Single-molecule science is a unique technique for unraveling molecular biophysical processes. Sensitivity to single molecules provides the capacity for the early diagnosis of low biomarker amounts. Furthermore, the miniaturization of instruments for portable diagnostic tools toward point-of-care testing (POCT) is a crucial development in this field. Herein, we discuss recent developments in single-molecule sensing platforms and their advantages for diagnostics over bulk measurements including molecular size measurements, interaction dynamics, and fast biomarker sensing and sequencing at low concentrations. We highlight the capabilities of dynamic optical and electrical sensing platforms for single-biomolecule and single-vesicle monitoring associated with neurodegenerative disorders, viral diseases, cancers, and more. Current approaches to instrument miniaturization have brought technology closer to portable diagnostics settings via smartphone-based devices, multifunctional portable microscopes, handheld electrical circuit devices, and remote single-molecule assays. Finally, we provide an overview of the clinical applications of single-molecule sensors in POCT assays. Altogether, single-molecule analyses platforms exhibit significant potential for the development of novel portable healthcare devices.

Early detection of pancreatic cancer is vital for patient survival. However, current diagnostic approaches remain constrained by insufficient precision and specificity inherent to single-biomarker detection strategies. Herein, we develop a nanochannel biosensing platform implementing cooperative dual-signal detection of pancreatic-specific biomarkers CA19-9 and miRNA-196a. Using liquid-liquid interface self-assembly, we constructed anodic aluminum oxide (AAO)-Au hybrid nanochannels integrated with a surface-modified double-key DNA nanolock (DDN). The conformational switch of DDN logic gating triggered by miRNA-196a exposes the CA19-9-aptamer, enabling specific target recognition and consequent ion current signal attenuation. Simultaneously, released miRNA-196a is quantified by catalytic hairpin assembly and hybridization chain reaction-mediated cascade amplification. Experiments show that the present DDN-based logic nanofluidic platform could achieve an ultralow detection limit of 0.000027 U·mL-1 for CA19-9 and 4.74 aM for miRNA-196a, which is 2-3 orders of magnitude higher than traditional ELISA/qPCR methods. Finally, clinical sample analysis confirms the high specificity of this platform in distinguishing pancreatic cancer and acute pancreatitis from healthy individuals. This DDN-functionalized nanofluidic biosensor provides valuable insights into designing precision detection platforms for pancreatic cancer, highlighting its significant potential for clinical diagnostics.

A highly suppressive tumor immune microenvironment and nonspecific target endow malignant tumors with CAR-T cells. CSF1R is highly expressed on pancreatic cancer tissues compares with normal tissues in GEPIA database and M2 macrophages mainly contributing to the suppressive tumor microenvironment (TME), suggesting that CSF1R is a suitable antigen. CSF1 is the natural ligand of CSF1R, so we constructed a CSF1-CAR and tested its cytotoxic effect on tumor cells and macrophages in vitro. Our results demonstrated that CSF1-CAR-T cells can lyse tumor cells dependent on CSF1R expression. Meanwhile, CSF1-CAR-T also lyse CSF1R+ M2 macrophages, suggesting that CSF1-CAR-T cells play a role in eliminating tumor cells and remodeling the TME.

The tumor microenvironment (TME) plays a crucial role in cancer development and spreading being considered as "the dark side of the tumor". Within this term tumor cells, immune components, supporting cells, extracellular matrix and a myriad of bioactive molecules that synergistically promote tumor development and therapeutic resistance, are included. Recent findings revealed the profound impacts of TME on cancer development, serving as physical support, critical mediator and biodynamic matrix in cancer evolution, immune modulation, and treatment outcomes. TME targeting strategies built on vasculature, immune checkpoints, and immuno-cell therapies, have paved the way for revolutionary clinical interventions. On this basis, the relevance of pre-clinical and clinical investigations has rapidly become fundamental for implementing novel therapeutical strategies breaking cell-cell and cell -mediators' interactions between TME components and tumor cells. This review summarizes the key players in the breast and pancreatic TME, elucidating the intricate interactions among cancer cells and their essential role for cancer progression and therapeutic resistance. Different tumors such breast and pancreatic cancer have both different and similar stroma features, that might affect therapeutic strategies. Therefore, this review aims to comprehensively evaluate recent findings for refining breast and pancreatic cancer therapies and improve patient prognoses by exploiting the TME's complexity in the next future.

Biliary brushing cytology during endoscopic retrograde cholangiopancreatography (ERCP) is used to assess the nature of a biliary stricture. Its low sensitivity challenges exclusion of malignancy through this technique. The aim was to evaluate the diagnostic yield of brush cytology in biliary strictures and to identify predictive factors associated with a positive diagnosis of malignancy.

Observational retrospective study in a tertiary center. All adult patients undergoing a biliary brushing during ERPC from 2016 to 2022 were included. Logistic regression analyses were performed to identify predictive factors for positive brush cytology.

A total of 5309 patients underwent ERCP within the evaluated period. Out of these, biliary brushing was performed in 518 patients including 568 cytology samples, 57.7% (299) were men, median age 74 (64-84) years old. There were 24% (126) benign strictures and 76% (392) malignant of which the most common etiology were pancreatic cancer 42.5% (220/518), followed by cholangiocarcinoma 22.6% (117/518). The sensitivity, specificity, positive predictive value, and negative predictive value were 48%, 98%, 98% and 37%, respectively. Sensitivity was 45% and 52% in pancreatic adenocarcinoma and cholangiocarcinoma, respectively. Older age (OR 1.02, 95% CI: 1.01-1.03, p=0.01) and higher bilirubin (OR 1.05, 95% CI: 1.03-1.08, p<0.001) were independent predictors for brush cytology positivity. There were 9.7% (45/518) post-ERCP complications.

Biliary brushing cytology during ERCP is a safe procedure with low sensitivity but high specificity. Older age and higher bilirubin are associated to positive biliary cytology.

Pancreatic cancer (PC) is a highly lethal and aggressive malignancy, currently one of the leading causes of cancer-related deaths worldwide, in both women and men. PC is highly resistant to standard chemotherapy (CT) because its immunosuppressive and hypoxic tumor microenvironment and a dense desmoplastic stroma compartment extensively limit drug accessibility and perfusion. Although CT is one of the main therapeutic strategies for PC management contributing to tumor eradication through a cytotoxic effect, CT is associated with a poor pharmacokinetic profile and provokes deleterious systemic toxicity. This low efficacy-poor safety scenario urgently calls for innovative and highly specific therapeutic strategies to counteract this urgent clinical challenge. Nanotechnology-based precision materials for cancer may help improve drug stability and minimize the systemic cytotoxic effects by increasing drug tumor accumulation and also enabling controlled release, but several drawbacks still persist, such as the poor targeting efficiency. In the last few years increased attention has been paid to bioinspired nanosystems that can mimic either partially or totally biological systems, including lipid layers as suitable stealth coatings resembling the composition of cell membranes, lipoprotein- and blood protein-based nanosystems, and cell membrane-derived systems, such as extracellular vesicles, cell membrane nanovesicles and cell membrane-coated nanosystems, which display intrinsic cancer-targeting abilities, enhanced biocompatibility, decreased immunogenicity, and prolonged blood circulation profile. This review covers the recent breakthroughs on advanced biomimetic PC-targeted nanosystems, focusing on their design, properties and applications as innovative, multifunctional and versatile tools paving the way to improved PC diagnosis and treatment.

To compare perioperative morbidity and mortality in patients receiving pancreatoduodenectomy or total pancreatectomy for pancreatic head adenocarcinoma using German Cancer Registry data.

Anonymized pooled data were retrieved from regional cancer registries participating in the German Cancer Registry Group of the Association of German Tumor Centers. Included were patients diagnosed with pancreatic head adenocarcinoma since 2016, receiving curative intent pancreatoduodenectomy or total pancreatectomy. Patients were propensity-score matched according to age, sex, and histopathology. Primary endpoints were 30- and 90-day postoperative mortality. Secondary endpoints were administration of adjuvant chemotherapy, long-term survival, and patterns of cancer recurrence. The data were analyzed using R.

In total, 756 patients per treatment group were matched for further analyses. R0-resection rate was comparable between pancreatoduodenectomy and total pancreatectomy (69.6 vs 73.4%, P = .154). The 30-day (9.5 vs 4.8%, P < .001) and 90-day postoperative mortality (18.0 vs 11.0%, P < .001) rates were significantly lower after pancreatoduodenectomy compared with total pancreatectomy. After pancreatoduodenectomy, more patients received adjuvant chemotherapy (43.6 vs 53.3%, P < .001) and time to adjuvant chemotherapy was shorter (60.1 vs 52.7 days, P = .002) compared with total pancreatectomy. Long-term overall survival was worse after total pancreatectomy (P < .001), also in patients receiving adjuvant chemotherapy (P = .019). The sites of recurrence were comparable between both groups (P = .274).

The results of this study show greater perioperative morbidity and mortality after total pancreatectomy compared with pancreatoduodenectomy for pancreatic head malignancy. Also, long-term survival was worse after total pancreatectomy. These results emphasize the role of pancreatoduodenectomy as a standard surgical procedure for pancreatic head adenocarcinoma and suggest that total pancreatectomy should only be performed in selected patients.

Pancreatic cancer is known for its high invasiveness and metastasis, making rapid visualization and precise treatment critical for improving patient outcomes. Current diagnostic tools lack abilities to provide rapid and accurate tumor localization, particularly for real-time intraoperative guidance. To address this gap, the study has developed a novel Förster Resonance Energy Transfer (FRET)-mediated dual-ratiometric near-infrared fluorescence (NIRF)/photoacoustic (PA) bimodal probe, SiRho-SHD-NTR, specifically designed for the fast and accurate navigation of pancreatic tumor resection. The probe, due to its excellent binding affinity with nitroreductase (NTR), can rapidly reach response saturation. Cellular experiments demonstrate that the probe rapidly and efficiently penetrates cancer cells, enhancing the effectiveness of PA imaging for preliminary diagnosis and tumor localization, while also enabling the rapid visualization of pancreatic tumors through NIRF imaging. Leveraging the rapid response characteristics of the probe to NTR, the study achieves precise tumor imaging in orthotopic pancreatic cancer mice by spraying the probe, within ≈5 min. More importantly, the probe even allows for the fast visualization of metastatic tumors and fluorescence-guided surgical resection. It is believed that SiRho-SHD-NTR will offer a promising method in the rapid visualization of pancreatic cancer and provide a powerful tool for imaging-guided tumor surgery, targeting both primary and metastatic tumors.

Reports indicate a growing role for artificial intelligence (AI) in the evaluation of pancreaticobiliary and hepatic conditions. A key focus is differentiating between benign and malignant lesions, which is crucial for treatment decisions. AI improves diagnostic accuracy through high sensitivity and specificity, while CNN algorithms enhance image analysis and reduce variability. These advancements aim to match the accuracy of pathologists in cancer detection. In addition, AI aids in identifying diagnostic markers, as early detection is essential. This article reviews the applications of machine learning and deep learning in the diagnosis of hepatic and pancreaticobiliary diseases. Although the use of AI in these specialized areas of gastroenterology is primarily confined to experimental trials, current models demonstrate significant potential for enhancing the detection, evaluation, and treatment planning of hepatic and pancreaticobiliary conditions.

Pancreatic cancer (PC) is a major global health challenge, with rising incidence and mortality rates, particularly in high-socio-demographic index regions. Given its high mortality and significant morbidity, research on patient quality of life (QoL) has gained momentum, addressing symptom burdens, psychological distress, and treatment-related outcomes. Bibliometric analysis provides a valuable approach to mapping research trends, identifying key contributors, and forecasting future directions.

This study aimed to map global research on QoL in pancreatic cancer patients, highlighting key findings, challenges, and future directions through bibliometric analysis over the past two decades.

Data for this study were collected from the Web of Science Core Collection (WoSCC) database, using specific search strategies to retrieve relevant documents on the quality of life in pancreatic cancer patients. The data were analysed using the Bibliometrix R package to create knowledge maps and visualize research trends, collaborations, and emerging hotspots in the field.

A total of 819 articles on pancreatic cancer and quality of life were identified, with an average citation count of 47.13 per article, highlighting moderate academic impact. The research revealed a growing trend in collaborative efforts, with an average of 9.42 co-authors per article and 16 % international collaborations. The United States emerged as the leading contributor, with 203 publications and the highest citation count, followed by France and the United Kingdom.

This bibliometric analysis highlights the growing volume of pancreatic cancer and quality of life research, with a steady annual growth rate of 6.9 % and increasing collaboration, especially from the United States. However, despite the rising number of publications, a decline in citation impact for recent studies suggests a need for continued innovation in therapeutic strategies to improve clinical outcomes.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, with a five-year survival rate below 15 %. Claudin 18.2 (CLDN18.2) has emerged as a novel potential therapeutic target in PDAC. Zolbetuximab, a monoclonal antibody targeting CLDN18.2, has demonstrated therapeutic benefit in gastric cancers and is now in phase 2 clinical trials for PDAC. Trial eligibility for zolbetuximab requires tumor membranous immunohistochemical staining with the pan-claudin 18 companion diagnostic antibody clone 43-14A. However, the expression of CLDN18 detected using this clone has only been evaluated in 62 patients from a single retrospective study. Herein, we report immunohistochemical staining using 43-14A on surgically resected PDAC samples (n = 120). Samples were stained following the protocol used in clinical trials, using the 43-14A VENTANA antibody in a prediluted kit, and according to the manufacturer's recommended protocol. Positive cases were defined as ≥ 75 % of tumor cells exhibiting membranous staining with an intensity of ≥ 2+. Out of 120 PDAC cases, 39 (32.5 %) stained positive for CLDN18 with 43-14A. A significant association was observed between lower tumor grade and higher 43-14A staining (p < 0.05). CLDN18-positive cases demonstrated significantly improved survival at the cohort's median overall survival (23 months, p < 0.05), suggesting that claudin expression could serve as a both a diagnostic and prognostic marker. Our findings indicate that 32.5 % of PDAC tumors in this cohort are positive for CLDN18, suggesting that a significant proportion of patients with PDAC could benefit from zolbetuximab and other CLDN18.2 targeted immunotherapies if pancreatic cancer therapeutic trials prove successful.

Pancreatic cancer has a high mortality rate, and both the incidence and mortality are continuing to increase in many countries globally. The poor prognosis of pancreatic cancer is in part due to the challenges in early diagnosis. Improving early-stage pancreatic cancer diagnosis would improve survival outcomes. Aptamer-based biosensors provide an alternative technological approach for the analysis of serum biomarkers with several potential advantages. This review summarizes the major pancreatic cancer serum biomarkers, as well as discusses recent progress in biomarker exploration and aptasensor development. Here, we review both established and novel serum biomarkers identified recently, emphasizing their potential for early-stage pancreatic cancer diagnosis. We also propose strategies for further expanding multiplex biomarker panels beyond the established CA19-9 biomarker to enhance diagnostic performance. We discuss technological advancements in aptamer-based sensors for pancreatic cancer-related biomarkers over the last decade. Optical and electrochemical sensors are highlighted as two primary modalities in aptasensor design, each offering unique advantages. Finally, we propose steps towards clinical application using aptamer-based sensors with multiplexed biomarker detection for improved pancreatic cancer diagnostics.

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.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, immunosuppressive tumor microenvironment (TME) that limits therapeutic efficacy. This study investigates the role of cellular communication network factor 1 (CCN1, also known as Cyr61), an extracellular matrix-associated protein, in modulating the TME of PDAC. It is demonstrated that Ccn1 promotes PDAC progression by upregulating collagen and chemokine expression, thereby facilitating immune cell exclusion and enhancing tumor growth. Using a Ccn1-deficient PDAC model, decreased collagen and chemokine levels are observed, resulting in increased infiltration of cytotoxic immune cells and reduced myeloid-derived suppressor cells (MDSCs). Furthermore, Ccn1-deficient tumors exhibit heightened sensitivity to gemcitabine and show enhanced responsiveness to anti-programmed cell death 1 (anti-PD1) therapy. Mechanistically, Ccn1 regulates chemokine production through collagen expression, with chemokine levels remaining suppressed even upon interferon-gamma treatment in collagen-deficient cells. These findings highlight Ccn1 as a potential therapeutic target that reprograms the TME to enhance the efficacy of both chemotherapy and immunotherapy in PDAC, providing a novel approach for overcoming immune resistance in PDAC.

Despite constitutive Ras/Raf/MAPK pathway activation in most pancreatic ductal adenocarcinomas (PDACs), treatment approaches targeting this pathway have primarily been unsuccessful. We conduct a drug library screen on an MEK inhibitor (MEKi)-resistant PDAC model and perform complementary pathway analysis to identify cellular resistance phenotypes. We use syngeneic models to investigate the molecular determinants of identified drug synergism. Our study reveals an enrichment for the hallmarks of G2/M checkpoints in MEKi-resistant phenotypes from all investigated models. We find overexpression of Polo-like kinase 1 (PLK1) and other G2/M checkpoint-related proteins in MEKi-resistant cells. We identify synergistic activity between MEK and PLK1 inhibition both in vitro and in vivo and mechanistically show that dual inhibition of the PLK1 and MEK pathways activates the JNK/c-JUN pathway. This causes the accumulation of DNA damage, ultimately leading to apoptotic cell death. Dual PLK1/MEK inhibition emerges as a promising targeted approach in PDAC.

Recent research suggests that new-onset diabetes mellitus (NODM) often results from pancreatic cancer (PC) rather than causing it. Determining if NODM is type 2 diabetes mellitus (T2DM) or PC-related NODM (NODM-PC) aids in the early diagnosis of PC. We developed a NODM-PC risk prediction model to stratify PC risk in patients with NODM.

This study utilized data from the UK Biobank, including 238 NODM-PC cases and 14,825 cancer-free T2DM controls. Polygenic risk scores (PRSs) for PC and T2DM were constructed using previously reported single nucleotide polymorphisms (SNPs) separately, while the NODM-PC PRS was developed by combining SNPs from both. Non-genetic factors were selected as candidate predictors based on prior NODM-PC prediction models. We developed three Cox models to estimate the risk of PC diagnosis within 3 years in the NODM population and evaluated them by internal-external cross-validation.

Elevated NODM-PC PRS and PC PRS scores positively correlated with NODM-PC risk, while T2DM PRS showed an inverse correlation. The NODM-PC PRS achieved the highest AUC at 0.719. Three Cox models were developed: Model 1 included age at T2DM diagnosis, smoking status, HbA1c, PC PRS, and T2DM PRS; Model 2 replaced PC and T2DM PRS with NODM-PC PRS; Model 3 included only non-genetic factors. Model 2 had the highest discrimination (Harrell's C-index 0.823 (95% CI: 0.806-0.840)), demonstrated the best clinical utility with good calibration, and showed significant classification improvement (continuous net reclassification index: 26.89% and 31.93% for cases, 28.51% and 30.90% for controls, compared to Models 1 and 3). The positive predictive value for the top 1% predicted risk in Model 2 was 13.25%.

This NODM-PC PRS enhances NODM-PC risk prediction, efficiently identifies individuals at high risk for PC screening, and improves PC screening efficiency at the population level among NODM individuals.

There has been increased use of neoadjuvant chemotherapy (NAC) in resectable pancreatic ductal adenocarcinoma (PDAC) patients. [18F]fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scan is being frequently used to determine treatment response in PDAC patients undergoing NAC. Maximum standardized uptake value (SUVmax) is conventionally used as an FDG-PET/CT parameter, but there are emerging parameters, such as total lesion glycolysis (TLG), which take into account mean standardized uptake (SUVmean) and metabolic tumour volume (MTV). This study compared the ability of emerging FDG-PET/CT parameters (i.e. SUVmean, MTV and TLG) to predict chemo-response compared to SUVmax.

In this single centre, retrospective study, NAC-treated PDAC patients (n = 74) for whom both pre- and post-NAC FDG-PET/CT scans were available were recruited. All scans were imported to a single analysis platform and reanalysed. Chemo-response was determined by the assessment of percentage viable tumour cells in the tumour bed. Statistical analysis was performed on the data.

A significant correlation was observed between post-treatment FDG-PET/CT scan parameters and viable cancer cells in the tumour bed, with TLG showing a higher degree of correlation (r = .3131) compared to all other parameters (r = .2722-.3008). The percentage decrease in the TLG (post-NAC scan vs. pre-NAC scan) demonstrated the highest degree of correlation with viable cancer cells in the tumour bed (r = -.3444) and had a statistically significant (p = .0157) effect between NAC responders (Median = 80.57) and non-responders (Median = 65.16). The difference between TLG (post-NAC scan vs. pre-NAC scan) was shown to be an independent prognostic indicator for overall survival (hazard ratio = .5033, p = .0361).

TLG was shown to be a superior predictor of chemo-response and patient prognosis compared to all other FDG-PET/CT parameters in PDAC patients treated with NAC.

Pancreatic Ductal Adenocarcinoma (PDAC) belongs to the types of cancer with the highest lethality. It is also remarkably chemoresistant to the few available cytotoxic therapeutic options. PDAC is characterized by limited mutational heterogeneity of the known driver genes, KRAS, CDKN2A, TP53, and SMAD4, observed in both early-stage and advanced tumors. In this review, we summarize the two proposed models of genetic evolution of pancreatic cancer. The gradual or stepwise accumulated mutations model has been widely studied. On the contrary, less evidence exists on the more recent simultaneous model, according to which rapid tumor evolution is driven by the concurrent accumulation of genetic alterations. In both models, oncogenic KRAS mutations are the main initiating event. Here, we analyze the emerging topic of KRAS allelic imbalances and how it arises during tumor evolution, as it is often detected in advanced and metastatic PDAC. We also summarize recent evidence on how it affects tumor biology, metastasis, and response to therapy. To this extent, we highlight the necessity to include studies of KRAS allelic frequencies in the design of future therapeutic strategies against pancreatic cancer.

Pancreatic cancer (PC) has high lethality due to multiple reasons, and its limited response to conventional chemotherapy like gemcitabine (GEM) is a non-negligible one. Therefore, our study introduces Chlorophyllin (CHL) as an effective therapeutic candidate to enhance the therapeutic efficacy of GEM. Our results demonstrate that the combination of CHL and GEM exhibits a significant synergistic anti-tumor effect by targeting multiple oncogenic processes in PC, including inhibiting cell proliferation, invasion, and migration, as well as inducing cell apoptosis. Further investigations of mechanism have revealed that CHL induces cuproptosis in PC cells through a multifaceted process, involving depleting cellular intracellular glutathione (GSH), increasing reactive oxygen species (ROS) levels, and subsequently upregulating the HSP70 protein in response to heightened oxidative stress. Additionally, CHL releases free Cu2+, binds to the Ferredoxin 1 (FDX1) protein, and ultimately leads to the oligomerization of Dihydrolipoamide S-Acetyltransferase (DLAT) proteins to amplify the copper toxicity within PC cells. Moreover, in vivo experiments have demonstrated that the combination of CHL and GEM effectively inhibits the growth of subcutaneously transplanted tumors while maintaining a favorable biosafety profile. In conclusion, our study identifies CHL as a potent enhancer of GEM's anti-tumor effects in PC through the induction of cuproptosis, thus providing a novel therapeutic avenue for patients with PC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging types of cancer with little or no response to immune checkpoint inhibitors (ICI). Photodynamic therapy (PDT) has been shown to ablate tumors and induce an immune response. In our study, we investigated the effect of PDT using the photosensitizer Bremachlorin, in its ability to reduce tumor burden and immunologically sensitize T-cell-high and T-cell-low murine PDAC tumors to the ICIs that blocks PD-1 immune checkpoint. In addition, we monitored the effect on survival and investigated if there was a response in PDT-treated and non-PDT-treated distant tumors. Our results showed that Bremachlorin PDT induces direct tumor killing that increased survival in both "hot" T-cell-high and "cold" T-cell-low PDAC tumors and that it can make T-cell-high tumors more sensitive to ICIs blocking PD-1. We found that T-cell-high tumor-bearing mice had an overall greater response to therapy than did T-cell-low tumor-bearing mice. One mouse with T-cell-high tumors exhibited complete tumor regression in both the treated and nontreated distant tumor 90 days after treatment. These results indicate that combining ICIs with Bremachlorin PDT could be a promising therapeutic intervention for enhancing PDAC's response to therapy.

The harsh biological barriers and bacteria within tumor microenvironment not only hinder drug penetration and induce drug inactivation, but also inhibit antitumor immune responses. Here a tumor microenvironment dual cascade-responsive multifunctional nanoparticle, Gem/Emo@NP@GHA is reported, which is engineered from a hyaluronidase (HAase)-responsive guanidine group functionalized hyaluronic acid (GHA) shell and a glutathione (GSH)-responsive biopolymer core (Gem/Emo@NP), that encapsulates anticancer drug gemcitabine (Gem) and two-photon-excited photosensitizer emodin (Emo). The constructed Gem/Emo@NP@GHA can specifically target the tumor and subsequently be degraded by HAase-abundant in the extracellular matrix. Thus, the resulting Gem/Emo@NP achieved size reduction and charge reversal, strengthening deep tumor penetration. Upon internalization, the positively charged Gem/Emo@NP effectively kills intratumor bacteria by inducing membrane depolarization. Furthermore, the high levels of GSH within tumor cells disrupt the disulfide bonds of Gem/Emo@NP, triggering drug release. Thereby, the undecomposed Gem successfully induces tumor cell apoptosis and necrosis. Under laser irradiation, photosensitizer Emo generates high singlet oxygen (1O2), further eliminating tumors and intracellular bacteria. More importantly, Gem/Emo@NP@GHA can activate T cell-mediated immune response, further enhancing antitumor activity. These findings provide a promising approach to treating bacterially infected tumors through the synergistic application of chem-immunotherapy and two-photon-excited photodynamic therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited early diagnostic methods and therapeutic options, contributing to its poor prognosis. Recent advances in high-throughput sequencing have highlighted the critical roles of noncoding RNAs (ncRNAs), particularly PIWI-interacting RNAs (piRNAs), in cancer biology. In this review, we systematically summarize the emerging roles of piRNAs and their associated PIWI proteins in PDAC pathogenesis, progression, and prognosis. We provide a comprehensive analysis of the molecular mechanisms by which piRNAs/PIWIs regulate gene expression and cellular signaling pathways in PDAC. Furthermore, we discuss their potential as novel biomarkers for early diagnosis and therapeutic targets. Importantly, this review identifies key piRNAs/PIWIs involved in PDAC and proposes innovative strategies for improving diagnosis and treatment outcomes. Our work not only consolidates current knowledge but also offers new perspectives for future research and clinical applications in PDAC management.

Pancreatic cancer is highly lethal, and survival chances improve only with early detection at a precancerous stage. However, there remains a significant gap in developing tools for large-scale, rapid screening. To this end, a high-throughput On-Target Array Extraction Platform (OTAEP) by direct sintering of a series of metal-organic frameworks (MOFs) for dual in situ extraction, encompassing both exosomes and their metabolic profiles, is developed. Based on the principle of geometry-dependent photothermal conversion efficiency and standard testing, the appropriate MOF functional unit is identified. This unit enables exosome enrichment within 10 min and metabolic fingerprint extraction in under 1 s of laser irradiation, with over five reuse. To further accelerate and enhance the quality of metabolic profile analysis, the application of Surrogate Variable Analysis to eliminate hidden confounding factors within the profiles is proposed, and five biomarkers demonstrated by MS/MS experiments are identified. These biomarkers enable early diagnosis, risk stratification, and staging of pancreatic cancer simultaneously, with sensitivity of 94.1%, specificity of 98.8%, and precision of 94.9%. This work represents a breakthrough for overcoming throughput challenges in large-scale testing and for addressing confounding factors in big data analysis.

In pancreatic ductal adenocarcinoma (PDAC), fibroblast activation leads to excessive secretion of extracellular matrix (ECM) and soluble factors that regulate tumor progression, prompting investigation into endoplasmic reticulum (ER)-resident proteins that may support this activation. We identified FKBP7, a peptidyl-prolyl isomerase in the ER, as overexpressed in PDAC stroma compared to cancer cells, and in patients with favorable prognosis. Analysis of single-cell RNA sequencing databases revealed FKBP7 expression in pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs). When analyzed by immunohistochemistry on PDAC patient tissues, FKBP7 emerged as an early activation marker in the preneoplastic stroma, preceding αSMA expression, and responding to FAK- and TGFβ-induced stiffening and pro-fibrotic programs in PSCs. Functional analyses revealed that FKBP7 knockdown in PSCs enhanced contractility, Rho/FAK signaling, and secretion of pro-inflammatory cytokines as well as remodeling of type I collagen, promoting an activated phenotype and accelerating tumor growth in vivo. Conversely, FKBP7 expression supported a tumor-restraining (i.e. encapsulating) ECM characterized by type IV collagen. Mechanistically, FKBP7 interacts with BiP, and blocking this interaction instead leads to increased PSC secretion of type I collagen. Thus, FKBP7 serves as a novel PSC marker and ER regulator in a complex with BiP of the secretion of specific collagen subtypes, highlighting its potential to mediate ECM normalization and constrain PDAC tumorigenesis.

This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

Pancreatic cancer stands as one of the most lethal malignancies, characterized by delayed diagnosis, high mortality rates, limited treatment efficacy, and poor prognosis. Disulfidptosis, a recently unveiled modality of cell demise induced by disulfide stress, has emerged as a critical player intricately associated with the onset and progression of various cancer types. It has emerged as a promising candidate biomarker for cancer diagnosis, prognosis assessment, and treatment strategies. In this study, we have effectively established a prognostic risk model for pancreatic cancer by incorporating multiple differentially expressed long non-coding RNAs (DElncRNAs) closely linked to disulfide-driven cell death. Our investigation delved into the nuanced relationship between the DElncRNA-based predictive model for disulfide-driven cell death and the therapeutic responses to anticancer agents. Our findings illuminate that the high-risk subgroup exhibits heightened susceptibility to the small molecule compound AZD1208, positioning it as a prospective therapeutic agent for pancreatic cancer. Finally, we have elucidated the underlying mechanistic potential of AZD1208 in ameliorating pancreatic cancer through its targeted inhibition of the peroxisome proliferator-activated receptor-γ (PPARG) protein, employing an array of comprehensive analytical methods, including molecular docking and molecular dynamics (MD) simulations. This study explores disulfidptosis-related genes, paving the way for the development of targeted therapies for pancreatic cancer and emphasizing their significance in the field of oncology. Furthermore, through computational biology approaches, the drug AZD1208 was identified as a potential treatment targeting the PPARG protein for pancreatic cancer. This discovery opens new avenues for exploring targets and screening drugs for pancreatic cancer.

Pancreatic cancer is an aggressive malignancy characterized by rapid progression, unfavorable outcomes, and a low early detection rate. Elucidating the mechanisms underlying the onset and progression of pancreatic tumors is essential for early detection and for developing preventive measures. Even though human rhomboid family-1 (RHBDF) acts as an oncogene in various tumors, the role of RHBDF in pancreatic cancer progression remains unexplored. Here, publicly available datasets, including samples of chronic pancreatitis associated with pancreatic cancer from our center, were used for bioinformatics analyses, including differential expression, survival, and enrichment studies. The findings were validated by immunohistochemical staining and in vitro experiments. We found that RHBDF1 was significantly upregulated in tumor samples relative to adjacent non-tumor and pancreatitis tissues, and its expression increased in correlation with the progression of pancreatitis to cancer. Furthermore, RHBDF1 promoted the proliferation, migration, and invasion of pancreatic cancer cells, and in vivo studies demonstrated that RHBDF1 promoted pancreatic cancer progression, tissue fibrosis, and the formation of new blood vessels. RNA-sequencing and cell functional experiments indicated that RHBDF1 promotes the progression of pancreatic cancer through the SRC-YAP signaling pathway. In summary, the pancreatitis-cancer transformation-related factor, RHBDF1, promotes pancreatic cancer progression by activating the SRC-YAP signaling cascade, indicating that RHBDF1 could be a viable target for the diagnosis and treatment of early-stage pancreatic cancer.

Pancreatic cancer (PC) remains one of the most lethal malignancies, primarily due to late-stage diagnosis, limited biomarker specificity, and aggressive metastatic potential. Recent glycoproteomic studies have illuminated the crucial role of glycosylation in PC progression, revealing altered glycosylation patterns that impact cell adhesion, immune evasion, and tumor invasiveness. Biomarkers such as CA19-9 remain the clinical standard, yet limitations in sensitivity and specificity, especially in early disease stages, necessitate the exploration of alternative markers. Emerging glycoproteins-such as mesothelin, thrombospondin-2, and glycan modifications like sialyl-Lewis x-offer diagnostic promise when combined with CA19-9 or used in profiling panels. Furthermore, therapeutic strategies targeting glycosylation processes, including sialylation, and fucosylation, have shown potential in curbing PC metastasis and enhancing immune response. Translational platforms, such as patient-derived xenografts and advanced in vitro models, are pivotal in validating these findings and assessing glycosylation potential therapeutic impact. Continued exploration of glycosylation-driven mechanisms and biomarker discovery in PC can significantly advance early detection and treatment efficacy, offering new hope in the management of this challenging disease.

Pancreatic Ductal Adenocarcinoma (PDAC) poses a significant health threat characterized by poor clinical outcomes, largely attributable to late detection, chemotherapy resistance, and the absence of tailored therapies. Despite progress in surgical, radiation, and chemotherapy treatments, 80% of PDAC patients do not benefit optimally from systemic therapy, often due to asymptomatic presentation or disease regression upon diagnosis. The disease's progression is influenced by complex interactions involving immunological, genetic, and environmental factors, among others. However, the precise molecular mechanisms underlying PDAC remain incompletely understood. A major challenge in elucidating PDAC's origins lies in deciphering the genetic variations governing its network. PDAC exhibits heterogeneity, manifesting diverse genetic compositions, cellular attributes, and behaviors across patients and within tumors. This diversity complicates diagnosis, treatment strategies, and prognostication. Identification of "Differentially Expressed Genes" (DEGs) between PDAC and healthy controls is vital for addressing these challenges. These DEGs serve as the foundation for constructing the PDAC protein interaction network, with their network properties being assessed for further insights. Our analysis revealed five key hub genes (KHGs): EGF, SRC, SDC1, ICAM1 and CEACAM5. The KHGs were predominantly enriched in pathways such as: ErbB signaling pathway, Rap1 signaling pathway, etc. Acknowledging the therapeutic promise and biomarker importance of PDAC KHGs, we have also pinpointed approved medications for the identified key genes. Nevertheless, it is crucial to conduct experimental validation on KHGs to confirm their effectiveness within the PDAC context. Overall, this study identified potential key hub genes implicated in the progression of PDAC, offering significant guidance for personalized clinical decision-making and molecular-targeted therapy for PDAC patients.

The TME is a critical niche for determining the fate of cancer therapy. Tumor cells often polarize nontumor cells, including immune cells, in the TME to favor cancer growth. In pancreatic cancer, macrophages are associated with poor therapy outcomes and unfavorable survival, especially when rendered into M2 macrophages. The latter show features also found in so-called tumor-associated macrophages (TAM), which are described as protecting and propelling tumor growth. In this context, it has been understudied which pancreatic cancer chemokines contribute to macrophage polarization. To this end, we analyzed murine RAW264.7 macrophages and Panc02 and PDA6606 pancreatic cancer cells in mono- and coculture to identify release patterns of 13 chemokines. Artificial macrophage polarization confirmed prominent changes in surface receptor and chemokine secretion profiles. Strikingly, RAW264.7 cocultures with Panc02 or PDA6606 were congruent in showing elevated levels of CCL2, CCL5, CCL17, CCL20, CCL22, CXCL5, and CXCL10. Further underlining the suitability of our in vitro model, both pancreatic cancer cell lines showed similar modulation of the critical macrophage polarization markers arginase, CD206, and iNOS, as well as chemokine receptors CCR2 and CCR4. Collectively, we demonstrated that our model is suitable for testing the roles and functions of chemokines in macrophage polarization by pancreatic cancer cells.

Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present with advanced-stage disease, preventing potentially curative surgery. The neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY and NPY1R are up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KPR172HC mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout of Npy1r significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPR172HC migratory capacity on cell-derived matrices. Pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing liver metastasis. Together, our results reveal that NPY/NPY1R signaling is a previously unidentified antimetastatic target in PC.

Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursor lesions. Detecting these precursors and monitoring their progression are crucial for early PDAC diagnosis. Digital PCR (dPCR) is a highly sensitive nucleic acid quantification technique and offers a cost-effective option for patient follow-up. However, the clinical utility of conventional dPCR is restricted by multiplexing constraints, particularly due to the challenge of simultaneously quantifying multiple mutations and amplifications. In this study, we applied highly multiplexed dPCR and melting curve analysis to simultaneously measure single nucleotide mutations and amplifications of KRAS and GNAS. The developed 14-plex assay included both wild-type and mutant KRAS, a common driver gene in both PanIN and IPMN, and GNAS, which is specifically mutated in IPMN, along with RPP30, a reference gene for copy number alterations (CNAs). This multiplex dPCR method detected all target mutations with a limit of detection below 0.2% while quantifying CNAs. Additionally, the assay accurately quantified variant allele frequencies in liquid biopsy and tissue samples from both pancreatic neoplasm precursor and PDAC patients, indicating its potential for use in comprehensive patient follow-up.

Randomized trials and meta-analyses have indicated longer survival with neoadjuvant than with adjuvant therapy in patients with resectable or borderline resectable (R/BR) pancreatic adenocarcinoma. Despite the efficacy of chemotherapy, the role of radiation therapy as an adjuvant or neoadjuvant treatment for patients with R/BR pancreatic adenocarcinoma remains unclear. In this systematic review and meta-analysis, we compared the benefits of additional chemoradiation therapy (CRT) to neoadjuvant chemotherapy (NAC) with NAC alone for R/BR pancreatic adenocarcinoma.

A systematic literature search was conducted on Embase, Web of Science, PubMed, Cochrane, and Google Scholar. Median overall survival (OS) was the primary endpoint. Secondary endpoints included disease-free survival (DFS), resection rate, and R0 resection rate.

This review and meta-analysis included 31 prospective studies, of which 9 were randomized trials. In these studies, 658 patients from 14 study arms received NAC alone and 912 patients from 19 study arms received both NAC and CRT (NAC-CRT). The pooled median OS was 25.55 months (95% CI, 21.59-30.24 months) for NAC alone and 17.55 months (95% CI, 16.47-18.70 months; P < .0001) for NAC-CRT. The pooled R0 resection rate was higher with NAC-CRT (83.43%) than with NAC (69.97%; P < .0001). No significant difference was observed in DFS or resection rate between the 2 groups. In patients who received 5 or more cycles of initial chemotherapy, NAC-CRT was associated with longer OS than NAC (23.30 vs 21.85 months; P = .856).

NAC provides significantly longer OS than NAC-CRT to R/BR pancreatic adenocarcinoma. NAC-CRT is associated with a significantly improved R0 resection rate. This positive local effect of CRT can be translated to extended survival when 5 cycles or more of NAC are prescribed.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest diseases, despite advancements in elucidating tumor biology and developing novel therapeutics. Importantly, lipids, such as phospholipids, are crucial for the survival and proliferation of tumor cells. However, the impact of chemotherapeutic drugs on phospholipid metabolism in PDAC remains poorly understood. Gemcitabine (a nucleoside analogue) is a first-line drug in PDAC treatment, but its clinical effectiveness is limited by multiple factors. Herein, we employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and proteomics approaches to investigate gemcitabine-induced lipid metabolism alterations in mouse pancreatic tumors following gemcitabine treatment (n = 3, control tumors; n = 3, gemcitabine-treated tumors). From MALDI MSI experiments, we observed elevated levels of several phosphatidylcholines (PCs), PC(30:0), PC(32:3), PC(34:2), PC(36:1), and PC(36:2), in gemcitabine-treated tumor tissues compared to the control. In addition, proteomics data revealed the differential abundance of several phospholipid-binding proteins in response to gemcitabine treatments. Furthermore, several endoplasmic reticulum stress-related proteins exhibited high expression in gemcitabine-treated tumor tissues. Altogether, our MALDI MSI and proteomics data provide important insights into alterations in PC metabolism in pancreatic tumors in response to gemcitabine treatment. Importantly, targeting the altered PC metabolism during gemcitabine therapy might help combat pancreatic cancer.

We aimed to investigate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) are associated with a decreased risk of gastrointestinal (GI) cancers in patients with type 2 diabetes (T2D) compared to other glucose lowering medications (oGLMs).

This active-comparator, new-user cohort study used the nationwide National Health Insurance Service database of the Republic of Korea from September 2014 to June 2020. From 79,423 new users of SGLT2is and 294,707 new users of oGLMs, we used a propensity score to match 59,954 from each of these two treatment groups. We calculated hazard ratios (HRs) and 95 % confidence intervals (CIs) for the incidence of GI cancers, encompassing stomach, colorectal, liver, and pancreatic cancers.

During the observation period, there were 814 and 916 GI cancers, and 794 and 1,140 deaths in the SGLT2is and oGLMs treatment groups, respectively. The use of SGLT2is was associated with a statistically significant reduction in the incidence of GI cancers, with an adjusted HR of 0.90 (95 % CI: 0.82 to 0.99). However, only the incidence of pancreatic cancer was significantly lower in SGLT2is users compared to non-users, with an adjusted HR of 0.72 (95 % CI: 0.55 - 0.95). In the entire cohort, the multivariable-adjusted HR for pancreatic cancer was 0.70 (95 % CI: 0.56 to 0.88).

For T2D patients, SGLT2i use was associated with a diminished pancreatic cancer risk compared to oGLMs. Future studies should ascertain the potential protective effect of SGLT2is against pancreatic cancer.

[Figure: see text].