PIDiff: Physics informed diffusion model for protein pocket-specific 3D molecular generation.

Designing drugs capable of binding to the structure of target proteins for treating diseases is essential in drug development. Recent remarkable advancements in geometric deep learning have led to unprecedented progress in three-dimensional (3D) generation of ligands that can bind to the protein pocket. However, most existing methods primarily focus on modeling the geometric information of ligands in 3D space. Consequently, these methods fail to consider that the binding of proteins and ligands is a phenomenon driven by intrinsic physicochemical principles. Motivated by this understanding, we propose PIDiff, a model for generating molecules by accounting in the physicochemical principles of protein-ligand binding. Our model learns not only the structural information of proteins and ligands but also to minimize the binding free energy between them. To evaluate the proposed model, we introduce an experimental framework that surpasses traditional assessment methods by encompassing various essential aspects for the practical application of generative models to actual drug development. The results confirm that our model outperforms baseline models on the CrossDocked2020 benchmark dataset, demonstrating its superiority. Through diverse experiments, we have illustrated the promising potential of the proposed model in practical drug development.

Different Neurogenic Bladders in Patients with Cervical and Thoracic Myelopathy: Direct Comparison from a Prospective Case Series.

Background/Objectives: This study aimed to identify the unique characteristics of neurogenic bladders and associated symptoms in patients with cervical or thoracic myelopathy using clinical surveys and urodynamic studies (UDSs). Methods: Patients with degenerative cervical (DCM) or thoracic (DTM) myelopathy and lower urinary tract symptoms (LUTSs) scheduled for decompressive surgery were prospectively enrolled. A UDS was performed one day preceding surgery to evaluate the preoperative urological function. Subjective symptoms were evaluated using the International Prostate Symptom Score (IPSS) and the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire before surgery and one year postoperatively. Results: Sixty-two patients (DCM: 50, DTM: 12) with a mean age of 63.2 years (men: 30, women: 32) were enrolled. The UDS revealed that 5 (8.1%) patients, all with DCM, exhibited completely normal UDS results, and the remaining 57 had at least one abnormal finding. Based on the International Continence Society classification, an underactive bladder was significantly more common in patients with DTM compared to patients with DCM (75.0% vs. 18.0%, p < 0.001). The results of the questionnaire showed that the voiding symptom IPSS were significantly worse, preoperatively, in patients with DTM (5.0 ± 4.4 [DCM] vs. 8.7 ± 4.5 [DTM]; p = 0.013). One year postoperatively, the IPSS grade of 24.0% of patients with DCM improved, whereas only one (8.3%) patient with DTM showed improvement. Conclusions: Patients with DTM reported worse voiding symptoms and exhibited more underactive bladders on UDS than patients with DCM before decompression. One year postoperatively, more patients with DCM showed subjective improvements in urinary function than those with DTM.

Spatio-Temporal Influence on the Distribution of Forensically Relevant Blowflies (Diptera: Calliphoridae) in Gyeongsangnam-do, South Korea.

The study of blowfly (Diptera: Calliphoridae) biodiversity and distribution is crucial for forensic investigations. Abiotic and biotic factors, such as season and habitat type, have a significant impact on blowfly populations. However, only a few forensic entomology studies have been conducted in South Korea, particularly in the Gyeongsangnam-do region. To address this, an extensive year-long survey was conducted to analyze the compositions, habitat preferences, distribution, and seasonal abundance of forensically relevant blowflies in urban and forested habitats of Gyeongsangnam-do, with sampling conducted twice a month using mouse carcass-baited traps set for 48 h each time. A total of 3470 adult blowflies were recorded, encompassing five genera and 13 species, with a noted absence of specimens during the winter months. The predominant species was Lucilia porphyrina, accounting for 37.2% of the total sample, followed by Chrysomya pinguis (27.6%), Lucilia sericata (7.6%), and Lucilia illustris (7.1%). The species composition was consistent across all surveyed regions; however, seasonal variation in species diversity was evident, with a peak in spring and a decline in summer. Notably, certain species exhibited clear preferences for either urban (Calliphora calliphoroides and L. sericata) or forested habitats (L. porphyrina and Ch. pinguis). This pioneering study elucidates the diverse blowfly communities in Gyeongsangnam-do, highlighting significant seasonal and habitat-dependent variations. These findings enrich our understanding of blowfly ecology in this region, offering valuable insights for forensic applications and underscoring the necessity for ongoing entomological surveillance and research.

Machine learning-based prediction of cerebral oxygen saturation based on multi-modal cerebral oximetry data.

This study develops machine learning-based algorithms that facilitate accurate prediction of cerebral oxygen saturation using waveform data in the near-infrared range from a multi-modal oxygen saturation sensor. Data were obtained from 150,000 observations of a popular cerebral oximeter, Masimo O3™ regional oximetry (Co., United States) and a multi-modal cerebral oximeter, Votem (Inc., Korea). Among these observations, 112,500 (75%) and 37,500 (25%) were used for training and test sets, respectively. The dependent variable was the cerebral oxygen saturation value from the Masimo O3™ (0-100%). The independent variables were the time of measurement (0-300,000 ms) and the 16-bit decimal amplitudes values (infrared and red) from Votem (0-65,535). For the right part of the forehead, the root mean square error of the random forest (0.06) was much smaller than those of linear regression (1.22) and the artificial neural network with one, two or three hidden layers (2.58). The result was similar for the left part of forehead, that is, random forest (0.05) vs logistic regression (1.22) and the artificial neural network with one, two or three hidden layers (2.97). Machine learning aids in accurately predicting of cerebral oxygen saturation, employing the data from a multi-modal cerebral oximeter.

A study on deep learning model based on global-local structure for crowd flow prediction.

Crowd flow prediction has been studied for a variety of purposes, ranging from the private sector such as location selection of stores according to the characteristics of commercial districts and customer-tailored marketing to the public sector for social infrastructure design such as transportation networks. Its importance is even greater in light of the spread of contagious diseases such as COVID-19. In many cases, crowd flow can be divided into subgroups by common characteristics such as gender, age, location type, etc. If we use such hierarchical structure of the data effectively, we can improve prediction accuracy of crowd flow for subgroups. But the existing prediction models do not consider such hierarchical structure of the data. In this study, we propose a deep learning model based on global-local structure of the crowd flow data, which utilizes the overall(global) and subdivided by the types of sites(local) crowd flow data simultaneously to predict the crowd flow of each subgroup. The experiment result shows that the proposed model improves the prediction accuracy of each sub-divided subgroup by 5.2% (Table 5 Cat #9)-45.95% (Table 11 Cat #5), depending on the data set. This result comes from the comparison with the related works under the same condition that use target category data to predict each subgroup. In addition, when we refine the global data composition by considering the correlation between subgroups and excluding low correlated subgroups, the prediction accuracy is further improved by 5.6-48.65%.

Long-Term Antioxidant Metal-Organic Frameworks.

Free radicals produced during metabolism induce effects, such as cell damage and cancer, because of their high reactivity. Although antioxidants in food products can eliminate free radicals, they are expelled within a relatively short period of time after serving their function. In this study, we investigated the possibility of using metal-organic frameworks (MOFs) with antioxidants as their ligands. Metal-organic frameworks are crystalline polymers with repetitively coordinated ligands and metal centers. We assume that once antioxidant-based MOFs are ingested, ligands are released on a long-term basis during the process of chemical and physical disintegration. To evaluate their eligibility, we established criteria for biocompatibility, particle size, and long-term antioxidant effects. For biocompatibility, we treated cells with various concentrations of MOFs and their precursors followed by a water-soluble tetrazolium 8 (WST-8) assay. The particle size distribution was analyzed using TEM and ImageJ software, and the antioxidant release was quantified using UV-vis spectroscopy. We concluded that Fe-based FeTHQ with the antioxidant tetrahydroxy-1,4-benzoquinone (THQ) as its ligand is the most effective long-term antioxidant with its effect lasting up to 7 days. Furthermore, microwave synthesis of FeTHQ was conducted to produce more suitable particles for in vivo antioxidant applications.

Evaluation of Swine Protection with Three Commercial Foot-and-Mouth Disease Vaccines against Heterologous Challenge with Type A ASIA/G-VII Lineage Viruses.

Outbreaks caused by foot-and-mouth disease (FMD) A/ASIA/G-VII lineage viruses have often occurred in Middle Eastern and Southeast Asian countries since 2015. Because A/ASIA/G-VII lineage viruses are reported to have distinct antigenic relatedness with available commercial FMD vaccine strains, it is necessary to investigate whether inoculation with vaccines used in Korea could confer cross-protection against A/ASIA/G-VII lineage viruses. In the present study, we conducted two vaccination challenge trials to evaluate the efficacy of three commercial FMD vaccines (O/Manisa + O/3039 + A/Iraq, O/Campos + A/Cruzeiro + A/2001, and O/Primorsky + A/Zabaikalsky) against heterologous challenge with ASIA/G-VII lineage viruses (A/TUR/13/2017 or A/BHU/3/2017 strains) in pigs. In each trial, clinical signs, viremia, and salivary shedding of virus were measured for 7 days after challenge. In summary, the O/Campos + A/Cruzeiro + A/2001 vaccine provided full protection against two A/ASIA/G-VII lineage viruses in vaccinated pigs, where significant protection was observed. Although unprotected animals were observed in groups vaccinated with O/Manisa + O/3039 + A/Iraq or O/Primorsky + A/Zabaikalsky vaccines, the clinical scores and viral RNA levels in the sera and oral swabs of vaccinated animals were significantly lower than those of unvaccinated controls.

In vivo effects of cell seeding technique in an ex vivo regional gene therapy model for bone regeneration.

When delivering cells on a scaffold to treat a bone defect, the cell seeding technique determines the number and distribution of cells within a scaffold, however the optimal technique has not been established. This study investigated if human adipose-derived stem cells (ASCs) transduced with a lentiviral vector to overexpress bone morphogenetic protein 2 (BMP-2) and loaded on a scaffold using dynamic orbital shaker could reduce the total cell dose required to heal a critical sized bone defect when compared with static seeding. Human ASCs were loaded onto a collagen/biphasic ceramic scaffold using static loading and dynamic orbital shaker techniques, compared with our labs standard loading technique, and implanted into femoral defects of nude rats. Both a low dose and standard dose of transduced cells were evaluated. Outcomes investigated included BMP-2 production, radiographic healing, micro-computerized tomography, histologic assessment, and biomechanical torsional testing. BMP-2 production was higher in the orbital shaker cohort compared with the static seeding cohort. No statistically significant differences were noted in radiographic, histomorphometric, and biomechanical outcomes between the low-dose static and dynamic seeding groups, however the standard-dose static seeding cohort had superior biomechanical properties. The standard-dose 5 million cell dose standard loading cohort had superior maximum torque and torsional stiffness on biomechanical testing. The use of orbital shaker technique was labor intensive and did not provide equivalent biomechanical results with the use of fewer cells.

Zeolite application mitigates NH3 and N2O emissions from pig slurry-applied field and improves nitrogen use efficiency in Italian ryegrass-maize crop rotation system for forage production.

The present study aimed to assess the efficiency of zeolite in mitigating the nitrogen (N) losses through ammonia (NH3) and nitrous oxide (N2O) emissions from pig slurry (PS) applied to Italian ryegrass (IRG)-maize fields under a crop rotation system and the consequent effect on nitrogen use efficiency (NUE) for forage production. PS was applied at rates of 150 and 200 kg N ha-1 for the IRG and maize growing seasons, respectively, with or without zeolite. Soil mineral N content and NH3 and N2O emissions were measured periodically throughout the year-round cultivation of IRG and maize. Forage yield and nutritional composition were also analyzed at the harvest time of each crop. The PS with/without zeolite application effects were interpreted by comparison with those obtained for the negative control (no-N fertilization). Soil ammonium (NH4+) content in the PS-applied plots sharply increased within the first week, then progressively decreased in both the IRG and maize growing seasons. Soil NH4+ contents in the zeolite-amended plots were higher compared to the treatment without zeolite except for the first 1 or 2 weeks after PS application when soil nitrate (NO3-) contents significantly decreased. The increase in soil NH4+ content as affected by zeolite application was more distinct in the maize growing season than in the IRG growing season. NH3 emission was predominant at the early 2 weeks after PS application. Zeolite application reduced the cumulative emission of NH3 from PS by 16.7% and 24.4% and that of N2O by 15.6% and 31.5% in the IRG growing and maize growing seasons, respectively. NUE for dry matter (DM) and total digestible nutrients (TDN) production significantly improved in annual yield basis of the IRG-maize cropping. Zeolite application in PS-applied field may represent effective management in mitigating N losses through odorous NH3 and greenhouse gas (N2O) emissions, thereby improving NUE forage production.

Recent trends in the epidemiology and clinical outcomes of inflammatory bowel disease in South Korea, 2010-2018.

BACKGROUND: Inflammatory bowel disease (IBD) was previously regarded as a Western disease; however, its incidence is increasing in the East. The epidemiology of IBD in Asia differs significantly from the patterns in the West. AIM: To comprehensively investigate the epidemiology of IBD in South Korea, including its incidence, prevalence, medication trends, and outcomes. METHODS: We analyzed claims data from the Health Insurance Review and Assessment Service and Rare and Intractable Diseases (RIDs), operated by the National Health Insurance Service of South Korea. Patients with IBD were identified based on the International Classification of Diseases, Tenth Revision, and RID diagnostic codes for Crohn's disease (CD) and ulcerative colitis (UC) from 2010 to 2018. RESULTS: In total, 14498 and 31409 patients were newly diagnosed with CD and UC, respectively, between 2010 and 2018. The annual average incidence of CD was 3.11 cases per 105 person-years, and that of UC was 6.74 cases per 105 person-years. Since 2014, the incidence rate of CD has been stable, while that of UC has steadily increased, shifting the peak age group from 50-year-olds in 2010 to 20-year-olds in 2018. The CD and UC prevalence increased consistently over the study period; the use of 5-aminosalicylates and corticosteroids gradually decreased, while that of immunomodulators and biologics steadily increased in both CD and UC. The clinical outcomes of IBD, such as hospitalization and surgery, decreased during the study period. CONCLUSION: The CD incidence has been stable since 2014, but that of UC has increased with a shift to a younger age at peak incidence between 2010 and 2018. IBD clinical outcomes improved over time, with increased use of immunomodulators and biologics.

Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation.

Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo-YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.

Polarization-selective four-wave mixing in a degenerate multi-level system.

This paper describes the first observation of polarization-selective four-wave mixing signals in conventional coupling-probe spectroscopy, specifically, saturation absorption spectroscopy in 85Rb atoms. The four-wave mixing signal is induced by two counter-propagating laser beams in a degenerate multi-level atomic system, involving the F g = 3 → F e = 2 , 3 , and 4 transitions of the 85Rb D2 line. Consequently, the four-wave mixing signals copropagating along the probe beam induce polarization rotation of a linearly polarized probe beam. To distinguish these four-wave mixing signals from the resulting probe beam, we detect the polarization components orthogonal to the polarization direction of the input probe beam, depending on the linear polarization angles between the probe and coupling beams. The experimental findings demonstrate excellent agreement with theoretical results.

Incidence and survival rates of primary cutaneous malignancies in Korea, 1999-2019: A nationwide population-based study.

Primary cutaneous malignancies are among the most commonly diagnosed types of cancer worldwide. We aimed to examine the incidence and 5-year survival rates of all types of primary cutaneous malignancies in the Korean population. Data from the Korean Nationwide Cancer Registry from 1999 to 2019 were analyzed. The crude incidence rates, age-standardized incidence rates, and 5-year relative survival rates of each type of skin cancer were calculated. A total of 89 965 patients were diagnosed with primary cutaneous malignancies, which was a 7-fold increase from 1999 to 2019. The age-standardized incidence rates increased 3.4-fold in basal cell carcinoma (3.7/100 000 person-years), 2.0-fold in squamous cell carcinoma (1.6/100 000 person-years), 12.0-fold in Bowen disease (1.2/100 000 person-years), and 1.8-fold in malignant melanoma (0.7/10 000 person-years) in 2019. Average annual percentage changes in age-standardized incidence rates were statistically significant in basal cell carcinoma (15.8%), Bowen disease (5.8%), squamous cell carcinoma (5.1%), malignant melanoma (1.2%), melanoma in situ (1.1%), dermatofibrosarcoma protuberans (1.2%), mycosis fungoides (0.5%), primary cutaneous CD30+ T-cell proliferations (0.5%), adnexal and skin appendage carcinoma (0.4%), extramammary Paget's disease (0.2%), and Merkel cell carcinoma (0.2%). The 5-year relative survival rates were the highest in basal cell carcinoma (103.3%), followed by dermatofibrosarcoma protuberans (99.7%) and mycosis fungoides (96.6%), and lowest in angiosarcoma (24.7%). The 5-year relative survival rates steadily increased in extramammary Paget's disease (23.6%), cutaneous B-cell lymphoma (21.3%), mycosis fungoides (20.2%), extranodal NK/T-cell lymphoma, nasal type (18.1%), and malignant melanoma (16.1%) from 1996-2000 to 2015-2019. Most primary cutaneous malignancies have increased in incidence and survival rates in the Korean population, but to varying extents depending on the type of skin cancer.

Comparison of influence of intercalation and substitution of Cu on electrical and thermoelectric transport properties of InSe alloys.

Layered post-transition-metal chalcogenides, such as InSe, In4Se3, SnSe, and SnSe2, have recently been investigated as semiconducting electronic materials and thermoelectric materials owing to their adjustable electrical transport properties either by doping or alloying. Herein, the influence of intercalation doping and substitutional doping of Cu in layered InSe alloys on electrical and thermoelectric transport properties was investigated and compared by synthesizing varied compositions of CuxInSe and In1-yCuySe. It was found that Cu was intercalated in CuxInSe samples (x = 0.01 and 0.02) and behaved as an electron donor, resulting in an increase in the electron concentration and a decrease in the activation energy. Therefore, the power factor of CuxInSe samples was increased compared to that of InSe. In contrast, the substituted Cu in the In site of In1-yCuySe samples (y = 0.01 and 0.02) acted as an acceptor, and the power factor decreased owing to a decrease in the electron concentration and activation energy. Moreover, a decrease in thermal conductivity was seen for CuxInSe and In1-yCuySe samples due to increased phonon scattering after the addition of Cu. Consequently, an enhanced thermoelectric figure of merit (zT) was only observed for intercalated CuxInSe samples due to the increased power factor and decreased thermal conductivity, while substituted In1-yCuySe samples only show degraded zT. A maximum zT value of 0.062 was observed for the CuxInSe (x = 0.02) sample at 700 K, which showed a 77% enhancement compared to that of InSe.

Partial Molar Solvation Volume of the Hydrated Electron Simulated Via DFT.

Different simulation models of the hydrated electron produce different solvation structures, but it has been challenging to determine which simulated solvation structure, if any, is the most comparable to experiment. In a recent work, Neupane et al. [J. Phys. Chem. B 2023, 127, 5941-5947] showed using Kirkwood-Buff theory that the partial molar volume of the hydrated electron, which is known experimentally, can be readily computed from an integral over the simulated electron-water radial distribution function. This provides a sensitive way to directly compare the hydration structure of different simulation models of the hydrated electron with experiment. Here, we compute the partial molar volume of an ab-initio-simulated hydrated electron model based on density-functional theory (DFT) with a hybrid functional at different simulated system sizes. We find that the partial molar volume of the DFT-simulated hydrated electron is not converged with respect to the system size for simulations with up to 128 waters. We show that even at the largest simulation sizes, the partial molar volume of DFT-simulated hydrated electrons is underestimated by a factor of 2 with respect to experiment, and at the standard 64-water size commonly used in the literature, DFT-based simulations underestimate the experimental solvation volume by a factor of ∼3.5. An extrapolation to larger box sizes does predict the experimental partial molar volume correctly; however, larger system sizes than those explored here are currently intractable without the use of machine-learned potentials. These results bring into question what aspects of the predicted hydrated electron radial distribution function, as calculated by DFT-based simulations with the PBEh-D3 functional, deviate from the true solvation structure.

Predicting adequate segmental lordosis correction in lumbar spinal stenosis patients undergoing oblique lumbar interbody fusion: a focus on the discontinuous segment.

PURPOSE: To identify the factors associated with a correction of the segmental angle (SA) with a total change greater than 10° in each level following minimally invasive oblique lumbar interbody fusion (MIS-OLIF). METHODS: Patients with lumbar spinal stenosis who underwent single- or two-level MIS-OLIF were reviewed. Segments with adequate correction of the SA >10° after MIS-OLIF in immediate postoperative radiograph were categorized as discontinuous segments (D segments), whereas those without such improvement were assigned as continuous segments (C segments). Clinical and radiological parameters were compared, and multivariate logistic regression analysis was performed to identify factors associated with SA correction >10° after MIS-OLIF. RESULTS: Of 211 segments included, 38 segments (18.0%) were classified as D segments. Compared with C segments, D segments demonstrated a significantly smaller preoperative SA (mean ± standard deviation [SD], - 1.1° ± 6.7° vs. 6.6° ± 6.3°, p < 0.001), larger change of SA (mean ± SD, 13.5° ± 3.4° vs. 3.1° ± 3.9°, p < 0.001), and a higher rate of presence of facet effusion (76.3% vs. 48.6%, p = 0.002). Logistic regression revealed preoperative SA (odds ratio (OR) [95% confidence interval (CI)]:0.733 [0.639-0.840], p < 0.001) and facet effusion (OR [95% CI]:14.054 [1.758-112.377], p = 0.027) as significant predictors for >10° SA correction after MIS-OLIF. CONCLUSION: Preoperative kyphotic SA and facet effusion can predict SA correction >10° following MIS-OLIF. For patients with lordotic SA and no preoperative facet effusion, supplemental procedures, such as anterior column release or posterior osteotomy, should be prepared for additional lumbar lordosis correction required for remnant global sagittal imbalance after MIS-OLIF.

Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics.

Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.

Cumulative exposure to impaired fasting glucose and gastrointestinal cancer risk: A nationwide cohort study.

BACKGROUND: Impaired fasting glucose (IFG) is associated with the risk of various cancers, but the cumulative effect of IFG on gastrointestinal cancer risk remains unclear. This study evaluated the association between the cumulative exposure to IFG and gastrointestinal cancer risk. METHODS: The authors extracted data from the Korean National Health Insurance Service and health examination data sets. Among individuals ≥40 years old who were free of diabetes or cancer, 1,430,054 who underwent national health examinations over 4 consecutive years from 2009 to 2012 were selected and followed up until gastrointestinal cancer diagnosis, death, or December 31, 2019. The IFG exposure score (range, 0-4) was based on the number of IFG diagnoses over 4 years. RESULTS: The median follow-up duration was 6.4 years. Consistent normoglycemia for 4 years was found in 44.3% of the population, whereas 5.0% had persistent IFG and 50.7% had intermittent IFG. Compared to the group with an IFG exposure score of 0, groups with IFG exposure scores of 1, 2, 3, and 4 had a 5%, 8%, 9%, and 12% increased risk of gastrointestinal cancer, respectively (score 1: adjusted hazard ratio [aHR], 1.05; 95% confidence interval [CI], 1.01-1.08; score 2: aHR, 1.08; 95% CI, 1.04-1.12; score 3: aHR, 1.09; 95% CI, 1.05-1.14; score 4: aHR, 1.12; 95% CI, 1.06-1.19). Persistent IFG exposure was also associated with higher risks of individual cancer types (colorectum, stomach, pancreas, biliary tract, and esophagus). CONCLUSIONS: Cumulative exposure to IFG is associated with an increased risk of developing gastrointestinal cancer, in a dose-dependent manner. PLAIN LANGUAGE SUMMARY: Hyperglycemia, including both diabetes and prediabetes, has been associated with an increased risk of various cancers. However, the cumulative effect of impaired fasting glucose on the risk of developing gastrointestinal cancer remains unclear. A frequent diagnosis of impaired fasting glucose was dose-dependently associated with a higher risk of developing overall gastrointestinal cancer. Furthermore, risks of individual cancer types increased with persistent impaired fasting glucose. Early detection of hyperglycemia and strict glycemic control can lower the risk of gastrointestinal cancer by reducing hyperglycemic burden. Additionally, for some individuals, lifestyle changes such as managing metabolic syndrome or abstaining from alcohol may also be helpful.