Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.

MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

Concise Synthesis of 11-Noriridoids via Pauson-Khand Reaction.

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.

Advancements in minimally invasive endoscopic treatment: Navigating deeper layers for upper gastrointestinal lesion.

The field of minimally invasive endoscopic treatment has seen a continual progression, marked by significant advancements in treatment devices and the refinement of endoscopic techniques. While endoscopic resection has become the standard for treating superficial gastrointestinal neoplasms, a proactive approach becomes imperative when dealing with lesions that extend beyond the submucosal layer and deeper into the muscularis propria. The ongoing evolution of endoscopic closure techniques has facilitated the introduction of advanced procedures such as endoscopic muscularis dissection, endoscopic subserosal dissection, and endoscopic full-thickness resection. This evolution is achieved by the commitment to improve the efficacy and precision in treating challenging lesions. Nevertheless, there is currently a lack of definitive guidelines or consensus regarding the specifics of deeper layer dissection. Drawing from prior research and clinical insights, this review discusses indications, techniques, clinical outcomes, and future perspectives of deeper layer dissection.

Enhancing closure efficacy in antireflux mucoplasty through endoscopic hand-suturing technique.

Video 1XXX.

Glomerular Endothelial Cell Receptor ADGRF5 and the Integrity of the Glomerular Filtration Barrier.

BACKGROUND: Glomerular endothelial cells are recognized to be important for maintaining the glomerular filtration barrier. ADGRF5, an adhesion G protein-coupled receptor, has been suggested to be involved in endothelial cell function. However, the role of ADGRF5 in the glomerular filtration barrier integrity remains elusive. METHODS: Cellular expression of ADGRF5 in mouse glomerulus was determined by histological analyses. The impact of ADGRF5 deletion on the glomerular morphology, kidney function, and glomerular endothelial gene/protein expression was then analyzed using ADGRF5 knockout (Adgrf5-/-) mice and human primary glomerular endothelial cells. RESULTS: ADGRF5 was specifically expressed in the capillary endothelial cells within the glomerulus. Adgrf5-/- mice developed albuminuria and impaired kidney function with morphological defects in the glomeruli, namely glomerular hypertrophy, glomerular basement membrane splitting and thickening, diaphragmed fenestration and detachment of the glomerular endothelial cells, and mesangial interposition. These defects were accompanied by the altered expression of genes responsible for glomerular basement membrane organization (type IV collagens and laminins) and Krüppel-like factor 2 (Klf2) in glomerular endothelial cells. Moreover, ADGRF5 knockdown decreased COL4A3 and COL4A4 expression and increased KLF2 expression in human primary glomerular endothelial cells. CONCLUSIONS: The loss of ADGRF5 resulted in altered gene expression in glomerular endothelial cells, and perturbed the structure and permselectivity of the glomerular filtration barrier.

Characterization of co-fired sodium-ion conductive Na2Ni2TeO6 and Na2Zn2TeO6 with honeycomb layer structure.

We investigated the reactivity of P2-type honeycomb layered oxides Na2Ni2TeO6 (NNTO) and Na2Zn2TeO6 (NZTO) co-fired at the temperature from 500 °C to 800 °C. From X-ray diffraction measurements, it was found that the reaction between NNTO and NZTO is unremarkable at the temperature below 700 °C. However, when annealed at 800 °C, they formed the solid-solution phase without any secondary phases. The NNTO and NZTO composite pellets co-fired at 800 °C showed sodium-ion conductivity well above 10-4 S cm-1 at room temperature, indicating that the solid-solution phase of NNTO and NZTO has good ionic conductivity. A maximum room temperature conductivity of 7.4 × 10-4 S cm-1 was confirmed at the mixing ratio NNTO: NZTO = 0.5 : 1.5. These results can be applied to the fabrication of all-solid-state batteries using NNTO as the cathode active material and NZTO as the solid electrolyte via a simple co-sintering process.

Endoscopic pressure study integrated system using an ultrathin gastroscope for the functional assessment of the lower esophageal sphincter.

OBJECTIVES: The endoscopic pressure study integrated system (EPSIS) represents an innovative approach for evaluating lower esophageal sphincter function by monitoring intragastric pressure using diagnostic gastroscopes. This study aimed to assess the feasibility and validity of employing ultrathin gastroscopes for EPSIS. METHODS: A retrospective analysis was conducted on a database of consecutive patients who underwent EPSIS using both ultrathin and regular gastroscopes between September 2021 and October 2023. The study compared EPSIS parameters between the two gastroscope types to evaluate the correlation of key metrics. RESULTS: Thirty patients underwent EPSIS with both ultrathin and regular gastroscopes. Significant positive correlations were observed in the pressure waveform: maximum intragastric pressure (mmHg) (ρ = 0.82, P < 0.001) and intragastric pressure gradient (mmHg/s) (ρ = 0.80, P < 0.001) when comparing the two gastroscopes. Maximum intragastric pressure (15.5 [5.3-20.3] vs. 18.5 [3.4-21.6], P < 0.001) and pressure gradient (0.16 [0.013-0.41] vs. 0.24 [0.0039-1.13], P < 0.001), (median [range]) were significantly lower with ultrathin gastroscopes. CONCLUSIONS: This study establishes that EPSIS parameters obtained with an ultrathin gastroscope exhibit a significant correlation with those obtained using a regular gastroscope, with each EPSIS parameter consistently lower. These findings support the viability of EPSIS for ultrathin gastroscopy and highlight its potential as a diagnostic tool for assessing lower esophageal sphincter function.

Exploring the neural underpinnings of chord prediction uncertainty: an electroencephalography (EEG) study.

Predictive processing in the brain, involving interaction between interoceptive (bodily signal) and exteroceptive (sensory) processing, is essential for understanding music as it encompasses musical temporality dynamics and affective responses. This study explores the relationship between neural correlates and subjective certainty of chord prediction, focusing on the alignment between predicted and actual chord progressions in both musically appropriate chord sequences and random chord sequences. Participants were asked to predict the final chord in sequences while their brain activity was measured using electroencephalography (EEG). We found that the stimulus preceding negativity (SPN), an EEG component associated with predictive processing of sensory stimuli, was larger for non-harmonic chord sequences than for harmonic chord progressions. Additionally, the heartbeat evoked potential (HEP), an EEG component related to interoceptive processing, was larger for random chord sequences and correlated with prediction certainty ratings. HEP also correlated with the N5 component, found while listening to the final chord. Our findings suggest that HEP more directly reflects the subjective prediction certainty than SPN. These findings offer new insights into the neural mechanisms underlying music perception and prediction, emphasizing the importance of considering auditory prediction certainty when examining the neural basis of music cognition.

Clinical outcomes of anti-reflux mucosal ablation for gastroesophageal reflux disease: An international bi-institutional study.

BACKGROUND AND AIM: Anti-reflux mucosal ablation (ARMA) is an emerging endoscopic treatment aimed at enhancing the gastroesophageal junction flap valve. This study aimed to evaluate its feasibility, effectiveness, and safety. METHODS: Between May 2018 and December 2022, patients with gastroesophageal reflux disease (GERD) symptoms refractory to acid suppression medications or those dependent on such medications were enrolled for ARMA. This retrospective analysis utilized prospectively collected data from an international bi-center study. GERD questionnaire, upper endoscopy, and 24-h pH monitoring were conducted at 2-6 months and 12 months post-ARMA. Clinical success was defined as a > 50% reduction in a validated GERD questionnaire. RESULTS: A total of 68 patients underwent ARMA. Definitive GERD was diagnosed in 44 (64.7%) patients, while 24 (35.3%) exhibited reflux hypersensitivity. Clinical success rates at 2-6 months and 1 year post-ARMA were 60% (39/65) and 70% (21/30), respectively. The median GERD-health-related quality of life score significantly improved from 26 to 11 at 2-6 months (P < 0.001). Among the 51 patients (71.8%) who underwent 24-h pH monitoring, the median acid exposure time decreased from 5.3% to 0.7% (P = 0.003), accompanied by a significant reduction in esophagitis rates (P < 0.001). Multivariate analysis did not identify predictors of short-term success. Nine (13.2%) patients experienced transient stenosis requiring balloon dilation. CONCLUSIONS: ARMA demonstrates both technical feasibility and reproducibility as a safe procedure that effectively ameliorates GERD symptoms in approximately two-thirds of patients during short-term follow up. Both reflux hypersensitivity and confirmed GERD patients, regardless of their response to acid suppression medication, may be suitable candidates.

Feasibility and safety of per-oral endoscopic septotomy for Killian-Jamieson diverticulum: Case series with video.

BACKGROUND AND AIMS: Killian-Jamieson diverticulum (KJD) is a relatively uncommon variant of pharyngoesophageal diverticula, distinct from the more prevalent Zenker diverticulum. However, literature on endoscopic management of KJD remains limited. This study aimed to elucidate the efficacy and safety of peroral endoscopic septotomy (POES) as a treatment approach for symptomatic KJD. METHODS: In this retrospective observational study, we investigated the outcomes of nine consecutive patients who underwent POES for KJD between January 2019 and May 2023. Follow-up data of at least 2 months post-treatment were analyzed. The primary outcome measure was the technical success rate of POES. Secondary outcomes encompassed the clinical success rate, defined as symptomatic improvement 2 months after POES, and the incidence of adverse events. RESULTS: All patients presented with dysphagia, with a median symptom duration of 6 months (interquartile range [IQR]: 3-12 months). The median diverticulum size was 32 mm (IQR: 24-42 mm). The median duration of the operation time was 66 min (IQR: 60-109). A 100% technical success rate was achieved, with complete closure of the defect in all cases. There were no adverse events related to this treatment. The median hospitalization duration was 5 days (IQR: 4-6), and the clinical success rate was 88.9%. Follow-up barium esophagograms exhibited significant improvement in the flow of the barium for all patients. CONCLUSIONS: Despite the relatively limited case volume, our findings underscore that POES is a safe and efficacious approach for managing symptomatic KJD.

Hood attached vs conventional triangular tip-jet knife in peroral endoscopic myotomy: a propensity score matching cohort study.

BACKGROUND & AIM: Peroral endoscopic myotomy (POEM) is a safe and effective endoscopic treatment for achalasia and other esophageal motility disorders, and TTJ (Triangle Tip Knife J; Olympus, Tokyo, Japan) is currently widely used in POEM. Recently, we reported a novel modification of TTJ, which was adjusted to knife length 2 mm by attaching a disposable clip (QuickClip Pro; Olympus) sheath to the tip as a hood attachment. In this study, we compared the safety and effectiveness of TTJ and TTJ with hood attachment (TTJ-H) in POEM. METHODS: In this 1:1 propensity score matched retrospective cohort study, we compared the procedure time, myotomy efficiency, number of coagulation forceps usage, adverse events, length of hospital stay after POEM, procedural success and clinical success between TTJ and TTJ-H groups. RESULTS: We examined 682 consecutive patients who underwent POEM between January 2021 and June 2023. We excluded 134 patients who had already undergone POEM or laparoscopic Heller myotomy as prior myotomy. Finally, we identified 98 propensity score-matched pairs (n = 196). The mean procedure time was shortened from 93.5 to 80.2 min (14% reduction, P = 0.012) when comparing TTJ-H group to TTJ group. The mean myotomy efficiency was improved from 2.76 to 2.32 min/cm (16% improvement, P = <0.001), and usage of coagulation forceps for hemostasis was decreased from 3.87 to 0.55 (86% reduction, P = <0.001). CONCLUSIONS: This study showed that use of TTJ-H could reduce total procedure time, improve myotomy efficiency, and reduce costs compared to TTJ.

Antireflux mucoplasty, an evolution of endoscopic antireflux therapy for refractory GERD.

Video 1We present a new therapeutic approach called antireflux mucoplasty for proton pump inhibitor-refractory GERD.

Effect on Hemoglobin A1c (HbA1c) and Body Weight After Discontinuation of Tirzepatide, a Novel Glucose-Dependent Insulinotropic Peptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist: A Single-Center Case Series Study.

Introduction The purpose of this study was to examine changes in blood glucose levels and body weight after discontinuation of tirzepatide, a novel long-acting dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). Methods Nine subjects (five males, four females, age 54.3±5.4 years, body mass index 33.5±3.3 kg/m2) participating with type 2 diabetes in the SURPASS J-mono study were included. Subjects were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or a dulaglutide 0.75 mg group. Fifty-two weeks after randomization, study drug administration was discontinued. To investigate progress after the end of administration, changes in hemoglobin A1c (HbA1c) and body weight were further examined two, four, and six months after discontinuation of the study drug. Results After fifty-two weeks, all tirzepatide groups had improved HbA1c and body weight compared with the dulaglutide group. At two, four, and six months after the end of study drug administration, re-elevation of HbA1c was observed in all groups. Furthermore, in the tirzepatide groups, dose-dependent weight regain was observed from an early stage. Conclusions Compared to dulaglutide, tirzepatide exhibited excellent blood-glucose-improving and weight-reducing effects. However, exacerbation of blood glucose and rebound of weight gain occurred relatively early after administration was ended. For type 2 diabetes patients who need weight loss and are prescribed tirzepatide, these findings suggest a necessity for continuous prescription or careful follow-up when stopping.

Pilot study on anti-reflux mucoplasty: Advancing endoscopic anti-reflux therapy for gastroesophageal reflux disease.

OBJECTIVES: Anti-reflux mucosectomy (ARMS) and anti-reflux mucosal ablation (ARMA) were developed as interventions for proton pump inhibitor (PPI)-refractory/-dependent gastroesophageal reflux disease (GERD). Although ARMS and ARMA are established treatments for PPI-refractory GERD, reliance on natural healing for ulcer scar formation introduces uncertainty and bleeding risk. To address these issues, we introduced a novel approach called anti-reflux mucoplasty (ARM-P), which involves immediate closure of mucosal defects following mucosectomy. This pilot study aims to evaluate the safety, feasibility, and efficacy of ARM-P. METHODS: A retrospective single-center study was conducted using prospectively collected data from October 2022 to July 2023. Patients with PPI-refractory/-dependent GERD who underwent ARM-P were included. The study evaluated technical success of ARM-P, before and after ARM-P GERD-Health Related Quality of Life Questionnaire, GerdQ, and Frequency Scale for the Symptoms of GERD scores, along with PPI discontinuation and endoscopic esophagogastric junction morphology. RESULTS: A total of 20 patients with a median age of 61.5 years underwent the ARM-P procedure. The procedure achieved 100% technical success without adverse events. After ARM-P, 55.0% discontinued PPI usage and 15.0% reduced PPI dose by half. Median GERD-Health Related Quality of Life Questionnaire score improved from 21 to 6 (P = 0.0026), median GerdQ score improved from 9 to 7 (P = 0.0022), and median Frequency Scale for the Symptoms of GERD score decreased from 16 to 7 (P = 0.0003). Median Hill's Classification significantly improved from grade III to grade I (P = 0.0001). CONCLUSIONS: This study presents the first pilot report of ARM-P, demonstrating its procedural safety, technical feasibility, and short-term efficacy.

Endoscopic pressure study integrated system for the diagnosis of achalasia.

OBJECTIVES: The endoscopic pressure study integrated system (EPSIS) is a novel diagnostic tool used to evaluate lower esophageal sphincter (LES) function. EPSIS allows the measurement of intragastric pressure (IGP) during gastric insufflation through esophagogastroduodenoscopy (EGD) and records its pressure waveform. This study aimed to assess the usefulness and applicability of EPSIS as an adjunct diagnostic modality for achalasia. METHODS: This case-control study was conducted using a database of patients who underwent EGD, barium swallow (BS), high-resolution manometry (HRM), and EPSIS between January 2022 and December 2022. The achalasia (experimental) group (n = 35) consisted of patients with a definitive diagnosis of achalasia. The control group (n = 34) consisted of patients with no abnormalities in EGD, BS, or HRM and no abnormal acid reflux confirmed with 24-h pH-impedance monitoring. EPSIS findings were compared between the two groups and characterized by the waveform pattern (uphill or flat), maximum IGP (IGP-Max), pressure difference, and the gradient of the waveform. RESULTS: All patients in the achalasia group showed an uphill pattern, in contrast to 21 patients (61.8%) in the control group. IGP-Max demonstrated the best diagnostic accuracy for achalasia, with a cut-off value of 15.8 mmHg (100% sensitivity, 58.8% specificity, and area under the curve [AUC] 0.78). The pressure gradient also demonstrated good diagnostic accuracy, with a cut-off value of 0.40 mmHg/s (80% sensitivity, 61.8% specificity, and AUC 0.76). CONCLUSION: This study demonstrated that EPSIS can be applied as a diagnostic modality in patients with achalasia.

In Situ and Ex Situ Studies of Ring-Like Assembly of Silica Nanoparticles in the Presence of Poly(propylene oxide)-Poly(ethylene oxide) Block Copolymers.

Block copolymer-mediated self-assembly of colloidal nanoparticles has attracted great attention for fabricating various nanoparticle arrays. We have previously shown that silica nanoparticles (SNPs) assemble into ring-like nanostructures in the presence of temperature-responsive block copolymers poly[(2-ethoxyethyl vinyl ether)-block-(2-methoxyethyl vinyl ether)] (PEOVE-PMOVE) in an aqueous phase. The ring-like nanostructures formed within an aggregate of PEOVE-PMOVE when the temperature was increased to 45 °C, at which the polymer is amphiphilic. Herein, we report that SNPs assemble into ring-like nanostructures even with a different temperature-responsive, amphiphilic block copolymer poly(propylene oxide)-block-poly(ethylene oxide) (PPO-PEO) at 45 °C. Field-emission scanning electron microscopy for SNP assemblies that were spin-coated on a substrate indicated that SNP first assembled into chain-like nanostructures and then bent into closed loops over several days. In contrast, in situ small-angle X-ray diffraction measurements revealed the formation of SNP nanorings within 75 s at 45 °C in the liquid phase. These results indicated that ring-like assembly of SNPs occurs quickly in the liquid phase, but the slow formation of Si-O-Si bonds between SNPs leads to their structure being destroyed by spin-coating. Intriguingly, SNPs with a diameter of 15 nm form a well-defined nanoring structure, with five SNPs located at the vertex points of a regular pentagon. Additionally, small-angle neutron scattering, where the contrast of the solvent (a mixture of H2O and D2O) matches that of SNPs, clarified that SNPs are contained within the spherical micelle formed from PPO-PEO. This work offers a facile and versatile approach to preparing ring-like arrays from inorganic colloidal nanoparticles, leading to applications including sensing, catalysis, and nanoelectronics.

Solid-Phase Synthesis of Nannocystin Ax and Its Analogues.

Solid-phase total synthesis of nannocystin Ax (1) was disclosed. A coupling reaction between a peptide and a polyketide moiety was conducted on a solid support, and macrocyclization was achieved by Mitsunobu cyclization. The established synthetic route was efficient to prepare its analogues, which contain different types of peptide moieties.

Bulbar and post-bulbar duodenal ulcers: characteristics based on location.

OBJECTIVES: Most research on duodenal ulcers has focused on bulbar ulcers; details on post-bulbar ulcers remain largely unknown. This study was conducted to determine the characteristics of patients with post-bulbar duodenal ulcers depending on their location. METHODS AND MATERIALS: We conducted a retrospective study of hospitalized patients newly diagnosed with duodenal ulcers on endoscopy at a tertiary referral center in Japan between April 2004 and March 2019. Five hundred fifty-one patients diagnosed with duodenal ulcers were extracted for analysis. RESULTS: Ulcers were observed only in the bulbus in 383 cases, only in the post-bulbar duodenum in 82 cases, and were co-existing in both areas in 86 cases. The Bulbar group had less comorbidities and was more likely to have atrophic gastritis, while the Post-bulbar and Co-existing groups were more likely to be admitted for non-gastrointestinal conditions. Regular acid suppressant use was more common in the post-bulbar group than in the Bulbar group. Bulbar ulcers were associated with a shorter length of stay relative to post-bulbar and co-existing ulcers, but ulcer location was not an independent predictor of length of stay. Patients with co-existing bulbar and post-bulbar ulcers have characteristics similar to those with post-bulbar ulcers alone. CONCLUSION: Patients with post-bulbar ulcers and those with co-existing bulbar and post-bulbar ulcers have different characteristics and outcomes relative to patients with bulbar ulcers.

Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling.

Pathophysiological analysis and drug discovery targeting human diseases require disease models that suitably recapitulate patient pathology. Disease-specific human induced pluripotent stem cells (hiPSCs) differentiated into affected cell types can potentially recapitulate disease pathology more accurately than existing disease models. Such successful modeling of muscular diseases requires efficient differentiation of hiPSCs into skeletal muscles. hiPSCs transduced with doxycycline-inducible MYOD1 (MYOD1-hiPSCs) have been widely used; however, they require time- and labor-consuming clonal selection, and clonal variations must be overcome. Moreover, their functionality should be carefully examined. Here, we demonstrated that bulk MYOD1-hiPSCs established with puromycin selection rather than G418 selection showed rapid and highly efficient differentiation. Interestingly, bulk MYOD1-hiPSCs exhibited average differentiation properties of clonally established MYOD1-hiPSCs, suggesting that it is possible to minimize clonal variations. Moreover, disease-specific hiPSCs of spinal bulbar muscular atrophy (SBMA) could be efficiently differentiated via this method into skeletal muscle that showed disease phenotypes, suggesting the applicability of this method for disease analysis. Finally, three-dimensional muscle tissues were fabricated from bulk MYOD1-hiPSCs, which exhibited contractile force upon electrical stimulation, indicating their functionality. Thus, our bulk differentiation requires less time and labor than existing methods, efficiently generates contractible skeletal muscles, and may facilitate the generation of muscular disease models.

Liver injury indicators and subsequent cancer development among non-fatty liver population.

BACKGROUND: Little is known about the association between liver indicators (The FIB-4 index, nonalcoholic fatty liver disease fibrosis score (NFS), and fatty liver index (FLI)) and cancer development in patients without preexisting liver disease. METHODS: We conducted a retrospective cohort study with participants who underwent voluntary health checkups and without fatty liver between 2005 and 2018. Our primary outcome was the development of any type of cancer, and its association with each liver indicator was evaluated. RESULTS: A total of 69,592 participants (mean age: 43.9 years, 29,984 (43.1%) were men) were included. During a median follow-up of 5.1 years, 3779 (5.4%) patients developed cancer. Compared to participants with a low NFS, those with a medium NFS had a higher risk of developing any type of cancer (adjusted hazard ratio [HR]: 1.18, 95% confidence interval [CI]: 1.07-1.31), whereas those with a medium FIB-4 index had a decreased risk of developing any type of cancer compared to those with a low FIB-4 index (adjusted HR: 0.91, 95% CI: 0.83-0.99). Patients with higher scores tended to have a higher risk of digestive organ cancer, regardless of the indicator. A high FLI was also associated with an increased risk of breast cancer (adjusted HR: 2.42, 95% CI: 1.24-4.71); however, those with a medium FIB-4 index (adjusted HR: 0.65, 95% CI: 0.52-0.81) and NFS (adjusted HR: 0.50, 95% CI: 0.35-0.72) had decreased risks of developing breast cancer compared to those with a high FIB-4 index and NFS, respectively. CONCLUSION: Among patients without fatty liver, a higher liver indicator score was associated with an increased risk of cancer in the digestive organs, regardless of the indicator. Notably, those with a medium FIB-4 index or NFS had a lower risk of developing breast cancer, whereas those with a medium FLI had an increased risk.