Mining and exploration of rehabilitation nursing targets for colorectal cancer.

Background: There are often subtle early symptoms of colorectal cancer, a common malignancy of the intestinal tract. However, it is not yet clear how MYC and NCAPG2 are involved in colorectal cancer.

Method: We obtained colorectal cancer datasets GSE32323 and GSE113513 from the Gene Expression Omnibus (GEO).

Intercellular adhesion molecule 1 and selectin l play crucial roles in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that primarily affects the mucosal layer of the colon (large intestine). However, the relationship between Intercellular Adhesion Molecule-1 (ICAM1), SELL and UC is unclear. The UC datasets, GSE87466 and GSE36807, were downloaded from the gene expression omnibus database.

CALM3 affects the prognosis of leukemia and hemorrhoids.

Leukemia is an abnormal proliferation of white blood cells in the bone marrow, resulting in a large accumulation of abnormal leukemia cells in the blood and bone marrow. Hemorrhoids are dilated and swollen veins in the rectum or anal area. However, the relationship between CALM3 and leukemia and hemorrhoids remains unclear.

Construction and internal validation of a novel nomogram for predicting prognosis of infective endocarditis.

To develop a nomogram prediction model capable of early identification of high-risk infective endocarditis (IE) patients. We retrospectively analyzed the clinical data of 383 patients with IE and divided them into survival and non-survival groups according to different hospitalization outcomes. Univariate and multivariate logistic regression methods were used to screen independent risk factors affecting the survival outcome of IE, and a Nomogram prediction model was constructed by these factors.

Nomogram for Predicting In-hospital Mortality in Infective Endocarditis Based on Early Clinical Features and Treatment Options.

Aim: The aim of this study was to develop a nomogram based on early clinical features and treatment options for predicting in-hospital mortality in infective endocarditis (IE).

Methods: We retrospectively analyzed the data of 294 patients diagnosed with IE in our hospital from June 01, 2012 to November 24, 2021, determined independent risk factors for in-hospital mortality by univariate and multivariate logistic regression analysis, and established a Nomogram prediction model based on these factors. Finally, the prediction performance of nomogram is evaluated by C-index, bootstrapped-concordance index, and calibration plots.

Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease.

An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex.

The complete mitochondrial genome of (Pall.) Kuntze and its phylogenetic implications.

The complete mitochondrial genome sequence of (Pall.) Kuntze was assembled and characterized in the present study. The mitochondrial genome was 347,227 bp in length and had a GC content of 43.

scLRTD : A Novel Low Rank Tensor Decomposition Method for Imputing Missing Values in Single-Cell Multi-Omics Sequencing Data.

With the successful application of single-cell sequencing technology, a large number of single-cell multi-omics sequencing (scMO-seq)data have been generated, which enables researchers to study heterogeneity between individual cells. One prominent problem in single-cell data analysis is the prevalence of dropouts, caused by failures in amplification during the experiments. It is necessary to develop effective approaches for imputing the missing values.

Toward Orally Absorbed Prodrugs of the Antibiotic Aztreonam. Design of Novel Prodrugs of Sulfate Containing Drugs. Part 2.

Aztreonam, first discovered in 1980, is an FDA approved, intravenous, monocyclic beta-lactam antibiotic. Aztreonam is active against Gram-negative bacteria and is still used today. The oral bioavailability of aztreonam in humans is less than 1%.

Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors.

A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAF. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.

Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3.

In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position.

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model.

Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K.

PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment.

Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.

Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma).

Synthesis and SAR of acyclic HCV NS3 protease inhibitors with novel P4-benzoxaborole moieties.

We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.

Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors.

Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties.

Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.

We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency.

Synthesis of new acylsulfamoyl benzoxaboroles as potent inhibitors of HCV NS3 protease.

HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay.

Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern.

Synthesis and evaluation of novel alpha-amino cyclic boronates as inhibitors of HCV NS3 protease.

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.

The discovery of tetrahydro-beta-carbolines as inhibitors of the kinesin Eg5.

A series of tetrahydro-beta-carbolines were identified by HTS as inhibitors of the kinesin Eg5. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of removing potential metabolic liabilities and improving cellular potency.

Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application.

Compounds with in vitro anti-hepatitis C virus (HCV) activity are often advanced directly into clinical trials with limited or no in vivo efficacy data. This limits prediction of clinical efficacy of compounds in the HCV drug pipeline, and may expose human subjects to unnecessary treatment effects. The scid-Alb-uPA mouse supports proliferation of transplanted human hepatocytes and subsequent HCV infection.

4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitors.

CHK-1 is one of the key enzymes regulating checkpoints in cellular growth cycles. Novel 4-(amino-alkylamino)-3-benzimidazole-quinolinones were prepared and assayed for their ability to inhibit CHK-1. These compounds are potent cell permeable CHK-1 inhibitors and showed synergistic effect with a DNA-damaging agent, camptothecin.

Progress and development of small molecule HCV antivirals.

Hepatitis C virus (HCV) is a disease that has a growing impact worldwide. A combination therapy comprising interferon-alpha (IFNalpha) and ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes some serious side effects. Promising alternative approaches toward the control of HCV infection, and the development of new antiviral agents, include the use of NS3/4A serine protease and NS5B polymerase inhibitors.