Impact of non-obese metabolic dysfunction-associated fatty liver disease on risk factors for the recurrence of esophageal squamous cell carcinoma treated with endoscopic submucosal dissection: A multicenter study.

AIM: Metabolic dysfunction is a risk factor for esophageal squamous cell carcinoma (ESCC). We investigated the impact of the recently proposed metabolic dysfunction-associated fatty liver disease (MAFLD) and its subtypes on ESCC recurrence after endoscopic treatment. METHODS: This multicenter observational cohort study enrolled consecutive patients newly diagnosed with ESCC after endoscopic treatment. Patients were classified into MAFLD or non-MAFLD groups. The MAFLD group was further classified into non-obese and obese MAFLD groups with a body mass index cutoff value of 25 kg/m2 . The impact of MAFLD on the recurrence of ESCC was evaluated using a decision tree algorithm and random forest analysis. RESULTS: A total of 147 patients (average age 69 years; male : female, 127:20; observational period, 2.4 years) were enrolled. The 1-, 3-, and 5-year recurrence rates were 2.0%, 21.1%, and 33.7%, respectively. Independent risk factors for the recurrence of ESCC were MAFLD (HR 2.2812; 95% confidence interval 1.0497-4.9571; p = 0.0373), drinking status, and smoking status. Metabolic dysfunction-associated fatty liver disease was identified as the second most important classifier for recurrence, followed by drinking status. The cumulative incidence of ESCC recurrence was higher in the MAFLD group than in the non-MAFLD group. In a subanalysis, the cumulative incidence of recurrence was significantly higher in the non-obese than in the obese MAFLD group among abstainers/non-drinkers. Directed acyclic graphs revealed that MAFLD directly contributes to ESCC recurrence. CONCLUSIONS: MAFLD was independently and directly associated with ESCC recurrence after endoscopic treatment; a high recurrence rate was observed in patients with non-obese MAFLD. Metabolic dysfunction-associated fatty liver disease may identify patients at high risk for ESCC recurrence.

Impact of metabolic dysfunction-associated fatty liver disease on the incidence of Helicobacter pylori-negative gastric cancer.

AIM: The incidence of Helicobacter pylori-negative gastric cancer (HPNGC) is increasing worldwide. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been reported to be associated with various cancers, but its association with HPNGC has not been reported. We aimed to identify important independent factors associated with HPNGC, including MAFLD. METHODS: This multicenter observational cohort study enrolled patients with gastric cancer (n = 1078) and health checkup examinees (n = 17 408). We analyzed patients with HPNGC (n = 26) and healthy participants with no H. pylori infection or any abnormal findings on upper gastrointestinal endoscopy (n = 1130). A logistic regression model was used to identify independent factors associated with HPNGC. The priority of the factors associated with HPNGC was evaluated using a decision-tree algorithm and random forest analysis. RESULTS: Among all patients with gastric cancer, 2.4% (26/1078) were diagnosed with HPNGC (mean age, 64 years; male/female, 13/13). In the logistic regression analysis, age, smoking, and MAFLD (odds ratio, 6.5359; 95% confidence interval, 2.5451-16.7841; p < 0.0001) were identified as independent factors associated with HPNGC. Metabolic dysfunction-associated fatty liver disease was also identified as the most important classifier for the presence of HPNGC in decision-tree analyses. Helicobacter pylori-negative gastric cancer was observed in 5.2% of patients with MAFLD and 0.8% of patients without MAFLD. In the random forest analysis of the HPNGC, MAFLD was identified as the distinguishing factor with the highest variable importance (0.32). CONCLUSIONS: Metabolic dysfunction-associated fatty liver disease was the most influential independent factor associated with HPNGC. These findings suggest that fatty liver and metabolic dysfunction could be involved in the pathogenesis of HPNGC.

Non-Obese MAFLD Is Associated with Colorectal Adenoma in Health Check Examinees: A Multicenter Retrospective Study.

Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191; 95% CI 1.494-7.070; p = 0.003). MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (29 variable importance value). Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma (OR 3.351; 95% CI 1.589-7.262; p ≤ 0.001). Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (31 variable importance value). MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.

Design, synthesis, and biological evaluation of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation-Use of a conformation-based hypothesis to facilitate compound design.

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.

Discovery and structure-activity relationships of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation.

A novel series of spiroindoline derivatives was discovered for use as inducers of oligodendrocyte progenitor cell (OPC) differentiation, resulting from optimization of screening hit 1. Exploration of structure-activity relationships led to compound 18, which showed improved potency (rOPC EC50 = 0.0032 µM). Furthermore, oral administration of compound 18 significantly decreased clinical severity in an experimental autoimmune encephalomyelitis (EAE) model.

Prediction of colorectal tumor grade and invasion depth through narrow-band imaging scoring.

AIM: To determine the usefulness of assigning narrow-band imaging (NBI) scores for predicting tumor grade and invasion depth in colorectal tumors. METHODS: A total of 161 colorectal lesions were analyzed from 138 patients who underwent endoscopic or surgical resection after conventional colonoscopy and magnifying endoscopy with NBI. The relationships between the surface and vascular patterns of the lesions, as visualized with NBI, and the tumor grade and depth of submucosa (SM) invasion were determined histopathologically. Scores were assigned to distinct features of the surface microstructures of tubular and papillary-type lesions. Using a multivariate analysis, a model was developed for predicting the tumor grade and depth of invasion based on NBI-finding scores. RESULTS: NBI findings that correlated with a high tumor grade were associated with the "regular/irregular" (P < 0.0001) surface patterns and the "avascular area" pattern (P = 0.0600). The vascular patterns of "disrupted vessels" (P = 0.0714) and "thick vessels" (P = 0.0133) but none of the surface patterns were associated with a depth of invasion of ≥ 1000 µm. In our model, a total NBI-finding score ≥ 1 was indicative of a high tumor grade (sensitivity: 0.97; specificity: 0.24), and a total NBI-finding score ≥ 9 (sensitivity: 0.56; specificity: 1.0) was predictive of a SM invasion depth ≥ 1000 µm. Scores less than these cutoff values signified adenomas and a SM invasion depth < 1000 µm, respectively. Associations were also noted between selected NBI findings and tumor tissue architecture and histopathology. CONCLUSION: Our multivariate statistical model for predicting tumor grades and invasion depths from NBI-finding scores may help standardize the diagnosis of colorectal lesions and inform therapeutic strategies.

Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6).

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.

Molecular biological characteristics, diagnosis and treatment of the colorectal serrated lesions.

Previous data shows that colorectal serrated lesions are precursor of carcinogenesis. It has been advancing even molecular biological analysis, SSA/P become microsatellite instability (MSI) positive colon cancers and TSA become microsatellite stable (MSS) positive colon cancers. It is observed that redness and double elevation in conventional endoscopy, CP type II (Sano classification) in the NBI endoscopy, type III pit pattern in magnifying endoscopy, if SSA/P have cytological dysplastic change. Especially, if SSA/P have cancerous change, CP type III and type V pit pattern are observed.

Orally active zwitterionic factor Xa inhibitors with long duration of action.

We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-ß pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.

Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors.

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 µM) and in vivo antithrombotic efficacy.

2-aminomethylphenylamine as a novel scaffold for factor Xa inhibitor.

We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.

Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: exploration of 5-6 fused rings as alternative S1 moieties.

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.

Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: exploration of 6-6 fused rings as alternative S1 moieties.

A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure-activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.

Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride: a novel, potent and orally active direct inhibitor of factor Xa.

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.

Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

Cycloalkanediamine derivatives as novel blood coagulation factor Xa inhibitors.

This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity.

Design, synthesis, and biological activity of novel factor Xa inhibitors: improving metabolic stability by S1 and S4 ligand modification.

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.

Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites.

Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.

Design, synthesis, and biological activity of non-amidine factor Xa inhibitors containing pyridine N-oxide and 2-carbamoylthiazole units.

Based on the both of results for X-ray studies of tetrahydrothiazolopyridine derivative 1c and FXV673, we synthesized a series of thiazol-5-ylpyridine derivatives containing pyridine N-oxide and 2-carbamoylthiazole units to optimize the S4 binding element. N-Oxidation of thiazol-5-ylpyridine increased the anti-fXa activity more than 10-fold independent on the position of N-oxide. The 4-pyridine N-oxide derivatives 3a and 3d excelled over the tetrahydrothiazolopyridine 1b in potency. 2-Methylpyridine N-oxide 3d exhibited 49-fold selectivity over thrombin. Our modeling study proposed a binding mode that the pyridine N-oxide ring of 3a stuck into the "cation hole" , and the oxide anion of 3a occupied in the almost same space to that of FXV673. From observations of the SAR and modeling studies, we suggested the possibilities that the formation of hydrogen bond with the oxide anion in the "cation hole" and the affinity of cationic pyridine ring to S4 subsite were responsible for increase in anti-fXa activity.