, FTO, and WTAP expression levels were dramatically downregulated in tumor samples, whereas those of other signatures were remarkably upregulated. Three clusters of patients with MM were identified, and significant differences were found in terms of overall survival (p = .024). A prognostic two-gene signature (KIAA1429 and HNRNPA2B1) was constructed, which had a good prognostic significance using the ROC method (AUC = 0.792). Moreover, the risk score correlated with the infiltration immune cells. In addition, KEGG pathway analysis showed that 16 pathways were dramatically enriched. The m6A signature might be a novel biomarker for predicting the prognosis of patients with MM (p = .002). Our study is the first to explore the potential application value of m6A in MM. These findings may enhance the understanding of the functional organization of m6A in MM and provide new insights into the treatment of MM patients.

Low-threshold random lasers based on the DCM-DEG gain system with graphene nanosheets.

In this article, low-threshold random lasers based on DCM-DEG (DD) gain system with graphene nanosheets are studied. The experiment results show that the threshold of random lasers reduces rapidly when an appropriate amount of graphene nanosheets is added in DD solution. Meanwhile, the quantity and quality of random lasing modes raise significantly. We discussed the potential reasons why the graphene nanosheets can strengthen the sample's random lasing. And, the influence of the graphene nanosheet concentration on the radiation characteristics of random lasers is further studied. When the concentration of graphene nanosheets is 0.088wt%, the lasing threshold of DD samples with graphene nanosheets (GDD) is only about 31.8% of the lasing threshold of DD samples, and the quality of random lasing modes is five times higher than that of the DD sample. To further reduce the lasing threshold, the gold (Au) nanoparticles are added in the mixed solution to form the GDD solution with Au nanoparticles (GGDD). The results show that the lasing threshold of the GGDD sample is about 7.73 µJ/pulse, which is 5.2% of the lasing threshold of the DD sample. This experiment provides a new method to study low-threshold and high-quality random lasers based on graphene.

Synthesis of C4-Aminated Carbazoles and Their Derivatives via Pd/NBE Chemistry.

Carbazole, as one of the most important organic frameworks, has been used in optoelectronic materials and biochemistry. However, the synthesis of C4-substituted carbazole has always been an unsolved problem. This report describes the one-step synthesis of C4-aminated carbazoles and their derivatives through the series reaction of C-H amination and arylation. The substrate scope is wide. C4-Amino carbazoles substituted by C2, C6, C7, and C8 methyl groups, especially carbazole derivatives of fused rings, pyridine, and dibenzofuran, can be synthesized.

Template Synthesis to Solve the Unreachable Ortho C-H Functionalization Reaction of Aryl Iodide.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho-site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Deep Learning-Based Segmentation of Airway Morphology from Endobronchial Optical Coherence Tomography.

BACKGROUND: Manual measurement of endobronchial optical coherence tomography (EB-OCT) images means a heavy workload in the clinical practice, which can also introduce bias if the subjective opinions of doctors are involved. OBJECTIVE: We aim to develop a convolutional neural network (CNN)-based EB-OCT image analysis algorithm to automatically identify and measure EB-OCT parameters of airway morphology. METHODS: The ResUNet, MultiResUNet, and Siamese network were used for analyzing airway inner area (Ai), airway wall area (Aw), airway wall area percentage (Aw%), and airway bifurcate segmentation obtained from EB-OCT imaging, respectively. The accuracy of the automatic segmentations was verified by comparing with manual measurements. RESULTS: Thirty-three patients who were diagnosed with asthma (n = 13), chronic obstructive pulmonary disease (COPD, n = 13), and normal airway (n = 7) were enrolled. EB-OCT was performed in RB9 segment (lateral basal segment of the right lower lobe), and a total of 17,820 OCT images were collected for CNN training, validation, and testing. After training, the Ai, Aw, and airway bifurcate were readily identified in both normal airway and airways of asthma and COPD. The ResUNet and the MultiResUNet resulted in a mean dice similarity coefficient of 0.97 and 0.95 for Ai and Aw segmentation. The accuracy Siamese network in identifying airway bifurcate was 96.6%. Bland-Altman analysis indicated there was a negligible bias between manual and CNN measurements for Ai (bias = -0.02 to 0.01, 95% CI = -0.12 to 0.14) and Aw% (bias = -0.06 to 0.12, 95% CI = -1.98 to 2.14). CONCLUSION: EB-OCT imaging in conjunction with ResUNet, MultiResUNet, and Siamese network could automatically measure normal and diseased airway structure with an accurate performance.

Cannulation via the external jugular vein--An alternative to conventional peripherally inserted central catheterisation for paediatric patients.

PURPOSE: This study aimed to describe a peripherally inserted central catheterisation (PICC) for paediatric patients with inaccessible access and a high risk of general anaesthesia (GA). METHODS: This was a retrospective observational study involving all paediatric inpatients who performed the PICC via an EJV approach without GA between September 2014 and September 2021 in a provincial key clinical speciality. RESULTS: A total of 290 EJV line placement attempts were performed, and 29 were excluded due to missing placement results, resulting in a sample size of 261. The anatomical localisation, punctures, and catheterisation success rates for this practice were 100%, 100%, and 90.04%, respectively. The placement success rate in children younger than one year was 93.75% (45/48). The median line duration of use was 19 days, with a median length of catheter insertion of 13 cm. The most common complications were catheter malposition (n = 20) and dislodgement (n = 7). CONCLUSION: The PICC via an EJV approach without GA is a feasible and safe practice with acceptable success and complication rates, and low costs. It might be an attractive alternative for obtaining central vascular access for paediatric patients.

Analysis of the Influencing Factors of Delirium after PCI for Acute Myocardial Infarction and its Impact on the Quality of Life of Patients.

Objective: Delirium is a common and serious issue in patients recovering from percutaneous coronary intervention (PCI). It can lead to longer hospital stays, increased mortality, and decreased quality of life. This study aims to investigate different nursing interventions to improve care for post-PCI patients by reducing the incidence and duration of delirium. Methods: Between December 2021 and April 2023, we enrolled patients who underwent PCI surgery for acute myocardial infarction at our hospital as study participants. Utilizing a clinical randomized controlled trial design, we allocated these patients randomly into either the intervention group or the control group. The control group received conventional nursing care, while the intervention group received routine nursing care augmented by family visit nursing care, encompassing emotional support, education, and enhanced communication with family members. Upon the completion of all intervention measures, we assessed the incidence of delirium in post-PCI patients using the Richmond Agitation Sedation Scale (RASS) and the ICU Ambiguity Assessment Method for the Intensive Care Unit (CAM-ICU). Furthermore, we evaluated the patients' quality of life using the US Medical Bureau's Quality of Life Health Survey (SF-36). Result: Significant differences were observed in Richmond Agitation Sedation Scale (RASS) scores at 24 and 48 hours post-PCI, favoring the intervention group (P < .05). The intervention group also exhibited a lower incidence of delirium at 24 hours (P < .05) and a significantly shorter delirium duration (P < .05). While baseline quality of life scores did not differ significantly between the groups, post-intervention, the intervention group demonstrated significantly higher quality of life scores. These results underscore the positive impact of combined nursing interventions on sedation levels, delirium incidence and duration, and overall quality of life for post-PCI patients. Conclusion: The combined approach of routine nursing care and home visit interventions significantly reduced delirium incidence and duration in post-PCI patients. This personalized care strategy emphasizes patient well-being and is indicative of a broader shift towards individualized healthcare. It highlights the potential for enhanced patient outcomes and improved quality of life in the context of post-PCI patient management.

Hierarchical Aggregation for Numerical Data under Local Differential Privacy.

The proposal of local differential privacy solves the problem that the data collector must be trusted in centralized differential privacy models. The statistical analysis of numerical data under local differential privacy has been widely studied by many scholars. However, in real-world scenarios, numerical data from the same category but in different ranges frequently require different levels of privacy protection. We propose a hierarchical aggregation framework for numerical data under local differential privacy. In this framework, the privacy data in different ranges are assigned different privacy levels and then disturbed hierarchically and locally. After receiving users' data, the aggregator perturbs the privacy data again to convert the low-level data into high-level data to increase the privacy data at each privacy level so as to improve the accuracy of the statistical analysis. Through theoretical analysis, it was proved that this framework meets the requirements of local differential privacy and that its final mean estimation result is unbiased. The proposed framework is combined with mini-batch stochastic gradient descent to complete the linear regression task. Sufficient experiments both on synthetic datasets and real datasets show that the framework has a higher accuracy than the existing methods in both mean estimation and mini-batch stochastic gradient descent experiments.

CT-guided percutaneous microwave ablation for pulmonary metastases from colorectal cancer: Prognosis analyses based on the origin of the primary tumor.

BACKGROUND: Microwave ablation (MWA) is becoming an effective therapy for inoperable pulmonary metastases from colorectal cancer (CRC). However, it is unclear whether the primary tumor location affects survival after MWA. OBJECTIVE: This study aims to investigate the survival outcomes and prognostic factors of MWA based on different primary origins between colon and rectal cancer. METHODS: Patients who underwent MWA for pulmonary metastases from 2014 to 2021 were reviewed. Differences in survival outcomes between colon and rectal cancer were analyzed with the Kaplan-Meier method and log-rank tests. The prognostic factors between groups were then evaluated by univariable and multivariable Cox regression analyses. RESULTS: A total of 118 patients with 154 pulmonary metastases from CRC were treated in 140 MWA sessions. Rectal cancer had a higher proportion with seventy (59.32% ) than colon cancer with forty-eight (40.68% ). The average maximum diameter of pulmonary metastases from rectal cancer (1.09 cm) was greater than that of colon cancer (0.89 cm; p = 0.026). The median follow-up was 18.53 months (range 1.10 - 60.63 months). The disease-free survival (DFS) and overall survival (OS) in colon and rectal cancer groups were 25.97 vs 11.90 months (p = 0.405), and 60.63 vs 53.87 months (p = 0.149), respectively. Multivariate analyses showed that only age was an independent prognostic factor in patients with rectal cancer (HR = 3.70, 95% CI: 1.28 - 10.72, p = 0.023), while none in colon cancer. CONCLUSIONS: Primary CRC location has no impact on survival for patients with pulmonary metastases after MWA, while a disparate prognostic factor exists between colon and rectal cancer.

[Physicochemical properties of a novel chiral self-assembling peptide R-LIFE-1 and its controlled release to exosomes].

This research aims to investigate the encapsulation and controlled release effect of the newly developed self-assembling peptide R-LIFE-1 on exosomes. The gelling ability and morphological structure of the chiral self-assembling peptide (CSAP) hydrogel were examined using advanced imaging techniques, including atomic force microscopy, transmission electron microscopy, and cryo-scanning electron microscopy. The biocompatibility of the CSAP hydrogel was assessed through optical microscopy and fluorescent staining. Exosomes were isolated via ultrafiltration, and their quality was evaluated using Western blot analysis, nanoparticle tracking analysis, and transmission electron microscopy. The controlled release effect of the CSAP hydrogel on exosomes was quantitatively analyzed using laser confocal microscopy and a BCA assay kit. The results revealed that the self-assembling peptide R-LIFE-1 exhibited spontaneous assembly in the presence of various ions, leading to the formation of nanofibers. These nanofibers were cross-linked, giving rise to a robust nanofiber network structure, which further underwent cross-linking to generate a laminated membrane structure. The nanofibers possessed a large surface area, allowing them to encapsulate a substantial number of water molecules, thereby forming a hydrogel material with high water content. This hydrogel served as a stable spatial scaffold and loading matrix for the three-dimensional culture of cells, as well as the encapsulation and controlled release of exosomes. Importantly, R-LIFE-1 demonstrated excellent biocompatibility, preserving the growth of cells and the biological activity of exosomes. It rapidly formed a three-dimensional network scaffold, enabling the stable loading of cells and exosomes, while exhibiting favorable biocompatibility and reduced cytotoxicity. In conclusion, the findings of this study support the notion that R-LIFE-1 holds significant promise as an ideal tissue engineering material for tissue repair applications.

Extruded small extracellular vesicles: splinters of circulating tumour cells may promote cancer metastasis?

We speculate ruptured circulating tumour cells (CTC) in capillaries could release a large number of small extracellular vesicle-like vesicles, namely mechanically extruded sEV (sEVme), which can encapsulate chromosomal DNA fragments. These sEVme have similar physicochemical properties compared to small extracellular vesicles spontaneously secreted by living cells (sEVss), and thus sEVme and sEVss cannot be effectively distinguished based on their size or membrane protein markers. Meanwhile, these sEVme derived from CTC inherit oncogenic payloads, deliver cargo through the bloodstream to recipient cells, and thus may promote cancer metastasis. The validation of this speculation could facilitate our understanding of EV biogenesis and cancer pathology. The potential finding will also provide a theoretical foundation for burgeoning liquid biopsy using DNA fragments derived from harvested sEV.

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53.

BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.