Pancreatic ductal adenocarcinoma (PDAC) presents a unique challenge for researchers due to its late diagnosis caused by vague symptoms and lack of early detection markers. Additionally, PDAC is characterized by an immunosuppressive microenvironment (TME), making it a difficult tumor to treat. While γδ T cells have shown potential for anti-tumor activity, conflicting studies exist regarding their effectiveness in pancreatic cancer. This study aims to explore the hypothesis that the PDAC TME hinders the anti-tumor capabilities of γδ T cells through blockade of cytotoxic functions. For this reason, we chose to enroll PDAC treatment-naive patients to avoid the possibility of therapy modifying the TME. By flow cytometry, our research findings indicate that the presence of γδ T cells among CD45+ cells in tumor tissue is lower compared to CD66+ cells, but higher than in blood. Circulating Vδ1 T cells exhibit a terminal effector memory phenotype (TEMRA) more than Vδ2 T cells. Interestingly, Vδ1 and Vδ2 T cells appear to be more prevalent at different stages of tumor development. In our in vitro culture using conditioned medium derived from Patient-derived organoids ;(PDOs), we observed a shift in expression markers in γδ T cells of healthy individuals toward an activation and exhaustion phenotype, as confirmed by scRNA-seq analysis extracted from a public database. A deeper understanding of γδ T cells in PDAC could be valuable for developing novel therapies aimed at mitigating the impact of the pancreatic tumor microenvironment on this cell population.

Drosophila melanogaster is a highly versatile model organism that has profoundly advanced our understanding of human diseases. With more than 60% of its genes having human homologs, Drosophila provides an invaluable system for modelling a wide range of pathologies, including neurodegenerative disorders, cancer, metabolic diseases, as well as cardiac and muscular conditions. This review highlights key developments in utilizing Drosophila for disease modelling, emphasizing the genetic tools that have transformed research in this field. Technologies such as the GAL4/UAS system, RNA interference (RNAi) and CRISPR-Cas9 have enabled precise genetic manipulation, with CRISPR-Cas9 allowing for the introduction of human disease mutations into orthologous Drosophila genes. These approaches have yielded critical insights into disease mechanisms, identified novel therapeutic targets and facilitated both drug screening and toxicological studies. Articles were selected based on their relevance, impact and contribution to the field, with a particular focus on studies offering innovative perspectives on disease mechanisms or therapeutic strategies. Our findings emphasize the central role of Drosophila in studying complex human diseases, underscoring its genetic similarities to humans and its effectiveness in modelling conditions such as Alzheimer's disease, Parkinson's disease and cancer. This review reaffirms Drosophila's critical role as a model organism, highlighting its potential to drive future research and therapeutic advancements.

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.

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.

Treatment of advanced stage cancers is extremely challenging, and more effective systemic therapy is needed. Oncolytic adenoviruses (OAds) are one of the most promising anti-cancer agents. However, systemic delivery of OAd is challenging due to the low transduction in tumor cells caused by non-selective distribution and sequestration by non-target organs. To overcome this issue, we have previously generated a mesothelin (MSLN)-targeted OAd (AdML-VTIN). Here, we are reporting the potential of MSLN-targeted OAd as an agent for novel systemic treatment using MSLN-expressing lung and pancreatic cancer models. The in vivo biodistribution of AdML-VTIN after intravenous injection showed significantly lower liver sequestration compared to the wild type of OAd (AdML-5WT). By day 7, the intratumoral viral copy number of AdML-VTIN was significantly higher than that of AdML-5WT. For therapeutic efficacy, systemically injected AdML-VTIN exhibited statistically significant anti-tumor effects in both lung and pancreatic cancer xenograft tumor models. In addition, we tested the effect of preexisting immunity using human serum. In a neutralization assay, AdML-VTIN was more resistant to preexisting antibodies, compared to Ad5-WT. Interestingly, the hemagglutination profile of AdML-VTIN was also changed. Our results indicate that MSLN-targeted OAd has great potential to facilitate systemic therapy of advanced cancers.

The Imiqualines family is an original group of small heterocyclic compounds, diversely substituted around different scaffolds. Among these compounds, the lead EAPB02303 displays outstanding cytotoxic activity at nanomolar concentrations comparable to those of standard-of-care chemotherapy drugs in different cancer cell lines, including Pancreatic Ductal AdenoCarcinoma (PDAC) cell lines. Due to its high aggressiveness and resistance to therapies, PDAC has an extremely poor prognosis with limited treatment options. Here, we demonstrated the cytotoxic activities of EAPB02303 alone or combined with standard chemotherapy drugs in several PDAC cell lines and confirmed these results in patient-derived xenograft mouse models. EAPB02303 potently induced cell cycle arrest in the G2/M phase and in mitosis followed by apoptosis. Then, using a combination of transcriptomic, proteomic, biochemical and cellular assay, we found that EAPB02303 mechanism of action relies on its bioactivation by catechol-O-methyltransferase, resulting in the production of a methylated compound that effectively inhibits microtubule polymerization. Moreover, EAPB02303 had a synergistic effect when combined with paclitaxel (the standard-of-care agent in PDAC) providing the rationale to continue the development of EAPB02303 combination strategies for the treatment of catechol-O-methyltransferase-overexpressing PDAC.

Early detection of cancer is crucial for improving patient outcomes. Traditional modalities such as mammography and low-dose computed tomography are effective but exhibit inherent limitations, including radiation exposure and accessibility challenges. This review explores innovative, non-invasive cancer screening methods, focusing on liquid biopsy and volatile organic compound (VOC)-based detection platforms. Liquid biopsy analyzes circulating tumor DNA and other biomarkers in bodily fluids, offering potential for early detection and monitoring of treatment response. VOC-based detection leverages unique metabolic signatures emitted by cancer cells, detectable in exhaled breath or other bodily emissions, providing a rapid and patient-friendly screening option. We provide a comprehensive overview of these advanced multi-cancer detection techniques to enhance diagnostic accuracy, accessibility, and patient adherence, and ultimately enhance survival rates and patient outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.

Research studies aimed at improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have brought about limited progress, and in clinical practice, the optimized use of surgery, chemotherapy and supportive care have led to modest improvements in survival that have probably reached a plateau. As a result, PDAC is expected to be the second leading cause of cancer-related death in Western societies within a decade. The development of therapeutic advances in PDAC has been challenging owing to a lack of actionable molecular targets, a typically immunosuppressive microenvironment, and a disease course characterized by rapid progression and clinical deterioration. Yet, the progress in our understanding of PDAC and identification of novel therapeutic opportunities over the past few years is leading to a strong sense of optimism in the field. In this Perspective, we address the aforementioned challenges, including biological aspects of PDAC that make this malignancy particularly difficult to treat. We explore specific areas with potential for therapeutic advances, including targeting mutant KRAS, novel strategies to harness the antitumour immune response and approaches to early detection, and propose mechanisms to improve clinical trial design and to overcome various community and institutional barriers to progress.

Pancreatic adenocarcinoma (PAAD) represents a highly fatal form of cancer. The 5-year survival rate for patients with this disease is only around 10%. A significant hurdle in its management is the absence of characteristic early-stage symptoms. As a result, a large majority of pancreatic cancer patients are diagnosed when the disease has reached an advanced stage or has metastasized. Consequently, taking measures to suppress the occurrence of metastasis in pancreatic cancer can bring about a substantial improvement in patients' survival rates and overall prognosis. SKIL, known to promote cancer progression, is implicated in cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis, but its specific function in pancreatic cancer remains unclear.

We investigated the effects of SKIL on the proliferation, apoptosis, and metastasis of pancreatic cancer cells. Through ChIP-seq, we identified the SKIL downstream target gene and further explored the mechanism by which SKIL regulates the metastasis of pancreatic cancer cells through functional experiments and Western blot.

A high level of SKIL expression is associated with an unfavorable prognosis in PAAD; it promotes cell migration and EMT. Through ChIP-seq analysis, we identified that SKIL inhibits TSPYL2, a nuclear protein regulating the TGF-β pathway by binding to the TGFB1 promoter. Further studies carried out by us confirmed that SKIL modulates the TGF-β pathway via TSPYL2, facilitating EMT and metastasis in pancreatic cancer cells, independent of Smad4.

These findings reveal a novel regulatory mechanism involving SKIL, TSPYL2, and the TGF-β pathway, offering new therapeutic targets for PAAD.

Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy associated with poor prognosis. Baicalein, a flavonoid extracted from the roots of Scutellaria baicalensis, traditionally used in Chinese medicine, has demonstrated potential in inhibiting cancer development and progression. However, its mechanism of action remains poorly understood, particularly regarding epigenetic gene regulation through m6A RNA methylation. In this study, three human PDAC cell lines and one nonmalignant cell line were employed. The effects of baicalein were examined using multiple assays, including RT-qPCR, MeRIP-qPCR, Western blotting, spheroid formation, RNA stability, and MTT, to evaluate cellular functions and m6A regulation. Baicalein significantly reduced cell viability, migration, invasion, and colony formation. It also downregulated FTO, an enzyme critical for m6A RNA demethylation. Knockdown of FTO replicated the effects of baicalein, underscoring its oncogenic role in PDAC. Bioinformatic analysis identified ZEB1-a key transcription factor in epithelial-to-mesenchymal transition-as an m6A-modified target regulated by FTO. Both baicalein treatment and FTO knockdown enhanced m6A modification and decreased ZEB1 mRNA stability, thereby suppressing stemness-related features. Rescue experiments further confirmed that baicalein disrupts the TGF-β/FTO/ZEB1 signaling axis, highlighting its therapeutic potential in PDAC. This study offers fundamental insights for the development of novel therapeutic strategies targeting PDAC.

Pancreatic cancer's dire prognosis urgently calls for innovative therapeutic strategies. JQ1, a bromodomain 4 inhibitor, exhibits potent anti-tumor activity in preclinical models but faces limitations due to rapid resistance development. Here, we developed a novel multifunctional nanoplatform, JQ1@MSN/FeTA-iRGD, which implemented a triple-mode strategy integrating apoptosis, ferroptosis, and immunogenic cell death for optimized treatment of pancreatic cancer. The particles could precisely target tumors in mice and achieve efficient release of JQ1 and Fe2+ through internalization in the acidic tumor environment. The nanoplatform amplified reactive oxygen species and mitochondrial damage to disrupt the redox homeostasis, thus synergistically escalating apoptosis and ferroptosis for the destruction of tumor cells, circumventing the rapid drug resistance associated with monotherapy. Meanwhile, dying cancer cells released damage-associated molecular patterns, which facilitated immunogenic cell death and triggered antitumor immune responses, guaranteeing the sustained efficacy of the treatment. Moreover, the system exhibited favorable biocompatibility, supporting its feasibility for clinical translation. Our results demonstrated that this novel strategy, combining apoptosis, ferroptosis, and immunogenic cell death, overcame the limitations of monotherapy with JQ1, providing a superior, targeted, and sustainable treatment option for pancreatic cancer.

Pancreatic adenocarcinoma (PAAD) was characterized by dense fibrotic stroma and immunosuppressive tumor microenvironment (TME). TGFβ signaling pathways are highly activated in human cancers. However, the role of TGFβ2 in TME of PAAD remains to be elucidated. In this study, we showed that TGFβ2 was expressed at a relatively high level in PAAD tissues or cancer cells. Moreover, its high expression predicted unfavorable prognosis. In PAAD, gene set enrichment analysis showed that TGFβ2 correlated positively with leukocyte transendothelial migration, but negatively with aerobic metabolism, including oxidative phosphorylation. Results in Tumor and Immune System Interaction Database showed that TGFβ2 correlated with the infiltration of tumor-associated macrophages (TAMs), which could be attributed to that TGFβ2 promote CCL2 expression in PAAD. Moreover, correlation analysis showed that TGFβ2 could trigger cancer-associated fibroblasts (CAFs) activation in PAAD. The drug sensitivity analysis may indicate that patients with TGFβ2 high expression have higher sensitivity to chemotherapeutics, but the sensitivity to targeted drugs is still controversial. TGFβ2 could promote expansion of CAFs and infiltration of TAMs, thus participating in the construction of a fibrotic and immunosuppressive TME in PAAD. Targeting TGFβ2 could be a promising therapeutic approach, which needs to be elucidated by clinical and experimental evidences.

Pancreatic cancer (PC) is a malignant tumor with a low survival rate. Lipid modifiers show potential for PC therapy, but evidence is lacking.

This Mendelian randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes with PC risk.

Genetic instrumental variables associated with lipid traits and lipid-lowering drug target genes were used to perform MR analyses of PC risk. MR estimation was based on genome-wide association study data from two large sample sets, and the MR results were meta-analyzed to assess their impact on PC risk. To ensure the reliability of lipid-modifying drug targets, we conducted a Summary Data-based Mendelian Randomization (SMR) analysis. Additionally, a two-step MR analysis was employed to explore potential mediating effects.

In two independent datasets, HMG-CoA reductase (HMGCR) inhibition was statistically associated with a lower risk of PC (OR 0.50, [95% CI 0.25-1.00]; p = 0.0453). The results were further supported by SMR analysis, which showed a similar association (OR 0.51, [95% CI 0.28-0.96]; p = 0.0369). Mediation analysis revealed that 11.69% of the protective effect of HMGCR inhibitors on PC is mediated through lower BMI levels. No significant effect of lipid traits and the other eight lipid-lowering drug targets on PC risk was found.

This study suggests that HMGCR may be a potential drug target for the treatment or prevention of PC, providing important insights into the use of lipid-targeted drugs in PC therapy.

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.

Radiation therapy (RT) for locally advanced pancreatic cancer (LAPC) continues to be controversial. Advances in both systemic therapy and RT techniques have changed the landscape of LAPC management in recent years. Clinical outcomes of ablative RT have been encouraging, and randomized clinical trials may clarify the role of RT for LAPC. We present a contemporary critical review of key aspects regarding optimal patient selection, radiation dose escalation techniques, novel radiosensitizers and radioprotectors, and treatment response assessment for LAPC.

BackgroundIntrahepatic cholangiocarcinoma (ICC) presents a significant clinical challenge due to its high fatality rate and limited surgical candidacy. With only 30-40% of patients eligible for surgery upon diagnosis, alternative therapies are imperative. This study assesses the efficacy of Yttrium-90 (Y-90) radioembolization for unresectable ICC patients in a non-university tertiary care center (NUTCC).MethodsA retrospective analysis of 15 unresectable ICC patients treated with Y-90 radioembolization was conducted. Tumor response, survival, and adverse events were evaluated using RECIST criteria.Results60% of patients exhibited partial response, and 20% showed stable disease, with notable tumor size reduction and a median survival of 14 months. Minimal adverse effects were observed, indicating Y-90's favorable safety profile.ConclusionY-90 radioembolization shows potential in reducing tumor burden and enhancing survival rates with minimal adverse effects for unresectable ICC. Larger prospective studies are needed to confirm its efficacy and define its role in ICC treatment protocols.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types, characterized by an alarmingly low 5-year survival rate. DNA methylation has been implicated in the progression of various tumors, with DNA methyltransferase 1 (DNMT1) being the most extensively studied enzyme in this context. However, the expression patterns and underlying mechanisms of DNMT1 in PDAC remain poorly understood. The levels of DNMT1 and CBX7 in PDAC tissues and cells were determined by IHC and Western blot. ChIP and dual-luciferase reporter assays confirmed the interaction between DNMT1 and the CBX7 promoter. Cellular functions were evaluated through CCK-8, wound healing, and transwell assays. The expression of MAPK-related proteins was analyzed by Western blot. DNMT1 expression was upregulated in PDAC tissues and cell lines, whereas CBX7 expression was downregulated. Silencing DNMT1 inhibited cell proliferation, migration, and invasion in PDAC by modulating CBX7 expression. Moreover, DNMT1 methylates the CBX7 promoter region, leading to increased ERK phosphorylation, which subsequently drives tumorigenesis and metastasis in PDAC. DNMT1 promotes the malignant progression of PDAC through the CBX7/ERK pathway. Our study provides evidence for potential therapeutic targets for the comprehensive treatment of PDAC.

To enhance immunotherapy efficacy in pancreatic cancer, it is crucial to characterize its immune landscape and identify key factors driving immune alterations. To achieve this, we quantitatively analyzed the immune microenvironment using multiplex immunohistochemistry, assessing the spatial relationships between immune and tumor cells to correlate with patient survival rates and oncological factors. Additionally, through Whole Exome Sequencing analysis based on public data, we explored genetic mutations that could drive these compositions. Finally, we validated T cell (Tc) migration mechanisms using patient-derived tumor organoids with induced KRAS mutation subtypes. Through this approach, we obtained the following meaningful results. First, immune cells in pancreatic cancer are denser in stromal regions than near tumor cells, with higher Tc distribution linked to increased patient survival rates. Second, the distance between tumor and Tc was within 100 μm, with higher Tc density found within 15-30 μm of the tumor cells. Third, while increasing CAF levels correspond to higher Tc density, higher ECM density tends to decrease Tc presence. Fourth, compared to KRAS G12D, KRAS G12V mutation increases various immune cells, notably Tc, which is closely linked to a dramatic rise in vascular cells. Finally, Tc migration was enhanced in tumor organoids with the G12V mutation, attributed to a reduction in the secretion of immunosuppressive cytokines. Our results indicate that KRAS mutation subtypes influence immune cell composition and function in the pancreatic cancer microenvironment, leading to varied immunotherapy responses. This underscores the need for personalized immune therapeutics and research models specific to KRAS mutations.

Background: Pancreatic cancer has a high mortality rate worldwide. Most patients progress to advanced stages, often with metastasis, resulting in a low survival rate. Despite advancements in surgical and oncological treatments, early diagnosis and better risk stratification remain critical. Methods: This retrospective cross-sectional study focused on analyzing data from patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, in order to determine whether the neutrophil-to-lymphocyte ratio (NLR) and other immune-inflammatory markers, such as the systemic immune-inflammation index (SII) and prognostic nutritional index (PNI), can predict postoperative complications and survival outcomes. Results: Analysis of 136 patients revealed that a higher NLR (≥2.5) was significantly associated with longer overall survival (39 months, IQR: 17-100 months; p = 0.004), compared to lower NLR (<2.5; 18 months, IQR: 9-39 months). Higher SII (≥600) was also associated with significantly improved survival (34 months, IQR: 17-114 months; p = 0.001) compared to lower SII (<600; 20 months, IQR: 9-45 months). No significant differences were observed in postoperative complications or other clinical outcomes between NLR groups, although a trend toward more complications in the higher NLR group was noted (p = 0.06). PNI showed no significant impact on survival (PNI < 38.8: 22 months, IQR: 14-60 months; PNI ≥ 38.8: 33 months, IQR: 14-115 months; p = 0.1) or complications (p = 0.8). Conclusions: Our study highlights the prognostic utility of NLR and SII in patients with adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy. Regarding complications, there were no significant differences across groups stratified by NLR, SII, or PNI, suggesting that while NLR and SII are valuable for predicting long-term oncological outcomes in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas, they may not be reliable indicators of immediate postoperative morbidity.

Basal pancreatic ductal adenocarcinoma (PDAC) has the worst overall survival and is the only subtype that serves as an independent poor prognostic factor. We identify elevated levels of LIN28B and its downstream target, HMGA2, in basal PDAC. Notably, LIN28B significantly accelerates KRAS-driven PDAC progression in a mouse model. Here, we show that HMGA2 promotes basal PDAC pathogenesis by enhancing mRNA translation downstream of LIN28B. Mechanistically, HMGA2 suppresses leucine carboxyl methyltransferase 1 (LCMT1) at the chromatin level, reducing PP2A methylation and activity. This leads to increased phosphorylation of S6K and eIF4B, boosting mRNA translation. Additionally, HMGA2 downregulates B56α (PPP2R5A), disrupting functional PP2A holoenzyme assembly and further sustaining phosphorylated S6K levels. Impaired PP2A function mimics HMGA2's effects, reinforcing increased mRNA translation and basal lineage features. This work uncovers a critical link between the LIN28B/HMGA2 axis, protein synthesis, and PDAC lineage specificity via LCMT1-mediated PP2A methylation and B56α-PP2A disruption.

Alterations in glycolysis play a crucial role in cancer cells, influencing tumor aggressiveness and therapeutic effect, particularly in pancreatic adenocarcinoma (PAAD). However, the specific glycolysis-related genes involved in PAAD progression remain poorly understood. This study established glycolysis-related molecular subtypes with distinct survival outcomes using TCGA datasets. The favorable prognosis subtype exhibited enhanced immune infiltration and an activated tumor microenvironment. A glycolysis prognostic model effectively predicted PAAD survival, correlating with global glycolytic pathways, and AUCell evaluated neutrophil communication networks of models. Functional validation demonstrated that ENO1/PGM2L1 co-expression promoted tumor proliferation, migration, invasion, and glycolytic flux in vitro, while accelerating xenograft growth in vivo. Conversely, their knockdown suppressed malignancy. Our study demonstrated that the glycolytic prognostic risk model serves as a reliable tool for prognosis and prediction of PAAD progression. ENO1 and PGM2L1 emerge as key risk factors promoting the malignant progression of PAAD.

Pancreatic cancer (PC) poses a significant global health challenge due to its aggressive nature, late-stage diagnosis, and high mortality despite advancements in treatment. Early detection remains crucial for timely intervention. This study aimed to identify clinically relevant predictors of pancreatic cancer using a supervised machine learning approach and to develop a risk stratification tool with diagnostic capabilities.

A matched case-control study was conducted retrospectively at the Tenth People's Hospital of Tongji University (2017-2023), involving 353 cases and 370 matched controls. Demographic and hematological data were extracted from medical records. Variables were pre-selected using cluster dendrograms and subsequently refined using logistic regression with backward elimination and Support Vector Machine (SVM) models. A final risk scoring model was developed based on the best-performing model and internally validated.

Key predictors retained in the final logistic regression model included Hemoglobin A1c (HbA1c) (OR 1.28; 95% CI: 1.08-1.52), Alkaline Phosphatase (ALP) (OR 1.02; 95% CI: 1.01-1.03), CA19-9 (OR 1.01; 95% CI: 1.01-1.01), Carcinoembryonic Antigen (CEA) (OR 1.41; 95% CI: 1.20-1.66), and Body Mass Index (BMI) (OR 0.88; 95% CI: 0.81-0.97). The final model demonstrated excellent diagnostic performance (AUC = 0.969, p < 0.001), with high accuracy, sensitivity, and specificity. A nomogram was constructed to facilitate individualized PC risk assessment.

HbA1c, ALP, CA19-9, CEA, and BMI were independently associated with pancreatic cancer. The machine learning-derived risk scoring model demonstrated high predictive accuracy and may serve as a valuable clinical tool for early detection and screening of pancreatic cancer.

Over the last decade, immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 or CTLA-4, which reinvigorate T cells for tumor control have become standard-of-care treatment options. In response to the increasingly recognized mechanisms of resistance to T cell activation in immunologically cold tumors, immuno-oncology drug development has started to shift beyond T cell approaches. These include tumor-associated macrophages (TAMs), a major pro-tumor immune cell population in the tumor microenvironment known to silence immune responses.

Here we outline anti-TAM therapies in current development, either as monotherapy or in combination with other treatment modalities. We describe emerging drugs targeting TAMs under investigation in phase II and III testing with a focus on their distinguishing mechanism of action which include (1) reprogramming of TAMs toward anti-tumor function and immune surveillance, (2) blockade of recruitment, and (3) reduction and ablation of TAMs.

Several new immuno-oncology agents are under investigation to harness anti-tumor functions of TAMs. While robust anti-tumor efficacy of anti-TAM therapies across advanced solid organ cancers remains elusive to-date, TAM reprogramming therapies have yielded benefits in select cancers. The inherent heterogeneity of the diverse TAM population will require enhanced investments into biomarker-driven approaches to fully leverage its therapeutic potential.

Pancreatic cancer (PC) has become one of the leading causes of cancer-related deaths worldwide. Social media platforms are widely used for health information dissemination because of their visual appeal and entertainment value. This study evaluates the content, quality, and reliability of PC-related information on domestic short video platforms.

A total of 265 PC-related videos were retrieved from three short video-sharing platforms: TikTok, Bilibili, and Kwai. The Global Quality Scale (GQS) and the modified DISCERN score were employed to evaluate the quality and content of the videos, respectively. Correlation analysis was conducted to explore the relationships between different video variables.

The overall quality of the video content was low, with median scores of 2 (IQR: 2-3) for both the GQS and the modified DISCERN score. Most of the videos related to PC were posted by healthcare professionals (219/265, 82.6%). Videos from specialists received more likes on short social video platforms than those from nonspecialists did (median: 678 vs. 270, P = 0.005). Educational videos scored highest in both the GQS (median: 3, IQR 2-3) and the modified DISCERN score (median: 2.5, IQR 2-3). There was a positive correlation between GQS and video duration (r = 0.31, P < 0.01) and the modified DISCERN score (r = 0.434, P < 0.001).

The quality and reliability of the videos on these platforms were generally unsatisfactory in terms of source and content. Videos produced by healthcare professionals or institutions are more informative in terms of comprehensiveness, quality of information, and reliability than are those produced by non-healthcare professionals.

Pancreatic cancer (PC), the third leading cause of cancer-related mortality globally, exhibits a persistently low five-year survival rate (13%). While the global burden of PC among individuals aged 15-59 years has declined, trends in China remain understudied. This study evaluates global and national trends in PC incidence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021 and projects trajectories to 2045.

Using data from the Global Burden of Disease (GBD) 2021 study, we calculated age-standardized rates (ASRs) for 204 countries/territories. Joinpoint (version: 5.3.0.0) regression identified temporal trends via average annual percentage changes (AAPCs), and Bayesian age-period-cohort (BAPC) modeling forecasted future burdens.

Globally, PC burden declined among 15-59-year-olds (AAPC for incidence: -0.8%, 95% UI: -1.2 to -0.4). However, China experienced a significant reversal after 2009, with incidence rising by 1.5% annually (95% UI: 0.9-2.1), disproportionately affecting males. Smoking (contributing to 22.2% of DALYs in China) and high fasting plasma glucose (15%) emerged as key modifiable risk factors, while elevated BMI exacerbated burdens in high SDI regions (3.1% of DALYs). Projections indicate a continued surge in China's PC burden by 2045, particularly among males (incidence projected to increase by 50% from 2010 to 2045).

High SDI regions exhibit concentrated PC burdens linked to lifestyle factors, whereas China's rising trends align with healthcare expansion and metabolic disease proliferation. Targeted interventions-smoking cessation, glycemic control, and weight management-are imperative to mitigate growing burdens in younger populations. This study highlights the urgent need for region-specific strategies to address evolving epidemiological challenges in PC prevention and control.

Early detection of pancreatic cancer is essential for improving survival rates. However, noninvasive diagnostic methods are lacking. Novel biomarkers, detectable through liquid biopsy, such as circulating tumor DNA (ctDNA), microRNAs (miRNAs), protein markers, and metabolites, hold promise for early diagnosis.

A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted for studies published from January 2014 to May 2024. Studies were included if they evaluated novel biomarkers for early pancreatic cancer detection, reported diagnostic performance metrics (sensitivity, specificity), and had a QUADAS-2 score of ≥3. Data on study characteristics, patient demographics, biomarker types, and diagnostic performance were extracted following PRISMA guidelines. A bivariate random-effects model was used to calculate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). The area under the summary receiver operating characteristic (SROC) curve assessed overall diagnostic accuracy. The primary outcome was the diagnostic accuracy (sensitivity and specificity) of novel biomarkers in detecting early-stage pancreatic cancer.

A total of 43 studies involving 19,326 participants were included, with 2,749 patients having stage I or II pancreatic cancer. The pooled sensitivities and specificities were as follows:. miRNA Biomarkers: Sensitivity 0.88 (95% CI 0.79-0.93), Specificity 0.91 (95% CI 0.82-0.95), DOR 72.68 (95% CI 26.64-198.24), AUC 0.95. Protein Biomarkers: Sensitivity 0.79 (95% CI 0.70-0.86), Specificity 0.88 (95% CI 0.82-0.93), DOR 27.74 (95% CI 14.32-53.76), AUC 0.90. Metabolite Biomarkers: Sensitivity 0.84 (95% CI 0.73-0.92), Specificity 0.85 (95% CI 0.81-0.88), DOR 31.76 (95% CI 12.38-81.48), AUC 0.90. ctDNA Biomarkers: Sensitivity 0.65 (95% CI 0.48-0.81), Specificity 0.94 (95% CI 0.88-0.97), DOR 27.73 (95% CI 12.91-59.55), AUC 0.92. Subgroup analyses showed combining biomarkers with CA19-9 improved diagnostic accuracy. Sensitivity analyses confirmed the robustness of the findings.

Novel biomarkers, particularly miRNAs and protein markers, demonstrate high diagnostic accuracy for early pancreatic cancer detection and have potential for clinical application in improving early diagnosis and patient outcomes.

https://www.crd.york.ac.uk/prospero/, Identifier: PROSPERO (CRD42024553633).

The microbiome is key to understanding endometrial cancer (EC) etiology and prevention strategies, implicated in the regulation of estrogen in estrogen-driven cancers. Utilizing robust methodologies in the QIIME 2 platform, we examined 16S rRNA vaginal and rectal microbiome data from an EC cohort: 192 women with benign gynecologic conditions, endometrial hyperplasia, or endometrial cancer. Distinct microbial compositions and community networks specific to EC were identified and related to histological grade with adjustments for EC risk factors. Vaginal health-associated Lactobacillus and Limosilactobacillus, and rectal Prevotella and Peptoniphilus, were depleted in EC, while detrimental vaginal Anaerococcus, Porphyromonas, Prevotella, Peptoniphilus, and rectal Buttiaxella were enriched. Significant bacterial features were shared between rectal and vaginal sites in EC, such as Prevotella timonensis and Peptoniphilus A. Vaginal Lactobacillus abundance contributed to less feature sharing from the rectum. Putative microbial metabolic analysis identified dysregulation of amino acid, complex carbohydrate, and hormone metabolism amongst patients with EC.

The metabolism of lactate and lactylation of proteins are believed to influence tumor development through their effects on the tumor microenvironment and immune escape mechanisms. Nevertheless, its significance in pancreatic ductal adenocarcinoma (PDAC) has yet to be fully understood. This investigation sought to assess the predictive value and treatment implications of lactate-related genes (LRGs) in PDAC.

We analyzed PDAC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), identifying LRGs. Using weighted gene co-expression network analysis (WGCNA) and consensus clustering, we delineated lactate subtypes and extracted differentially expressed genes. Functional enrichment and gene set enrichment analysis (GSEA) analyses were conducted to explore pathways. A lactate-linked risk signature was constructed using Lasso-Cox regression, and its prognostic value was validated. In vitro experiments were executed to examine the function of MCU in PDAC cells. In vitro experiments were conducted to detect the malignant potential of MCU in PDAC cells and its effect on lactic acid metabolism.

Two lactate subtypes were identified, with distinct gene expression profiles and clinical outcomes. The risk signature, comprising four LRGs, predicted survival with significant accuracy. In vitro, MCU knockdown reduced cell proliferation, migration, invasion, and stemness, confirming its role in PDAC malignancy. At the same time, it can also inhibit lactate production and glycolysis processes.

Our investigation underscores the importance of LRGs in PDAC, providing a novel prognostic signature and therapeutic target.

This study evaluates the feasibility of using a simplified Patlak parametric imaging technique with a scaled population-based input function (sPBIF) in pancreatic cancer.

Twenty-six patients underwent multi-bed, multi-pass [18F]FDG PET/CT scans, from which both dynamic and static PET images were reconstructed. Patlak parametric images were generated from the dynamic PET series using both the image-derived input function (IDIF) and the sPBIF. The consistency between IDIF and sPBIF was evaluated by comparing the area under the curve (AUC) and Patlak parameters derived from both input functions. The detectability of pancreatic lesions, assessed by tumor-to-background ratio (TBR) and contrast-to-noise ratio (CNR), was compared between SUV and Patlak parametric images. Additionally, the correlation between clinicopathological features and PET parameters, including SUV and Patlak values, was analyzed.

We found good agreement between the AUC for IDIF and sPBIF with correlation coefficients of 0.87 and 0.93 for the 0-30 min and 0-50 min intervals, respectively. The Patlak parameters from IDIF and sPBIF presented correlation coefficients higher than 0.94. The SUV and Patlak Ki exhibited correlation coefficients greater than 0.92 and 0.73 in malignant and benign pancreatic lesions, respectively. The SUV and Patlak V0 correlated with correlation coefficients higher than 0.75 in benign lesions, but exhibited only a weak correlation in malignant lesions. The TBR of Patlak Ki was significantly higher in malignant lesions compared to SUV. However, the CNR of Patlak Ki was lower due to increased noise in the parametric images. Most clinicopathological features showed weak correlation with PET parameters, except for a marginal classification of lesion differentiation by the maximum Ki value.

The sPBIF approach enables the acquisition of additional Patlak parametric images alongside static SUV imaging in pancreatic cancer patients. Ki parametric imaging provided higher contrast than static imaging for detecting pancreatic lesions.

Pancreatic cancer (PC) remains one of the deadliest cancers, characterized by its high aggressiveness and low overall survival, with chemotherapy and immunotherapy showing limited efficacy. It is essential to investigate the molecular mechanisms driving the PC progression. In this study, we showed that One Cut homeobox 3 (ONECUT3) acted as an oncogene promoting PC progression and observed a significant increase of ONECUT3 levels in PC tissues and cells. The reduced ONECUT3 expression was positively correlated with decreased tumor volumes and weight, and the depressed proliferation, migration and invasion abilities. Mechanistically, ONECUT3 directly bound to the promoter of tripartite motif-containing 46 (TRIM46) and transcriptionally upregulated its expression. Tripartite motif (TRIM)-containing proteins have been identified as closely linked to the advancement of tumors. However, the role of TRIM46 in PC remains largely unexplored. The expression of ONECUT3 was found to be positively linked with TRIM46 in human PC tissues. The upregulation of TRIM46 rescued ONECUT3 knockdown-induced suppression of cell proliferation, migration and invasion abilities, and tumor growth in PC. TRIM46 overexpression also activated NF-κB signaling in PC cells. To sum up, ONECUT3 has been identified as a promising prognostic indicator in PC, and targeting this cancer-promoting pathway could offer an effective therapeutic approach to combat the PC progression.

More than 30% of patients with pancreatic cancer are unresectable because of the local extension with a median overall survival (OS) of <1 year. Combination of fluorouracil (FU), oxaliplatin, and irinotecan (FOLFIRINOX) is superior to gemcitabine in the treatment of metastatic pancreatic cancer, but standard of care remains gemcitabine in locally advanced pancreatic cancer (LAPC).

Patients with histologically proven LAPC not suitable for surgery, Eastern Cooperative Oncology Group WHO performance status (PS) ≤1 were eligible. Random assignment was stratified by center, tumor localization (pancreas head yes/no), WHO PS (0 v 1), and age (≤60 years v >60 years). Patients received FOLFIRINOX or gemcitabine for 6 months. The primary end point was progression-free survival (PFS). Main secondary end points were OS, time to treatment failure, quality of life, and safety. One hundred seventy patients (142 events) were needed to detect an increase of 3 months in PFS with 80% power (log-rank test, 5% two-sided α).

One hundred seventy one patients age 35-84 years were included and followed for a maximum of 5 years. With a median follow-up of 59.6 months (95% CI, 42.3 to not reached), 168 events were observed and the median PFS was 9.7 months (95% CI, 7.0 to 11.7) with FOLFIRINOX versus 7.7 months (95% CI, 6.2 to 9.2) with gemcitabine, hazard ratio (HR), 0.7 (95% CI, 0.5 to 1.0), P = .04. The median OS was 15.7 months (95% CI, 11.9 to 20.4) in the FOLFIRINOX group versus 15.4 months (95% CI, 11.7 to 18.6) in the gemcitabine group, HR, 1.02 (95% CI, 0.73 to 1.43), P = .95.

Results confirm that FOLFIRINOX improves PFS significantly compared with gemcitabine and is well tolerated in LAPC. No significant difference in OS was observed between both groups.