Tuning Selectivity to f-Elements through Bonding and Solvation Effects of a Sulfur Donor Ligand.

Bis(2,4,4-trimethylpentyl)dithiophosphinic acid, commonly referred to as HBTMPDTP or Cyanex301, is a sulfur-donating ligand that shows considerable promise in the challenging task of separating trivalent actinides (An3+) from lanthanides (Ln3+). Although its effectiveness has been established, the specific molecular details about the preference of HBTMPDTP for americium over europium have remained a mystery, puzzling researchers for over two decades. This study presents a comprehensive, dual-driven separation mechanism for this complex system combining experimental and theoretical approaches. A critical finding is the increased covalency in An-S bonds compared to Ln-S bonds, which plays a significant role in HBTMPDTP's intrinsic selectivity for An3+ over Ln3+. This leads to the formation of distinct An3+ and Ln3+ species, enhancing the ligand's actinide selectivity. Additionally, it provides crucial insights into the coordination chemistry of f-elements with sulfur-donating ligands, thereby deepening our understanding of this intricate field.

The significance of precisely regulating heme oxygenase-1 expression: Another avenue for treating age-related ocular disease?

Aging entails the deterioration of the body's organs, including overall damages at both the genetic and cellular levels. The prevalence of age-related ocular disease such as macular degeneration, dry eye diseases, glaucoma and cataracts is increasing as the world's population ages, imposing a considerable economic burden on individuals and society. The development of age-related ocular disease is predominantly triggered by oxidative stress and chronic inflammatory reaction. Heme oxygenase-1 (HO-1) is a crucial antioxidant that mediates the degradative process of endogenous iron protoporphyrin heme. It catalyzes the rate-limiting step of the heme degradation reaction, and releases the metabolites such as carbon monoxide (CO), ferrous, and biliverdin (BV). The potent scavenging activity of these metabolites can help to defend against peroxides, peroxynitrite, hydroxyl, and superoxide radicals. Other than directly decomposing endogenous oxidizing substances (hemoglobin), HO-1 is also a critical regulator of inflammatory cells and tissue damage, exerting its anti-inflammation activity through regulating complex inflammatory networks. Therefore, promoting HO-1 expression may act as a promising therapeutic strategy for the age-related ocular disease. However, emerging evidences suggest that the overexpression of HO-1 significantly contributes to ferroptosis due to its dual nature. Surplus HO-1 leads to excessive Fe2+ and reactive oxygen species, thereby causing lipid peroxidation and ferroptosis. In this review, we elucidate the role of HO-1 in countering age-related disease, and summarize recent pharmacological trials that targeting HO-1 for disease management. Further refinements of the knowledge would position HO-1 as a novel therapeutic target for age-related ocular disease.

Role of iron oxide in retarding the graphitization of de-oiled asphaltenes for amorphous carbon.

The solvent deasphalting (SDA) process is widely recognized as a significant technology in processing inferior oil. However, de-oiled asphaltene (DOA), which accounts for about 30% of feedstocks, is not well utilized in conventional processing methods to date. Considering its complicated structure and high heteroatom and metal contents, DOA is suitable for preparing amorphous carbon. Herein, we obtained amorphous carbon from inferior de-oiled asphaltene through direct carbonization of a mixture of DOA and Fe2O3 and revealed the mechanism of iron oxide in retarding graphitization to increase the disordered structure content. After the addition of Fe2O3, XRD results showed that the content of amorphous carbon increased from 25.57% to 59.48%, and a higher defect degree could also be observed in Raman spectra, thus resulting in better electrochemical performance in Na-ion half-cells. As a coke core, Fe2O3 could accelerate the polycondensation of asphaltene molecules; meanwhile, oxygen species derived from Fe2O3 could capture excess H free radicals in the initial pyrolysis stage, which inhibited the formation of planar polycyclic aromatic molecules and weakened π-π interactions. Moreover, O atoms could embed into the carbon skeleton by reacting with DOA at higher temperatures, which could further twist and break the intact carbon layer. Both of the factors enhanced the proportion of amorphous carbon. This work not only provides a new understanding of controlling the carbonization process, but it also promotes the development of the SDA process.

Encapsulated cell technology: Delivering cytokines to treat posterior ocular diseases.

Encapsulated cell technology (ECT) is a targeted delivery method that uses the genetically engineered cells in semipermeable polymer capsules to deliver cytokines. Thus far, ECT has been extensively utilized in pharmacologic research, and shows enormous potentials in the treatment of posterior segment diseases. Due to the biological barriers within the eyeball, it is difficult to attain effective therapeutic concentration in the posterior segment through topical administration of drug molecules. Encouragingly, therapeutic cytokines provided by ECT can cross these biological barriers and achieve sustained release at the desired location. The encapsulation system uses permeable materials that allow growth factors and cytokines to diffuse efficiently into retinal tissue. Moreover, the ECT based treatment can be terminated timely when we need to retrieve the implant, which makes the therapy reversible and provides a safer alternative for intraocular gene therapy. Meanwhile, we also place special emphasis on optimizing encapsulation materials and enhancing preservation techniques to achieve the stable release of growth factors and cytokines in the eyeball. This technology holds great promise for the treatment of patients with dry AMD, RP, glaucoma and MacTel. These findings would enrich our understandings of ECT and promote its future applications in treatment of degenerative retinopathy. This review comprises articles evaluating the exactness of artificial intelligence-based formulas published from 2000 to March 2024. The papers were identified by a literature search of various databases (PubMed/MEDLINE, Google Scholar, Cochrane Library and Web of Science).

Poor clinical outcomes and immunoevasive contexture in CD161+CD8+ T cells barren human pancreatic cancer.

BACKGROUND: The role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC. METHODS: This study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status. RESULTS: We observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules. CONCLUSION: CD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

A 36-nW Electrocardiogram Anomaly Detector Based on a 1.5-bit Non-Feedback Delta Quantizer for Always-on Cardiac Monitoring.

An always-on electrocardiogram (ECG) anomaly detector (EAD) with ultra-low power (ULP) consumption is proposed for continuous cardiac monitoring applications. The detector is featured with a 1.5-bit non-feedback delta quantizer (DQ) based feature extractor, followed by a multiplier-less convolutional neural network (CNN) engine, which eliminates the traditional high-resolution analog-to-digital converter (ADC) in conventional signal processing systems. The DQ uses a computing-in-capacitor (CIC) subtractor to quantize the sample-to-sample difference of ECG signal into 1.5-bit ternary codes, which is insensitive to low-frequency baseline wandering. The subsequent event-driven classifier is composed of a low-complexity coarse detector and a systolic-array-based CNN engine for ECG anomaly detection. The DQ and the digital CNN are fabricated in 65-nm and 180-nm CMOS technology, respectively, and the two chips are integrated on board through wire bonding. The measured detection accuracy is 90.6% ∼ 91.3% when tested on the MIT-BIH arrhythmia database, identifying three different ECG anomalies. Operating at 1 V and 1.4 V power supplies for the DQ and the digital CNN, respectively, the measured long-term average power consumption of the core circuits is 36 nW, which makes the detector among those state-of-the-art always-on cardiac anomaly detection devices with the lowest power consumption.

CX3CL1/CX3CR1 Signaling Mediated Neuroglia Activation Is Implicated in the Retinal Degeneration: A Potential Therapeutic Target to Prevent Photoreceptor Death.

Purpose: Retinal degeneration (RD) is a large cluster of retinopathies that is characterized by the progressive photoreceptor death and visual impairments. CX3CL1/CX3CR1 signaling has been documented to mediate the microglia activation and gliosis reaction during neurodegeneration. We intend to verify whether the CX3CL1/CX3CR1 signaling is involved in the RD pathology. Methods: A pharmacologically induced RD mice model was established. AZD8797, a CX3CR1 antagonist, was injected into the vitreous cavity of an RD model to modulate the neuroglia activation. Then, the experimental animals were subjected to functional, morphological, and behavioral analysis. Results: The CX3CL1/CX3CR1 signaling mediated neuroglia activation was implicated in the photoreceptor demise of an RD model. Intravitreal injection of AZD8797 preserved the retinal structure and enhanced the photoreceptor survival through inhibiting the CX3CL1/CX3CR1 expressions. Fundus photography showed that the distribution of retinal vessel was clear, and the severity of lesions was alleviated by AZD8797. In particular, these morphological benefits could be translated into remarkable functional improvements, as evidenced by the behavioral test and electroretinogram (mf-ERG) examination. A mechanism study showed that AZD8797 mitigated the microglia activation and migration in the degenerative retinas. The Müller cell hyper-reaction and secondary gliosis response were also suppressed by AZD8797. Conclusions: The neuroinflammation is implicated in the photoreceptor loss of RD pathology. Targeting the CX3CL1/CX3CR1 signaling may serve as an effective therapeutic strategy. Future refinements of these findings may cast light into the discovery of new medications for RD.

Ferroptosis in the ageing retina: A malevolent fire of diabetic retinopathy.

Ageing retina is prone to ferroptosis due to the iron accumulation and impaired efficiency of intracellular antioxidant defense system. Ferroptosis acts as a cell death modality that is characterized by the iron-dependent accumulation of lipid peroxidation. Ferroptosis is distinctively different from other types of regulated cell death (RCD) at the morphological, biochemical, and genetic levels. Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Its prevalence and severity increase progressively with age. Recent reports have shown that ferroptosis is implicated in the pathophysiology of DR. Under hyperglycemia condition, the endothelial cell and retinal pigment epithelium (RPE) cell will undergo ferroptosis, which contributes to the increased vascular permeability and the disrupted blood retinal barrier (BRB). The underlying etiology of DR can be attributed to the impaired BRB integrity and subsequent damages of the neurovascular units. In the absence of timely intervention, the compromised BRB can ultimately cause profound visual impairments. In particular, the ageing retina is vulnerable to ferroptosis, and hyperglycemia will accelerate the progression of this pathological process. In this article, we discuss the contributory role of ferroptosis in DR pathogenesis, and summarize recent therapeutic trials that targeting the ferroptosis. Further study on the ferroptosis mediated damage would enrich our knowledge of DR pathology, and promote the development of clinical treatment for this degenerative retinopathy.

Novel Role of Molecular Hydrogen: The End of Ophthalmic Diseases?

Molecular hydrogen (H2) is a colorless, odorless, and tasteless gas which displays non-toxic features at high concentrations. H2 can alleviate oxidative damage, reduce inflammatory reactions and inhibit apoptosis cascades, thereby inducing protective and repairing effects on cells. H2 can be transported into the body in the form of H2 gas, hydrogen-rich water (HRW), hydrogen-rich saline (HRS) or H2 produced by intestinal bacteria. Accumulating evidence suggest that H2 is protective against multiple ophthalmic diseases, including cataracts, dry eye disease, diabetic retinopathy (DR) and other fields. In particular, H2 has been tested in the treatment of dry eye disease and corneal endothelial injury in clinical practice. This medical gas has brought hope to patients suffering from blindness. Although H2 has demonstrated promising therapeutic potentials and broad application prospects, further large-scale studies involving more patients are still needed to determine its optimal application mode and dosage. In this paper, we have reviewed the basic characteristics of H2, and its therapeutic effects in ophthalmic diseases. We also focus on the latest progress in the administration approaches and mechanisms underlying these benefits.

Intravitreal Injection of ZYAN1 Restored Autophagy and Alleviated Oxidative Stress in Degenerating Retina via the HIF-1α/BNIP3 Pathway.

Mitochondrial autophagy plays a contributary role in the pathogenesis of retina degeneration (RD). ZYAN1 is a novel proline hydroxylase domain (PHD) inhibitor that can enhance the expression of hypoxia-inducible factor 1-alpha (HIF-1α). This study investigated whether ZYAN1 could alleviate progressive photoreceptor loss and oxidative damage in a pharmacologically induced RD model via the modulation of mitophagy. ZYAN1 was injected into the vitreous body of the RD model, and the retinal autophagy level was analyzed. The therapeutic effects of ZYAN1 were evaluated via a function examination, a morphological assay, in situ reactive oxygen species (ROS) detection, and an immunofluorescence assay. It was shown that the thickness of the outer nuclear layer (ONL) increased significantly, and visual function was efficiently preserved via ZYAN1 treatment. The mitochondria structure of photoreceptors was more complete in the ZYAN1-treated mice, and the number of autophagosomes also increased significantly. Membrane disc shedding and ROS overproduction were alleviated after ZYAN1 treatment, and the axonal cilia were more structurally intact. A Western blot analysis showed that the expression levels of the autophagy-related proteins LC3-B, Beclin-1, and ATG5 increased significantly after ZYAN1 treatment, while the expression of P62 was down-regulated. Moreover, the expression levels of HIF-1α and BNIP3 were up-regulated after ZYAN1 treatment. Therefore, an intravitreal injection of ZYAN1 can act as part of the pharmacologic strategy to modulate mitophagy and alleviate oxidative stress in RD. These findings enrich our knowledge of RD pathology and provide insights for the discovery of a therapeutic molecule.

Tumor Microenvironment Responsive CD8+ T Cells and Myeloid-Derived Suppressor Cells to Trigger CD73 Inhibitor AB680-Based Synergistic Therapy for Pancreatic Cancer.

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.

Probing Substituent Effect on Nickel-Sulfur Bond Covalency in Ni(II)-Dithiophosphinate Complexes by Sulfur K-Edge XAS and DFT Calculations.

Complexes of Ni(II) with a series of aryl or alkyl substituent dithiophosphinic acids were characterized by crystallographic structure, sulfur K-edge X-ray absorption spectroscopy (XAS), and density functional theory (DFT). In these complexes, Ni(II) coordinates with four sulfur atoms from two dithiophosphinate anions form a well-defined square-planar structure. Despite the minor differences in the geometry parameters among the complexes, the electronic structure is affected significantly by the substituent group attached to dithiophosphinic acid. In particular, the addition of ortho-CF3 group to the aryl ring constrains the orientation of the aryl ring and enhances the conjugation between the aryl ring and the coordinating core. Sulfur K-edge XAS spectra help further reveal the electronic structure of the complexes. Both the pre-edge feature and rising-edge feature provide abundant information on the molecular orbitals and show a distinctive effect of the substituent groups on the electronic structure of the complexes, which is supposedly relevant to the ligand's performance in Ln(III)/An(III) separation.

The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications.

Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.

Biological and clinical implications of early-onset cancers: A unique subtype.

In recent years, the incidence of cancers is continuously increasing in young adults. Early-onset cancer (EOC) is usually defined as patients with cancers under the age of 50, and may represent a unique subgroup due to its special disease features. Overall, EOCs often initiate at a young age, present as a better physical performance but high degree of malignancy. EOCs also share common epidemiological and hereditary risk factors. In this review, we discuss several representative EOCs which were well studied previously. By revealing their clinical and molecular similarities and differences, we consider the group of EOCs as a unique subtype compared to ordinary cancers. In consideration of EOC as a rising threat to human health, more researches on molecular mechanisms, and large-scale, prospective clinical trials should be carried out to further translate into improved outcomes.

Application of Hydrogels in the Device of Ophthalmic Iontophoresis: Theory, Developments and Perspectives.

The human eye is a consolidated organ with delicate structures and unique immune privileges. Ocular diseases are intractable due to the intrinsic biological barriers within the eyeball. Hydrogels are excellent drug-carrying substances with soft material and excellent properties. They have been extensively used to deliver drugs into ocular tissue via iontophoresis devices. Ophthalmic iontophoresis is an electrochemical technique using tiny electrical currents to deliver drugs into the eye non-invasively. The early infantile iontophoresis technique often required long applying time to achieve therapeutic dose in the posterior ocular segment. The potential limitations in the initial drug concentration and the maximum safe currents would also impede the efficiency and safety of iontophoresis. Moreover, the poor patient compliance always leads to mechanical damage to the cornea and sclera during application. Advantageously, the flexible drug-carrying hydrogel can be in direct contact with the eye during iontophoresis, thereby reducing mechanical damage to the ocular surface. Moreover, the water absorption and adjustable permeability of hydrogels can reduce the electrochemical (EC) reactions and enhance the efficiency of iontophoresis. In this review, we focus on recent developments of hydrogels iontophoresis in ophthalmologic practice. Refinements of the knowledge would provide an outlook for future application of hydrogels in treating ocular disease.

Therapeutic advances targeting tumor angiogenesis in pancreatic cancer: Current dilemmas and future directions.

Pancreatic cancer (PC) is one of the most lethal malignancies, which is generally resistant to various treatments. Tumor angiogenesis is deemed to be a pivotal rate-determining step for tumor growth and metastasis. Therefore, anti-angiogenetic therapy is a rational strategy to treat various cancers. However, numerous clinical trials on anti-angiogenetic therapies for PC are overwhelmingly disappointing. The unique characteristics of tumor blood vessels in PC, which are desperately lacking and highly compressed by the dense desmoplastic stroma, are reconsidered to explore some optimized strategies. In this review, we mainly focus on its specific characteristics of tumor blood vessels, discuss the current dilemmas of anti-angiogenic therapy in PC and their underlying mechanisms. Furthermore, we point out the future directions, including remodeling the abnormal vasculature or even reshaping the whole tumor microenvironment in which they are embedded to improve tumor microcirculation, and then create therapeutic vulnerabilities to the current available therapeutic strategies.

Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving systemic neoadjuvant chemotherapy (NAC), particularly those with borderline resectable and locally advanced disease. However, the specific role of additional adjuvant chemotherapy (AC) in these patients is unknown. The objective of this study is to further assess the clinical benefit and impact of systemic AC in patients with resected PDAC after NAC. METHODS: Data on PDAC patients with or without AC following systemic NAC and surgical resection were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2006 and 2019. A matched cohort was created using propensity score matching (PSM), and baseline characteristics were balanced to reduce bias. Overall survival (OS) and cancer-specific survival (CSS) were calculated using matching cohorts. RESULTS: The study enrolled a total of 1589 patients, with 623 (39.2%) in the AC group and 966 (51.8%) in the non-AC group [mean age, 64.0 (9.9) years; 766 (48.2%) were females and 823 (51.8%) were males]. All patients received NAC, and among the crude population, 582 (36.6%) received neoadjuvant radiotherapy, while 168 (10.6%) received adjuvant radiotherapy. Following the 1:1 PSM, 597 patients from each group were evaluated further. The AC and non-AC groups had significantly different median OS (30.0 vs. 25.0 months, P =0.002) and CSS (33.0 vs. 27.0 months, P =0.004). After multivariate Cox regression analysis, systemic AC was independently associated with improved survival ( P =0.003, HR=0.782; 95% CI, 0.667-0.917 for OS; P =0.004, HR=0.784; 95% CI, 0.663-0.926 for CSS), and age, tumor grade, and AJCC N staging were also independent predictors of survival. Only patients younger than 65 years old and those with a pathological N1 category showed a significant association between systemic AC and improved survival in the subgroup analysis adjusted for these covariates. CONCLUSION: Systemic AC provides a significant survival benefit in patients with resected PDAC following NAC compared to non-AC patients. Our study discovered that younger patients, patients with aggressive tumors and potentially well response to NAC might benefit from AC to achieve prolonged survival after curative tumor resection.

Application of iontophoresis in ophthalmic practice: an innovative strategy to deliver drugs into the eye.

Delivery of drugs to special locations of ocular lesions, while minimizing systemic and local toxic effects, is recognized as a critical challenge in the ophthalmic practice. The special anatomy and physiology barriers within the eyeball entail effective drug delivery systems. Emerging attempts in drug delivery has led to developments in ocular iontophoresis, which acts as a noninvasive technology to enhance drug penetration using a small electric current. This technique offers greater flexibility to deliver desired drug dose in a controlled and tolerable manner. In previous studies, this technique has been testified to deliver antibiotics, corticoid, proteins and other gene drugs into the eye with the potency of treating or alleviating diverse ophthalmological diseases including uveitis, cataract, retinoblastoma, herpes simplex and cytomegalovirus retinitis (CMVR), etc. In this review, we will introduce the recent developments in iontophoresis device. We also summarize the latest progress in coulomb controlled iontophoresis (CCI), hydrogel ionic circuit (HIC) and EyeGate II delivery system (EGDS), as well as overview the potential toxicity of iontophoresis. We will discuss these factors that affect the efficacy of iontophoresis experiments, and focus on the latest progress in its clinical application in the treatment of eye diseases.

Circulating cytokines allow for identification of malignant intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are the precursor lesions of pancreatic cancers, requiring active surgical intervention during cancer development. However, the current criteria for predicting malignant IPMNs remain challenging and limited. Hence, this study aimed to assess the discriminatory performance of circulating cytokines, including TNF-α, IL-2R, IL-6, and IL-8, then build a novel predictive model to improve the diagnostic accuracy. METHOD: A total of 131 retrospective (from March 2016 to December 2019) and 53 prospective (from March 2020 to January 2021) patients who were histologically confirmed as IPMNs were consecutively collected and analyzed. RESULT: The circulating levels of TNF-α, IL-2R, IL-6, and IL-8 were significantly elevated in malignant IPMNs, and were verified as independent factors for malignant IPMNs (p < 0.05). Then, a novel score, the circulating cytokine score (CCS), was calculated and demonstrated as an independent predictive indicator with a higher area under the curve (AUC) than each cytokine alone (p < 0.001). Besides the CCS, two high-risk stigmata features, the presence of solid component (PSC), and main pancreatic duct (MPD) dilation ≥10 mm were also demonstrated as independent indicators for predicting malignant IPMNs. Finally, a novel nomogram incorporating the CCS and these two high-risk stigmata features presented a remarkable diagnostic performance, both in the training and validation cohorts with AUCs of 0.928 and 0.873, respectively. CONCLUSION: The CCS can be considered a novel independent predictive indicator for malignant IPMNs. Additionally, the formulated nomogram model integrating the CCS, PSC, and MPD ≥10 mm can be a valuable and promising tool for predicting the malignant transformation of IPMNs during long-term follow-ups to assist in timely and accurate surgical decisions.