Pancreatic cancer is a highly aggressive gastrointestinal tumor with limited treatment options, such as surgery and chemotherapy. Thus, further research into its pathogenesis and new treatments is necessary.

Fluorescence-activated cell sorting was employed to sort pancreatic cancer stem cells (PCSCs). Sphere formation assays and Cell Counting Kit-8 (CCK-8) assays were conducted to assess stemness and proliferation capacity. Quantitative real-time PCR and Western blot analysis were employed to assess gene expression levels. Furthermore, immunofluorescence microscopy and chromatin immunoprecipitation assays were conducted to examine alterations in signaling pathways and gene expression.

Quercetin and gemcitabine may inhibit PANC-1 cells and PCSCs by affecting energy metabolism. Chromatin immunoprecipitation assays revealed an interaction between STAT3 and CPT1B in PCSCs. Quercetin and gemcitabine might affect energy metabolism by inhibiting STAT3 and CPT1B. Manipulating STAT3 expression (overexpression plasmids and siRNA knockdown) altered CPT1B mRNA and protein expression. Although acetyl-CoA reversed the quercetin- and gemcitabine-induced expression of N-cadherin, DECR1, and ALDH, it had minimal influence on CPT1B and STAT3 levels.

Quercetin inhibits the expression of CPT1B via the STAT3 signaling pathway, affecting lipid metabolism and exerting antitumor effects. Furthermore, the combined administration of quercetin and gemcitabine exhibits enhanced therapeutic efficacy.

In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.

Pancreatic adenocarcinoma (PDAC) is one of the cancers with a very poor prognosis for its highly invasive and metastatic ability. Epithelial-mesenchymal transition (EMT) is critical for metastasis and invasion of PDAC cells, in which the expression of epithelial genes, such as E-cadherin (CDH1), decreases and that of mesenchymal genes increases. Transcription factor BTB and CNC homology 1 (BACH1) promotes EMT of PDAC cells in part by indirectly suppressing the expression of CDH1. However, the mechanism behind this is not yet clear. Considering recent reports on a link between intracellular iron and CDH1 expression in cancer cells, we examined whether BACH1 represses CDH1 expression by regulating ferritin gene. When AsPC-1 PDAC cells were treated with the iron chelator deferasirox (DFX), CDH1 expression was increased. While BACH1 knockdown resulted in increased CDH1 expression, combined knockdown of BACH1 and ferritin heavy chain gene (FTH1) reversed CDH1 expression. Tank-binding kinase 1 (TBK1), an upstream regulator of BACH1, was necessary to maintain EMT gene expression patterns in AsPC-1 cells. TBK1 was redundant with BACH1 to maintain VIM expression in SW1990 PDAC cells, suggesting its BACH1-independent role in EMT. Therefore, the regulation of CDH1 and EMT by BACH1 involves FTH1 and intracellular iron as mediators and TBK1 as an upstream and parallel regulator.

Liposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) improves survival in gemcitabine-refractory metastatic pancreatic cancer (PC) but requires a central venous port. S-1, an oral fluoropyrimidine with proven efficacy in PC, may replace 5-FU/LV in nal-IRI plus 5-FU/LV, potentially enhancing both convenience and antitumor effect.

This single-arm, open-label, phase 1/2 study included patients with histologically or cytologically confirmed adenocarcinoma, aged 20-80 years, an Eastern Cooperative Oncology Group performance status of 0-1, with metastatic disease, and refractory to gemcitabine-based treatment. The primary endpoint in phase 1 part was the frequency of dose-limiting toxicity (DLT) to nal-IRI plus S-1. The primary endpoint in phase 2 part was overall survival. This trial was registered in the Japan Registry of Clinical Trials database (jRCTs031210040).

In phase 1 part, one patient with DLT was observed at nal-IRI 70 mg/m2 (day 1) with S-1 80 mg/m2/day (day 1-7) in a 2-week cycle, establishing this as the recommended phase 2 dose (RP2D). Forty-nine patients from phase 1 (n = 6) and phase 2 part (n = 43) were treated with the RP2D, and their results were pooled. Median overall survival was 10.3 months (95 % confidence interval, 8.1-12.0 months). A confirmed partial response was achieved in 10 patients (20.4 %). The most frequent treatment-emergent adverse events were hypoalbuminemia (98.0 %), anemia (98.0 %), and anorexia (81.6 %). There were no treatment-related deaths.

This study demonstrated that nal-IRI plus S-1 exhibited promising efficacy and an acceptable safety profile in patients with metastatic PC refractory to gemcitabine-based treatment.

Pancreatic cancer (PaCa) is a deadly malignancy that is often diagnosed at an advanced stage, limiting treatment and reducing survival. There is an urgent need for convenient and accurate diagnostic markers for the early detection of PaCa.

In this multicenter case-control study, we performed transcriptome analysis of 673 platelet samples from different in-house and public cohorts. RNA sequencing and RT-qPCR were used to discover and validate potential platelet biomarkers. A multi-gene signature was developed using binomial generalized linear model and independently validated in multicenter cohorts.

Two platelet RNAs, SCN1B and MAGOHB, consistently showed robust altered expression patterns between PaCa and healthy controls across cohorts, as confirmed by both RNA sequencing and RT-qPCR. The diagnostic two-RNA signature, PLA2Sig, demonstrated remarkable performance in detecting PaCa, with area under the receiver operating characteristic curve (AUC) values of 0.808, 0.900, 0.783, and 0.830 across multicenter cohorts. Furthermore, PLA2Sig effectively identified resectable stage I&II PaCa cases with an AUC of 0.812. Notably, PLA2Sig outperformed the traditional serum markers carcinoembryonic antigen and carbohydrate antigen 19-9 in distinguishing PaCa from healthy controls, and is complementary to established blood-based screening biomarkers.

These findings provide preliminary but promising evidence for the potential utility of platelet RNAs as an alternative non-invasive liquid biopsy tool for the early detection of PaCa.

Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.

Cannabinoids have attracted increasing attention in cancer research in recent decades. A major focus of current preclinical and clinical studies is on the interactions and potential risks when combined with chemotherapeutic agents, targeted therapies and other anticancer strategies. Given the extensive preclinical data on additive, synergistic and, in some cases, antagonistic tumor cell killing effects of chemotherapeutic agents and cannabinoids when co-administered, a critical analysis of these data seems essential. The available data mainly relate to combination treatments for glioblastoma, hematological malignancies and breast cancer, but also for other cancer types. Such an analysis also appears necessary because cannabinoids are used as an option to treat nausea and vomiting caused by chemotherapy, as well as tumor-related pain, and cancer patients sometimes take cannabinoids without a medical prescription. In addition, numerous recent preclinical studies also suggest cannabinoid-mediated relief of other chemotherapy-related side effects such as peripheral neuropathy, nephrotoxicity, cardiotoxicity, cystitis, bladder complications and mucositis. To summarize, the data available to date raise the prospect that cannabinoids may increase the efficacy of chemotherapeutic agents while reducing their side effects. However, preclinical studies on anticancer interactions are mostly limited to cytotoxicity analyses. An equally thorough investigation of the effects of such combinations on the immune system and on the tumorigenic levels of angiogenesis, invasion and metastasis is still pending. On this basis, a comprehensive understanding for the evaluation of a targeted additional treatment of various cancers with cannabinoids could be established.

The metabolic pathway of sulfur-containing amino acids in organisms begins with methionine, which is metabolized to produce important sulfur-containing biomolecules such as adenosylmethionine, adenosylhomocysteine, homocysteine, cystine, and hydrogen sulfide (H2S). These sulfur-containing biomolecules play a wide range of physiological roles in the body, including anti-inflammation, antioxidant stress, DNA methylation, protein synthesis, etc., which are essential for maintaining cellular function and overall health. In contrast, dysregulation of the metabolic pathway of sulfur-containing amino acids leads to abnormal levels of sulfur-containing biomolecules, which produce a range of pathological consequences in multiple systems of the body, such as neurodegenerative diseases, cardiovascular diseases, and cancer. This review traces the milestones in the development of these sulfur-containing biomolecules from their initial discovery to their clinical applications and describes in detail the structure, physiochemical properties, metabolism, sulfide signaling pathway, physiopathological functions, and assays of sulfur-containing biomolecules. In addition, the paper also explores the regulatory role and mechanism of sulfur-containing biomolecules on cardiovascular diseases, liver diseases, neurological diseases, metabolic diseases and tumors. The focus is placed on donors of sulfur-containing biological macromolecule metabolites, small-molecule drug screening targeting H2S-producing enzymes, and the latest advancements in preclinical and clinical research related to hydrogen sulfide, including clinical trials and FDA-approved drugs. Additionally, an overview of future research directions in this field is provided. The aim is to enhance the understanding of the complex physiological and pathological roles of sulfur-containing biomolecules and to offer insights into developing effective therapeutic strategies for diseases associated with dysregulated sulfur-containing amino acid metabolism.

Cyclophilin-B (CypB) is overexpressed in pancreatic cancer, thus, the potential screening of CypB in biofluids and tissue samples may boost the identification of early-stage pancreatic cancer. A novel strategy of CypB detection utilizing the molecularly imprinted polymer platform, comprising higher binding affinity exhibiting cavities against the CypB protein was developed. Specifically, a nanocatalyst consisting of Pt single atom (Ptsa)-doped selenium disulfide (SeS2)/Ti3CNTx MXene nanocomposite is designed. The sluggish diffusion of Ptsa caused by the highest migration energy barrier of 6.39 eV unveils exceptionally high stability (2.89 ×1088 d (300 K) and 1.053 × 1024 d (750 K)) with (SeS2)/Ti3CNTx surface. The Ptsa boosted charge transfer kinetics paves the improved performance of the CypB sensor, while SeS2/Ti3CNTx supports the stable current density overall. The system establishes a dynamic linear range from 0.12 to 250 nm of CypB detection which correlates with the physiological existence of the CypB in human biofluids and tissues and the excellent detection limit of 80 pm. The liquid chromatography integrated mass spectrometer investigation warranted the significant enhancement of CypB associates with the progression of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense extracellular matrix (ECM) and a uniquely immunosuppressive tumor microenvironment (TME), which together form a formidable barrier that hinders deep drug penetration, limiting the efficacy of conventional therapies and leading to poor patient outcomes. Nanocarrier technology emerges as a promising strategy to improve treatment efficacy in PDAC. Nanocarriers can not only improve drug penetration through their adjustable physicochemical properties but also effectively regulate immune cell function in pancreatic cancer TME and promote anti-tumor immune response. This mini-review discusses the effects of nanocarriers on the immune microenvironment of PDAC, analyzing their mechanisms in modulating immune cells, overcoming ECM barriers, and reshaping the TME.

This study aimed to analyze the trends and epidemiological characteristics of pancreatic cancer (PC) mortality in China from 2004 to 2021, focusing on gender, age, and regional disparities. The goal was to provide a comprehensive understanding of PC mortality and identify key risk factors to support future prevention and control strategies.

Using data from the national Disease Surveillance Point (DSP) system, which covers a large and representative sample of the Chinese population, the study examined pancreatic cancer mortality trends across different age groups, sexes, and regions. Statistical analyses, including the independent-sample t-test and age-period-cohort (APC) model, were employed to assess mortality differences and annual percentage changes from 2004 to 2021.

The study recorded a significant increase in pancreatic cancer mortality, particularly among males and older adults. Mortality was consistently higher in urban areas, but the growth rate in rural areas surpassed that of urban areas. Regional disparities were also observed, with the eastern region showing the highest mortality rates but slower increases compared to the central and western regions. Key risk factors, including aging, diabetes, smoking, and chronic pancreatitis, were identified, with gender-specific differences linked to lifestyle factors such as smoking and alcohol consumption.

Pancreatic cancer mortality in China has shown significant increases over the past 18 years, especially among males, older adults, and rural populations. The findings highlight the urgent need for targeted public health interventions to address gender- and age-specific risks, as well as healthcare access inequalities in less developed regions. Future research should focus on gathering more granular, individual-level data to better understand the complex interplay of risk factors and inform more effective prevention and treatment strategies.

Emerging evidence suggests that harnessing the microbiome holds promise for innovative diagnostic and therapeutic strategies in the management of pancreatic cancer (PC). This study aims to systematically summarize the microbial markers associated with PC and assess their potential application in clinical outcome. Forty-one studies were included to assess the associations between microbial markers and PC. Among these, 13 were developed prediction models related to the microbiome in which the highest diagnostic and prognostic model belong to blood and intratumor markers, respectively. Notably, findings that utilize microbiotas from various body sites were elucidated, demonstrating their importance as unique signatures in biomarker discovery for diverse clinical applications. This review provides unique perspectives on overcoming challenges in PC by highlighting potential microbial-related markers as non-invasive approaches. Further clinical studies should evaluate the utility and accuracy of key indicators in the microbiome as a personalized tool for managing PC.

Pancreatic ductal adenocarcinoma (PDA) is a highly challenging malignancy to treat, with a high mortality rate and limited therapeutic options. Despite advances in cancer research, the prognosis for patients diagnosed with PDA is often poor due to late-stage detection and resistance to conventional therapies. Consequently, there is growing interest in the potential of bioactive compounds as alternative or adjuvant treatments, given their ability to target multiple aspects of cancer biology, offering a more holistic approach to treatment. In the context of PDA, certain bioactive compounds, such as polyphenols (found in fruits, vegetables, and tea), flavonoids, carotenoids and compounds in cruciferous vegetables, have shown potential in inhibiting cancer cell growth, reducing inflammation, and promoting cancer cell apoptosis. This review aims to elucidate the mechanisms, by which these bioactive compounds exert their effects, modulating the oxidative stress, influencing inflammatory pathways and regulating cell survival and death. It also highlights current clinical trials that are paving the way toward incorporating these natural agents into mainstream treatment strategies, with the goal of boosting the efficacy of conventional therapies for PDA.

Pancreatic cancer, a highly lethal malignancy with limited therapeutic options, necessitates the identification of novel prognostic biomarkers and therapeutic targets. The extracellular matrix protein vitronectin (VTN) has been implicated in tumor progression, but its specific role in pancreatic cancer progression and immunotherapy response remains unclear.

This study employed an integrative approach combining single-cell RNA sequencing, analysis of public databases, and functional assays. In vitro experiments assessed the impact of VTN knockdown and overexpression on pancreatic cancer cell proliferation, invasion, and migration. Mechanistic investigations explored associations between VTN expression and immune regulatory factors. A syngeneic mouse subcutaneous tumor model evaluated the therapeutic efficacy of VTN overexpression combined with anti-PD1 immunotherapy.

VTN was significantly downregulated in pancreatic cancer tissues compared to normal tissues. Lower VTN levels correlated with poorer overall survival. VTN knockdown promoted pancreatic cancer cell proliferation, invasion, and migration in vitro, whereas VTN overexpression suppressed these phenotypes. VTN expression was linked to immune regulatory pathways. High VTN levels predicted improved survival in patients receiving anti-PD1/PD-L1 therapy. In a mouse model, VTN overexpression inhibited tumor growth and synergized with anti-PD1 therapy to enhance antitumor efficacy, suggesting combinatorial therapeutic potential.

This study identifies VTN as a dual-functional regulator in pancreatic cancer, acting as both a suppressor of tumor progression and a modulator of immunotherapy response. These findings position VTN as a prognostic biomarker and a therapeutic target to sensitize pancreatic tumors to anti-PD1-based immunotherapy, providing a potential strategy for overcoming treatment resistance in this aggressive malignancy.

Pancreatic cancer is projected to become the second leading cause of cancer-related deaths by 2030, with its mortality continuing to rise, unlike other common cancers such as breast or colorectal. Late-stage diagnosis, often accompanied by metastatic dissemination, drastically impairs patient survival and underscores the urgent need for improved biomarkers to guide therapeutic strategies. While molecular signatures have been proposed to stratify pancreatic cancer patients, their ability to predict outcomes remains limited. In this study, we applied established molecular signatures to our in-house transcriptomic data from a cohort of pancreatic cancer patients. We took advantage of published datasets to construct comprehensive atlases of cells present in primary and metastatic pancreatic cancers. The atlas of metastasis samples, representative of routinely harvested patient biopsies, revealed that monocyte/macrophage signatures provided superior discriminatory power compared to existing molecular classifications. Notably, the abundance of TREM2-expressing macrophages emerged as a significant parameter for stratifying patients. Our findings position TREM2+ macrophages as a promising biomarker for pancreatic cancer, with potential to enhance patient stratification and inform the development of targeted therapies. This work highlights the critical role of tumor-associated macrophages in pancreatic cancer progression and lays the groundwork for further functional and translational studies.

Immune checkpoint inhibitor (ICI) have shown promising results against a variety of solid tumors across clinical trials. However, ICI monotherapy is often ineffective in patients with non-immunogenic tumors that exhibit high level of immunosuppression and low level of tumor infiltrating lymphocytes. To address these limitations, we have investigated a combination of ICIs [anti-PD-1 antibody (αPD-1), anti-PD-L1 antibody (αPD-L1), or anti-CTLA-4 antibody (αCTLA-4)] with several different immune stimulatory oncolytic adenoviruses (Ads) expressing different combinations of antitumor cytokines or immune modulatory factors [e.g., (1) interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF; RdB/IL12/GMCSF), (2) IL-12 and short hairpin ribonucleic acid (shRNA) targeting vascular endothelial growth factor (RdB/IL12/shVEGF), (3) IL-12 and decorin (RdB/IL12/DCN), (4) GM-CSF, and thymidine kinase (RdB/IL12/GMCSF-TK), or (5) IL-12, GM-CSF, and relaxin (RdB/IL12/GMCSF-RLX)] to overcome tumor-induced immunosuppression. Through comparative evaluation of combination therapy regimens, our findings have identified αPD-1 as the optimal ICI candidate to synergize with different oncolytic Ads to induce potent antitumor immune response against poorly immunological solid tumors.

Pancreatic cancer (PC), known as the ″king of cancer," is a prevalent and aggressive form of malignant tumor affecting the digestive tract. Triptolide (TP), an epoxidized diterpenoid lactone extracted from Tripterygium wilfordii, shows promising antitumor activity. However, the systemic toxicity and poor water solubility of TP inhibit its clinical application. In this work, Lycium barbarum polysaccharide (LBP)-modified selenium nanoparticles (SeNPs), capable of reducing severe toxicity and enhancing solubility, have been designed, synthesized, and applied for the treatment of PC. In vitro release results revealed that TP showed an acid-dependent and sustained-release effect. In Pan02 cells, the IC50 values of TP and LBP-SeNPs@TP were 26.03 ± 2.82 ng/mL and 11.80 ± 2.64 ng/mL, respectively. Similarly, the IC50 values of TP and LBP-SeNPs@TP for L02 cells were 15.76 ± 0.58 ng/mL and 32.73 ± 2.61 ng/mL, suggesting enhanced antitumor efficacy along with reduced toxicity. Flow cytometry analysis demonstrated that LBP-SeNPs@TP exerted the most potent apoptotic effect, achieving an early apoptosis rate of 24.5% and a late apoptosis rate of 45.3%. Notably, the mitochondrial membrane potential was significantly reduced, while ROS production was increased in the LBP-SeNPs@TP group. LBP-SeNPs@TP could significantly inhibit tumor growth while minimizing toxicity. RT-qPCR analysis demonstrated that LBP-SeNPs@TP upregulated the mRNA expression of Bax, Cyt C, and Caspase-3, while downregulating Bcl-2 expression in vitro and in vivo. The immunohistochemical analysis of the tumor tissue further confirmed these results. Overall, LBP-SeNPs emerge as a promising platform for poorly soluble drugs, offering a potential therapeutic approach for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a low survival rate and limited responsiveness to current therapies. The role of hypoxia in the tumor microenvironment is critical, influencing tumor progression and therapy resistance. The aim of this study was to implement the complex dynamics of the hypoxic tumor microenvironment in PDAC in a hypoxia-related prognosis model.

We utilized single-cell RNA sequencing (scRNA-seq) data and integrated it with TCGA-PAAD database to identify hypoxia-responsive macrophage subsets and related genes. Kaplan-Meier survival analysis, Cox regression, and Lasso regression methods were employed to construct and validate a hypoxia-related prognostic model. The model's effectiveness was evaluated through its predictive capabilities regarding chemotherapy sensitivity and overall survival.

Our research integrated data from scRNA-seq and the TCGA-PAAD database to construct a hypoxia-related prognostic model that encompassed 13 critical genes. This hypoxia model independently predicted chemotherapy response and poor outcomes, outperforming traditional clinicopathologic features. Additionally, a pan-cancer analysis affirmed the relevance of our hypoxia-related genes across multiple malignancies, particularly highlighting KRTCAP2 as a pivotal biomarker associated with worse prognosis and reduced immune infiltration.

Our findings underscored the prognostic potential of hypoxia-related model and offered a novel avenue for therapeutic targeting, aiming to ameliorate outcomes in pancreatic cancer.

Metastatic spread can follow either the linear route-dissemination of fully malignant cells from the primary tumor, or the parallel route-dissemination of immature tumor cells and independent maturation to metastases in target organs. The linear/parallel ratio (LPR) is a model that uses metastases diameter comparisons to decipher dissemination route. LPR of +1 suggests pure linear and -1 pure parallel spread.

To examine the metastases trajectory in pancreatic duct adenocarcinoma (PDAC).

A total of 133 patients with PDAC, including 97 patients (72.9%) with synchronous and 36 (27.1%) with metachronous metastases with a total of 1054 lung and 2898 liver metastases, were evaluated. We found that metastatic spread to both liver and lungs is almost exclusively via the linear route (lungs median LPR + 1, interquartile range [IQR] 0.97,1. Liver median LPR + 0.98, IQR 0.83,1). Calculated from the primary diagnosis, overall survival (OS) of patients with metachronous metastases was significantly better compared to patients with synchronous disease (14 months, IQR 10,26, vs. 7 months, IQR 6,9, p < 0.0001). However, calculated from the time of metastases diagnosis, OS of both groups was similar (4 months, IQR 3,8, vs. 7 months, IQR 6,9, p = 0.235).

These two observations suggest that metastatic spread of PDAC is almost exclusively via the linear route, that is, directly from the primary tumor. Therefore, liver or lung metastases are already present in most patients with PDAC at the time of initial diagnosis. This suggests that local treatment in patients with seemingly localized disease does not decrease their risk of developing metastases and that systemic treatment must follow.

Pancreatic cancer is an aggressive malignancy with a poor prognosis and limited treatment options. Cdc-like kinase 4 (CLK4), a kinase that regulates alternative splicing by phosphorylating spliceosome components, is implicated in aberrant splicing events driving pancreatic cancer progression. In this study, we established a computational model that integrates pharmacological interactions of CLK4 inhibitors with an improved hit rate. Through this model, we identified a novel CLK4 inhibitor, compound 150441, with a 50% inhibitory concentration (IC50) value of 21.4 nm. Structure-activity relationship analysis was performed to investigate key interactions and functional groups. Kinase profiling revealed that compound 150441 is selective for CLK4. Subsequent in vitro assays demonstrated that this inhibitor effectively suppressed cell growth and viability of pancreatic cancer cells. In addition, it inhibited the phosphorylation of key splicing factors, including serine- and arginine-rich splicing factor (SRSF) 4 and SRSF6. Cell cycle analysis further indicated that the compound induced G2/M arrest, leading to apoptosis. RNA-seq analysis revealed that the compound induced significant changes in alternative splicing and key biological pathways, including RNA processing, DNA replication, DNA damage, and mitosis. These findings suggest that compound 150441 has promising potential for further development as a novel pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance.

Multi-omics data were integrated to analyze the correlation between hypoxia score of PDAC, SQOR expression and prognosis, and ferroptosis resistance level. A deep learning model of Whole Slide Images (WSIs) were constructed to predict the hypoxia level of patients. In vitro hypoxia cell models, SQOR knockdown experiments and nude mouse xenograft models were used to verify the regulatory function of SQOR on ferroptosis.

PDAC exhibited significantly higher hypoxia levels than normal tissues, correlating with reduced overall survival in patients. In slide level, our deep learning model can effectively identify PDAC hypoxia levels with good performance. SQOR was upregulated in tumor tissues and positively associated with both hypoxia score and ferroptosis resistance. SQOR promotes the malignant progression of PDAC in hypoxic environment by enhancing the resistance of tumor cells to ferroptosis. SQOR knockdown resulted in decreased cell viability, decreased migration ability and increased MDA level under hypoxic Ersatin induced conditions. Furthermore, SQOR inhibitor in combination with ferroptosis inducer has the potential to inhibit tumor growth in vivo in a synergistic manner.

This study has established a hypoxia detection model of PDAC based on WSIs, providing a new tool for clinical evaluation. The study revealed a new mechanism of SQOR mediating ferroptosis resistance under hypoxia and provided a basis for targeted therapy.

The efficacy of neoadjuvant chemoradiotherapy for resectable pancreatic ductal adenocarcinoma (R-PDAC) remains unclear. This study was designed to evaluate neoadjuvant chemoradiotherapy by using intensity-modulated radiotherapy (NAC-IMRT) for R-PDAC compared with upfront surgery (UpS).

Among 198 patients with R-PDAC who were indicated for resection between 2013 and 2021, 130 were included in this study after excluding patients who underwent neoadjuvant chemotherapy and did not meet the NAC-IMRT criteria (Eligible set). NAC-IMRT was planned for 58 patients, and UpS was planned for 72 patients. Additionally, in 105 patients who could undergo the planned treatment (As-treated set), the surgical, pathological, and oncological outcomes were evaluated.

In the Eligible set, median overall survival (OS) was 50.5 months with NAC-IMRT and 34.7 months with UpS and progression-free survival was 20.4 months with NAC-IMRT and 13.9 months with UpS. In the As-treated set, OS was longer in the NAC-IMRT group (66.7 months vs. 34.7 months, p = 0.007). On multivariate analysis, NAC-IMRT was identified as an independent factor for better OS (hazard ratio 0.617, 95% confidence interval 0.382-0.995, p = 0.047, in the Eligible set). The incidence of postoperative complications did not show a difference between the two groups, and NAC-IMRT suppressed local tumor invasion, including lymphatic, venous, perineural invasion, and lymph node metastases.

NAC-IMRT may offer superior survival outcomes and manageable toxicity in R-PDAC patients compared with upfront surgery. This study supports the efficacy and safety of NAC-IMRT and recommends its consideration in R-PDAC treatment protocols.

Pancreatic cancer is a highly malignant tumor that remains a significant global health burden. In this study, we demonstrated the anticancer potential of stevia leaf extract fermented with plant-derived Lactobacillus (L.) plantarum SN13T strain. Evaluation of antioxidant capacity (including DPPH and ABTS radical scavenging activities and H2O2-induced oxidative damage repair in HEK-293 cells), as well as cytotoxicity against pancreatic cancer cells (PANC-1) and non-cancerous human embryonic kidney (HEK-293), revealed that the fermented extract exhibited significantly enhanced antioxidant activity and cytotoxicity against PANC-1 cells while showing minimal toxicity to HEK-293 cells compared to the unfermented extract. Further, validation through clonogenic, migration, and wound-healing assays demonstrated that the fermented extract effectively inhibited the proliferation and migration of PANC-1 cells. The active compound in the fermented extract has been identified as chlorogenic acid methyl ester (CAME), with a concentration of 374.4 μg/mL. Flow cytometry analysis indicated that CAME significantly arrested PANC-1 cells in the G0/G1 phase and induced apoptosis. Furthermore, CAME upregulated the expression of pro-apoptotic genes Bax, Bad, Caspase-3/9, Cytochrome c, and E-cadherin, while downregulating the anti-apoptotic gene Bcl-2. These findings suggest that CAME exerts potent cytotoxic effects on PANC-1 cells by inhibiting cell proliferation and migration, arresting the cell cycle, and regulating apoptosis-related gene expression. In conclusion, stevia leaf extract fermented with L. plantarum SN13T, which contains CAME, may serve as a promising candidate for pancreatic cancer treatment.

The myocyte enhancer factor-2 (MEF2) family genes were involved in the carcinogenesis and prognosis of multiple human tumors. The impact of MEF2s on the occurrences, progression, and clinical outcome of pancreatic cancer (PAAD) remains unknown.

This study used the CCLE, HPA, EMBL-EBI, and GEPIA2 databases to study MEF2s expression in PAAD patients. We also investigated the relationship between MEF2s expression and methylation through the DiseaseMeth database, and used MEXPRESS to verify the association. Then we utilized the Kaplan-Meier Plotter and GEPIA2 databases to evaluate the prognostic value of MEF2s in PAAD. The cBioPortal database was used to explore the alteration features of MEF2s in PAAD. We then investigated the association between MEF2s expression, immune cells infiltration, and immune infiltration markers using the TIMER database. Finally, Metascape, STRING, and Cytoscape tools were used for functional enrichment analysis.

MEF2A, MEF2C, and MEF2D were found to be highly expressed in PAAD patients' tissues compared to normal tissues, whereas MEF2B expression did not show significant differential expression. In addition, the protein expression of MEF2A, MEF2C, and MEF2D was higher in PAAD tissues. Negative correlations were observed between the expression level of MEF2A, MEF2C, and MEF2D and the methylation levels in multiple sites. High expression of MEF2A was related to poor overall survival (p = 0.0071) and relapse-free survival (RFS) (p = 0.0089) of PAAD. High expression of MEF2C was associated with worse RFS of PAAD (p = 0.043). MEF2A was a Truncating mutation, and it was shown that the "G27Wfs*8" mutation point was distributed in the SRF-TF domain. Both MEF2C and MEF2D were a Missense mutation. MEF2A, MEF2C, and MEF2D expression was positively corresponded with five immune cells infiltration (CD8 + T cells, B-cells, neutrophils, macrophages, and dendritic cells), especially for CD8 + T cells and macrophages. Among the 20 pathways, hsa05140 (Leishmania infection), hsa04022 (cGMP-PKG signaling pathway), hsa05145 (Toxoplasmosis), hsa04371 (Apelin signaling pathway), and hsa04064 (NF-kappa B signaling pathway), were closely connected with the occurrence and development of PAAD.

Our results indicated that the overexpression of MEF2A, MEF2C, and MEF2D in patients with PAAD. MEF2A could be used as a prognostic biomarker for PAAD, MEF2C might be a potential oncogene for PAAD, and MEF2D had potential biological significance.

Pancreatic cancer is characterised by its aggressive progression, late-stage diagnosis and poor prognosis. This case report illustrates the intricate interplay between pancreatic adenocarcinoma, disseminated intravascular coagulation with diffuse alveolar haemorrhage and bone metastasis in an elderly woman. Presenting with asthenia, significant hip pain and haemoptysis, her work-up revealed multiple supradiaphragmatic adenopathies and infradiaphragmatic adenopathies, pancreatic parenchymal heterogeneity and lytic bone lesions. Despite extensive diagnostic efforts, a diagnosis of adenocarcinoma of probable pancreatobiliary origin was established only at an advanced stage, leading to a fatal outcome within a week. The patient experienced rapid clinical deterioration, characterised by refractory respiratory failure, haematological dysfunction and circulatory shock, highlighting the aggressive course of pancreatic cancer and its complications. This case underscores the diagnostic challenges and the critical need for early recognition and tailored strategies in managing complex presentations of pancreatic cancer, especially with rare and severe systemic manifestations.

Da ChaiHu decoction (DCHD) is used in Chinese medicine to treat pancreatic cancer (PC), but its exact mechanism is not known. The aim of this study was to investigate the main active ingredients and specific mechanisms of DCHD against PC. Firstly, the active ingredients and targets of DCHD and PC-related targets were searched from the TCMSP, DrugBank, NCBI and GeneCards databases, respectively. The intersected targets of both were then taken to construct a PPI network using STRING, and this network was visualized by Cytoscape 3.8.2. GO and KEGG enrichment analyses of the intersected targets were performed using R 4.2.1 "clusterProfiler", "enrichplot", and "ggplot2" packages. Molecular docking was performed utilizing MOE software to detect the binding capacity between compounds and targets. Cell proliferation, apoptosis, invasion and migration were examined through a CCK8 kit, Muse® Cell Analyzer, transwell and wound healing experiment, respectively. The expression levels of five core targets were assessed by RT-qPCR in PANC-1 cells treated with stigmasterol. Molecular dynamic simulations analysis was conducted to analyze the binding affinities and modes of interaction between molecules and stigmasterol using the GROMACS 5.1.4 program package. In this study, 141 common targets of DCHD and PC were obtained. GO-MF items indicated that DCHD exerts its effects on PC primarily by influencing the binding activity of DNA-binding transcription factors. The KEGG analysis revealed that these genes were implicated in various signaling pathways, including the IL-17 signaling pathway and the PI3K/Akt signaling pathway. Stigmasterol was chosen as the final ingredient for subsequent investigation due to its derivation from herb (Da ChaiHu), its encompassment of more common targets, and the scarcity of existing research on its role in PC. The results of molecular docking and Molecular dynamic simulations analysis showed that stigmasterol had good binding activity with BCL2, and ICAM1. In vitro experiments suggested that stigmasterol could effectively inhibit the proliferation, invasion and migration of PANC-1 cells, and promote cell apoptosis. Moreover, stigmasterol treatment led to the reduced expression of AKT1, HIF1A, BCL2, IL1B, and ICAM1. This study is the first to reveal the main active components and potential mechanisms of DCHD against PC, which provides a theoretical basis for studying the role of DCHD in the treatment of PC. Especially, the anti-PC mechanism of active compound stigmasterol might be associated with inhibiting proliferation, invasion and migration and accelerating apoptosis. Furthermore, five targets (AKT1, HIF1A, BCL2, IL1B, and ICAM1) were identified as key targets of stigmasterol, and the mRNA expressions of these genes were down-regulated by stigmasterol through in vitro experiments.

Pathological examination of lymph node metastasis (LNM) is crucial for treating pancreatic ductal adenocarcinoma (PDAC). Although the tumour stroma is correlated with prognosis in multiple solid tumors, its role in detecting LNM in PDAC is unclear. Thus, this study aimed to investigate the relationship of tumor-stroma ratio (TSR) with LNM, survival and mutational profile in PDAC.

In this multicenter retrospective study, we examined molecular and clinicopathologic features of 737 PDAC patients from 5 independent cohorts, including surgically resected and endoscopic ultrasound fine-needle aspiration (EUS-FNA) biopsy specimens. TSR was evaluated on hematoxylin and eosin-stained slides and classified as stroma-low (<50% stroma) or stroma-high (≥50% stroma).

Compared to TSR-high cases, TSR-low cases were significantly associated with LNM (P < 0.001). TSR could accurately distinguish patients with and without LNM with an area under curve (AUC) of 0.749, with the sensitivity and specificity of 76.5% and 71.6%, respectively. This accuracy of TSR for identifying LNM was further increased by adding other factors including PD-L1 expression or pretreatment serum CA19-9 levels. TSR showed similar levels of accuracy in analysis of resected tumor specimens and EUS-FNA biopsies. Moreover, we found that TSR could also identify residual nodal involvement after neoadjuvant therapy (NAT) using pretreatment EUS-FNA biopsy samples. Heterogeneous genetic alterations were observed between TSR-low and TSR-high subgroups. TSR was identified as an independent predictor of LNM and worse disease-free survival. Major findings were all reproducible in validation, EUS-FNA biopsy, and pre-treatment NAT EUS-FNA biopsy cohorts.

TSR served as a robust and reproducible biomarker that identifies patients at risk for LNM. TSR might be used to select treatment and management strategies for PDAC patients.

Pancreatic cancer (PC) is a highly lethal malignancy, ranking seventh among cancer-related deaths worldwide. This study utilizes data from the 2021 Global Burden of Disease (GBD) study to examine the global burden of PC and associated health inequalities from 1990 to 2021, with a focus on key risk factors such as obesity, high fasting plasma glucose, and the Socio-Demographic Index (SDI).

Disability-Adjusted Life Years (DALYs) for PC were estimated using GBD 2021 data. The analysis incorporated SDI, age, gender, and major risk factors, including obesity and high fasting plasma glucose. Descriptive statistics and visualizations, such as age-sex pyramids and geographic maps, were employed to assess global, regional, and national burdens. Health disparities were quantified using the Concentration Index (CI) and the Slope Index of Inequality (SII), with CI assessing relative health distribution by income and SII measuring absolute socioeconomic inequality.

Globally, PC-related DALYs rose from 1.76 million in 1990 to 4.25 million in 2021 (141.48% increase), with the age-standardized DALY rate up 11.57% to 48.71 (95% UI 23.43 to 74.33). The burden was highest in high SDI regions, while low SDI areas still faced elevated rates; transitional and developing economies showed the highest age-standardized DALY rates. The SII increased from 189.63 (95% CI 177.65 to 245.17) in 1990 to 321.17 (95% CI 294.48 to 379.722) in 2021, indicating widening socioeconomic disparities.

PC remains a significant global health challenge with growing socioeconomic and geographic disparities. Urgent action is needed to address modifiable risk factors (e.g., obesity, diabetes) through enhanced healthcare infrastructure, early detection, and treatment access in low SDI countries, alongside improved data systems and international collaboration.

This study examines the cellular heterogeneity of epithelial cells within pancreatic ductal adenocarcinoma (PDAC) and their contributions to tumor progression, metastasis, and immunosuppressive interactions using single-cell RNA sequencing.

Single-cell RNA-sequencing data from two datasets (GSE154778 and GSE158356) were integrated using the Harmony algorithm, followed by quality control, clustering, and differential gene expression analysis. Distinct subpopulations of epithelial cells were identified, and their gene expression profiles were analyzed. To assess the malignancy of these subpopulations, single-cell copy number variation (CNV) analysis and trajectory analysis were conducted. Additionally, intercellular communication was examined using the CellChat platform.

The analysis revealed pronounced heterogeneity among PDAC epithelial cells, with specific subpopulations exhibiting distinct roles in tumor proliferation, extracellular matrix remodeling, and metastatic dissemination. Subpopulations 4 and 6 were characterized by increased CNV levels and a more malignant phenotype, suggesting an enhanced capacity for metastasis. Single-cell trajectory analysis, along with CellChat, mapped the temporal evolution of epithelial cells, identifying key regulatory genes such as DCBLD2 and JUN. A prognostic model incorporating five key genes, including KLF6, was developed and demonstrated strong predictive accuracy for patient outcomes. Notably, KLF6 emerged as a critical prognostic marker associated with immune modulation, particularly through interactions with M2 macrophages.

The study highlights the pronounced heterogeneity of epithelial cells in PDAC and their distinct contributions to tumor progression, metastasis, and immune modulation. Through single-cell transcriptomic and CNV analyses, we identified epithelial subpopulations with varying malignant potentials and distinct interactions with the tumor microenvironment. Among these, KLF6 emerged as a key regulator associated with immune modulation and metastasis. Our findings emphasize the significance of epithelial cell heterogeneity in shaping pancreatic cancer progression. These insights provide a foundation for future investigations into novel prognostic markers and therapeutic strategies.

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant with a poor prognosis, posing significant clinical challenges. SUMOylation, a reversible post-translational modification, plays a critical role in tumor progression, yet its prognostic significance in PDAC remains unclear.

We assessed SUMOylation expression patterns and function in PDAC using Western blot and the SUMOylation inhibitor TAK-981. Differentially expressed SUMOylation substrate encoding genes (DE-SSEGs) were identified from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx) datasets. A SUMOylation-based prognostic model, Sscore, was constructed using LASSO and Cox regression. Additional analyses included somatic mutation, immune infiltration, TIDE, drug sensitivity, and single-cell RNA sequencing. The role of SAFB2 in PDAC was validated in vitro.

PDAC cells showed elevated SUMOylation, and its inhibition reduced cell proliferation. The Sscore model, based on DE-SSEGs (CDK1, AHNAK2, SAFB2), predicted overall survival and correlated with genome variation, immune infiltration, and drug sensitivity. Single-cell analysis further confirmed a link between high Sscore and malignancy. SAFB2, identified as a pivotal gene within the Sscore model, was significantly downregulated in PDAC tissues and cell lines; its overexpression was shown to inhibit PDAC cell proliferation, migration, and invasion by suppressing the Wnt/β-Catenin signaling pathway.

This study underscores the role of SUMOylation in PDAC and introduces the Sscore as a prognostic tool. SAFB2 is identified as a potential tumor suppressor, offering new therapeutic targets for PDAC.

Pancreatic cancer is recognized as one of the most lethal types of cancer globally, characterized by a high mortality rate and a bleak prognosis, which greatly contributes to cancer-related deaths. Forecasts suggest that by 2030, pancreatic cancer will exceed other cancer types in prevalence. The disease presents considerable difficulties owing to the lack of prominent symptoms in its early stages, restricted options for early detection, rapid progression, and unfavorable outcomes. Presently, traditional methods for diagnosing pancreatic cancer primarily rely on imaging techniques. However, these methods often entail significant costs, require considerable time, and necessitate specialized skills for both operating the equipment and interpreting the resulting images. To overcome these obstacles, the use of biosensors has been proposed as a potentially valuable tool for the early detection of pancreatic cancer. MicroRNAs (miRs), a type of small non-coding RNA molecules, have emerged as highly sensitive molecular diagnostic tools that have the potential to function as precise indicators for a range of diseases, including cancer. Biosensors have been suggested as a potential solution for tackling these challenges, offering a promising approach for the early detection of pancreatic cancer. Small non-coding RNA molecules known as MicroRNAs (miRs) have become recognized as extremely sensitive molecular diagnostic tools and can act as precise biomarkers for different diseases, such as cancer. Moreover, this manuscript presents a thorough summary of the latest innovations in nano-biosensors that have been specifically developed for the identification of non-coding RNAs related to pancreatic cancer.

The metastatic cascade is a complicated process where cancer cells travel across multiple organs distant from their primary site of onset. Despite the wide acceptance of the 'seed and soil' theory, mechanisms driving metastasis organotropism remain mystery. Using breast cancer of different subtypes as the disease model, we characterized the 'metastatic profile of cancer cells' and the 'redox status of the organ microenvironment' as the primary determinants of cancer metastasis organotropism. Mechanically, we identified a positive correlation between cancer metabolic plasticity and stemness, and proposed oxidative stress as the selection power of cancer cells succeeding the metastasis cascade. Therapeutically, we proposed the use of pro-oxidative therapeutics in ablating cancer cells taking advantages of this fragile moment during metastasis. We comprehensively reviewed current pro-oxidative strategies for treating cancers that cover the first line chemo- and radio-therapies, approaches relying on naturally existing power including magnetic field, electric field, light and sound, nanoparticle-based anti-cancer composites obtained through artificial design, as well as cold atmospheric plasma as an innovative pro-oxidative multi-modal modality. We discussed possible combinations of pro-oxidative approaches with existing therapeutics in oncology prior to the forecast of future research directions. This paper identified the fundamental mechanics driving metastasis organotropism and proposed intervention strategies accordingly. Insights provided here may offer clues for the design of innovative solutions that may open a new paradigm for cancer treatment.

Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.

Stereotactic magnetic resonance guided adaptive radiation therapy (SMART) is a new option for local treatment of unresectable pancreatic ductal adenocarcinoma, showing interesting survival and local control (LC) results. Despite this, some patients will experience early local and/or metastatic recurrence leading to death. We aimed to develop multiparametric prognostic models for these patients.

All patients treated in our institution with SMART for an unresectable pancreatic ductal adenocarcinoma between October 21, 2019, and August 5, 2022 were included. Several initial clinical characteristics as well as dosimetric data of SMART were recorded. Radiomics data from 0.35-T simulation magnetic resonance imaging were extracted. All these data were combined to build prognostic models of overall survival (OS) and LC using machine learning algorithms.

Eighty-three patients with a median age of 64.9 years were included. A majority of patients had a locally advanced pancreatic cancer (77%). The median OS was 21 months after SMART completion and 27 months after chemotherapy initiation. The 6- and 12-month post-SMART OS was 87.8% (IC95%, 78.2%-93.2%) and 70.9% (IC95%, 58.8%-80.0%), respectively. The best model for OS was the Cox proportional hazard survival analysis using clinical data, with a concordance index inverse probability of censoring weighted of 0.87. Tested on its 12-month OS prediction capacity, this model had good performance (sensitivity 67%, specificity 71%, and area under the curve 0.90). The median LC was not reached. The 6- and 12-month post-SMART LC was 92.4% [IC95%, 83.7%-96.6%] and 76.3% [IC95%, 62.6%-85.5%], respectively. The best model for LC was the component-wise gradient boosting survival analysis using clinical and radiomics data, with a concordance index inverse probability of censoring weighted of 0.80. Tested on its 9-month LC prediction capacity, this model had good performance (sensitivity 50%, specificity 97%, and area under the curve 0.78).

Combining clinical and radiomics data in multiparametric prognostic models using machine learning algorithms showed good performance for the prediction of OS and LC. External validation of these models will be needed.

Due to the highly heterogeneous and immunosuppressed tumor microenvironment (TME), pancreatic adenocarcinoma (PAAD) has limited therapeutic options and an abysmal prognosis. Ephrin A 1-5 (EFNA1-5) have been shown to regulate tumorigenesis and metastasis in various cancers, but its role in PAAD remains unclear.

We comprehensively analyzed EFNA gene expression levels in pan-cancer and PAAD using the GEPIA and HPA databases. Then, we assessed the prognostic value of EFNA1-5 using the Kaplan-Meier plotter and nomogram model. Further exploration of the association of EFNA1-5 with clinicopathological features of PAAD used information from the UALCAN database, and the TIMER dataset was used to reveal the correlation between EFNA1-5 and the tumor immune microenvironment (TIME) of pancreatic cancer. In addition, cBioPortal Databases, GSEA, and GSCALite were used to explore gene changes, protein interactions, and biological functions. Finally, the oncogenic effect of EFNA5 was verified in vivo and in vitro.

The expression levels of EFNA1-5 were significantly upregulated in PAAD. The expression of EFNA1/3/4/5 were significantly associated with overall survival (OS) and relapse-free survival (RFS) in PAAD patients. The high expression of EFNA2-5 were related to poor clinical features, such as higher tumor stage or grade and a wider range of lymph node metastasis. EFNA1-5 were closely associated with immune cell infiltration, CAFs, and MDSCs expression. Furthermore, EFNA5 is an independent risk factor for poor prognosis in PAAD patients, and it can promote the malignant progression of pancreatic cancer in vitro and in vivo.

Differential expression of EFNA1-5 is associated with TIME in pancreatic cancer, predicts different survival outcomes, and maybe a novel prognostic marker reflecting an immunosuppressive state and a potential therapeutic target.

Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.

Kinesins are a family of motor proteins essential for intracellular transport and cellular dynamics, with kinesin family member C1 (KIFC1) emerging as a key regulator of cancer progression. Recent studies highlight KIFC1's crucial role in mitotic spindle assembly, chromosome segregation, and cell migration-processes frequently dysregulated in cancer. Its involvement in promoting malignant cell proliferation and metastasis underscores its significance in tumor biology. In various cancer types, aberrant KIFC1 expression correlates with poor prognosis and aggressive phenotypes, suggesting its potential as a biomarker for disease severity. Mechanistically, KIFC1 influences signaling pathways linked to cell cycle regulation and programmed cell death, reinforcing its role in oncogenesis. Given its pivotal function in cancer cell dynamics, KIFC1 represents a promising therapeutic target. Strategies aimed at modulating its activity, including small molecules or RNA interference, could disrupt cancer cell viability and proliferation. The current review article highlights KIFC1's importance in cancer biology, advocating for further investigation into its mechanisms and the development of KIFC1-targeted therapies to enhance treatment efficacy and improve patient outcomes across various malignancies.

Pancreatic cancer is a highly invasive malignant tumor with a complex pathogenesis that makes early diagnosis challenging. The potential association between Helicobacter pylori infection and pancreatic cancer risk has been noted; however, the available results are still highly divergent. The aim of the present study was to systematically evaluate the association between different types of H. pylori infection and pancreatic cancer risk as well as to explore the possible causes. A systematic search was conducted using the PubMed, Embase and Cochrane Library databases up to August 2023. The literature quality was evaluated using the Newcastle-Ottawa Scale. All studies that met the criteria were included in the overall meta-analysis to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). In addition, subgroup analyses were performed based on factors such as diagnostic criteria for H. pylori infection, study region, type of study design and CagA status. The effect of publication bias on the quantitative synthesis results was assessed using the trim-and-fill analysis, and sensitivity analyses were used to verify the robustness of the quantitative synthesis results. A total of 17 studies involving 67,910 participants, including 64,372 controls and 3,538 patients with pancreatic cancer, were included in the present study. The overall analysis showed that no significant association was observed between H. pylori infection and pancreatic cancer risk (OR, 1.15; 95% CI, 0.93-1.41). Further subgroup analyses, which did not consider the effects of study quality, diagnostic criteria, geographical distribution and the type of study design, did not produce new findings that contradicted the results of the overall analysis. CagA+ H. pylori infection did not significantly affect the risk of pancreatic cancer (OR, 0.95; 95% CI, 0.78-1.16), whereas CagA- H. pylori infection may be a possible risk factor for pancreatic cancer (OR, 1.24; 95% CI, 1.004-1.541). The H. pylori infection did not significantly increase the risk of pancreatic cancer. However, it is noteworthy that CagA- H. pylori infection could be a potential factor that elevated the risk of pancreatic cancer.