Development and Validation of a Pathological Upgrading Prediction Model for Low-grade Gastric Mucosal Dysplasia.

Objective: The objective of this study is to develop a prediction model for the pathological upgrading of low-grade dysplasia (LGD) in gastric mucosa. The study aims to compare the performance of a traditional model based on clinical and endoscopic factors with an enhanced model that incorporates AMACR staining of biopsy tissues.

Methods: The study utilized a training dataset of 405 LGD cases to establish and compare the traditional and enhanced prediction models.

Efficacy of real-time artificial intelligence-aid endoscopic ultrasonography diagnostic system in discriminating gastrointestinal stromal tumors and leiomyomas: a multicenter diagnostic study.

Background: Gastrointestinal stromal tumors (GISTs) represent the most prevalent type of subepithelial lesions (SELs) with malignant potential. Current imaging tools struggle to differentiate GISTs from leiomyomas. This study aimed to create and assess a real-time artificial intelligence (AI) system using endoscopic ultrasonography (EUS) images to differentiate between GISTs and leiomyomas.

A rapid and high-throughput multiplex genetic detection assay for detection, semi-quantification and virulence genotyping of in non-invasive oral samples.

Aim: This study established a high-throughput multiplex genetic detection assay (HMGA) for rapid identification, semi-quantification and virulence analysis of directly from the clinical non-invasive oral samples.

Methods: The gastric mucosa and oral samples were collected from 242 patients in Shanghai from 2021 to 2022. All the samples were detected by routine clinical tests for and Sanger sequenced for inconsistent results.

Strong Synergistic Molecular Interaction in Catanionic Surfactant Mixtures: Unravelling the Role of the Benzene Ring.

Noncovalent interactions play a crucial role in driving the formation of diverse self-assembled structures in surfactant systems. Surfactants containing a benzene ring structure are an important subset of surfactants. These surfactants exhibit unique colloid and interfacial properties, which give rise to fascinating transformations in the aggregate structures.

Structure-activity relationship study of central pyridine-derived TYK2 JH2 inhibitors: Optimization of the PK profile through C4' and C6 variations.

Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described.

Application of Artificial Intelligence in Early Gastric Cancer Diagnosis.

Background: With the development of new technologies such as magnifying endoscopy with narrow band imaging, endoscopists achieved better accuracy for diagnosis of gastric cancer (GC) in various aspects. However, to master such skill takes substantial effort and could be difficult for inexperienced doctors. Therefore, a novel diagnostic method based on artificial intelligence (AI) was developed and its effectiveness was confirmed in many studies.

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.

To improve the metabolic stability profile of BMS-741672 (), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate , the -butyl amine showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability.

Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.

Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by with heterocyclic moieties led to the identification of three novel aza analogs -. The hexahydropyrrolo[3,2-]quinoline series (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series but with improved membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series , culminating in the discovery of as a potent and selective RORγt inverse agonist with an excellent profile, good pharmacokinetic properties, and biologic-like efficacy in preclinical models of rheumatoid arthritis and psoriasis.

Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313.

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound (BMS-986251) led to tricyclic-carbocyclic analogues represented by - and culminated in the identification of (BMS-986313), with structural differences distinct from . The X-ray co-crystal structure of with the ligand binding domain of RORγt revealed several key interactions, which are different from . The in vitro and in vivo PK profiles of are described.

Bicyclic Ligand-Biased Agonists of S1P: Exploring Side Chain Modifications to Modulate the PK, PD, and Safety Profiles.

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P has been shown to result in lymphopenia.

Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P) Modulators: Optimization of the PK, PD, and Safety Profiles.

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of and led to the identification of aryl ether and thioether-derived bicyclic S1P differentiated modulators -. The effects of analogs - on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded , and the predicted margin of safety against the cardiovascular effects of would be large enough for human studies.

Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist.

Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.

We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability.

Identification and Preclinical Pharmacology of ((1 R,3 S)-1-Amino-3-(( S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-phosphate Receptor 1 (S1P) Modulator Advanced into Clinical Trials.

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P receptor modulator. In comparison to fingolimod (1), a full agonist of S1P currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P.

Loss of Fas expression and high expression of HLA-E promoting the immune escape of early colorectal cancer cells.

Previous studies have investigated the mechanisms of immune evasion of tumor cells in numerous types of advanced solid malignant tumor, and several types of immune preparations have been administered as antitumor adjuvant therapies. However, in the majority of studies, the efficacy of therapies has been revealed to be limited. The present study aimed to investigate the immune evasion mechanisms employed by early colorectal cancer cells and the expression of the molecules associated with immune evasion during the malignant transformation process of normal colorectal epithelial cells to measure the effects of immune intervention for early colorectal cancer, and to improve the efficacy of immunotherapy.

Asymmetric Hydroboration Approach to the Scalable Synthesis of ((1R,3S)-1-Amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986104) as a Potent S1P Receptor Modulator.

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds.

Genomic expression profiling and bioinformatics analysis on diabetic nephrology with ginsenoside Rg3.

Diabetic nephropathy (DN), a common diabetes-related complication, is the leading cause of progressive chronic kidney disease (CKD) and end‑stage renal disease. Despite the rapid development in the treatment of DN, currently available therapies used in early DN cannot prevent progressive CKD. The exact pathogenic mechanisms and the molecular events underlying DN development remain unclear.

Bioaugmentation treatment of PV wafer manufacturing wastewater by microbial culture.

The wastewater of silicon photovoltaic (PV) battery manufacturing contained polyethylene glycol (PEG) and detergents, which possessed the characteristics of high content of organics and low bioavailability, and then resulted in high treatment costs. To address the difficulties of existing treatment facilities in stably meeting discharge standards, eight tons of microbial culture (consisting of Bacillus sp. and Rhodococcus sp.

Improving the pharmacokinetic and CYP inhibition profiles of azaxanthene-based glucocorticoid receptor modulators-identification of (S)-5-(2-(9-fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341).

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.

Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists.

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.

Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists.

We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.

Structure-activity relationship studies of thalidomide analogs with a taxol-like mode of action.

Anti-microtubule agents such as paclitaxel and docetaxel have played an important role in the treatment of cancer for many years. Recently, a small molecule that has a taxol-like mode of action (5HPP-33) was reported. Herein, the detailed structure-activity relationship (SAR) studies of 5HPP-33 analogs that are substituted at the isoindole and phenyl rings are described.

Synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamide-derived antagonists of CC chemokine receptor 2 (CCR2).

We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.

Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521).

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target.