Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING.

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization.

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified.

Epithelial progenitor 1, a novel factor associated with epithelial cell growth and differentiation.

The growth and renewal of epithelial tissue is a highly orchestrated and tightly regulated process occurring in different tissue types under a variety of circumstances. We have been studying the process of pancreatic regeneration in mice. We have identified a cell surface protein, named EP1, which is expressed on the duct epithelium during pancreatic regeneration.

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model.

FGFR3 is a negative regulator of the expansion of pancreatic epithelial cells.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are key signaling molecules for pancreas development. Although FGFR3 is a crucial developmental gene, acting as a negative regulator of bone formation, its participation remains unexplored in pancreatic organogenesis. We found that FGFR3 was expressed in the epithelia in both mouse embryonic and adult regenerating pancreata but was absent in normal adult islets.

PYY in the expanding pancreatic epithelium.

Gut peptide YY (PYY) plays an important role in regulating metabolism and is expressed during the ontogeny of the pancreas. However, its biological role during endocrine cell formation is not fully understood, and its role, if any, during pancreatic regeneration in the adult has not yet been explored. The knowledge of factors involved in beta cell renewal in adult animals is clearly relevant for the design of treatment strategies for type 1 diabetes.

[Association of fibrinogen B beta -1420G/A, -993C/T and -854G/A gene polymorphism with coronary heart disease].

Objective: To analyze the frequency of FGB gene -1420G/A, -993C/T and -854G/A polymorphisms, and their association with plasma fibrinogen levels in patients with coronary heart disease and in health adults.

Methods: The FGB gene -1420G/A, -993C/T and -854G/A polymorphisms were analyzed with restriction fragment length polymorphisms, polymerase chain reaction with allele-specific primer and nucleotide sequencing methods. Plasma fibrinogen levels were determined by turbidimetry.

[Changes and clinical significance of serum soluble Apo-1/Fas in pancreatic cancer].

Objective: To detect changes of serum soluble Apo-1/Fas (sApo-1/Fas) in pancreatic cancer patients and to investigate its clinical value in assessing the effect of chemotherapy.

Methods: The serum level of sApo-1/Fas in 30 normal control subjects and 58 pancreatic cancer patients were detected using enzyme-linked immunosorbent assay (ELISA), and the sApo-1/Fas level of 48 pancreatic cancer patients, before and after chemotherapy was compared.

Results: Compared with the level of the control group, the level of serum soluble Apo-1/Fas was significantly correlated with clinical stage but not with age, sex or pathologic type of pancreatic cancer.

[A related analysis for alpha, beta fibrinogen gene haplotypes and nucleotide polymorphisms associated with the ischemic stroke in Hainan Han population].

Objective: To analyze the association of that the polymorphisms and haplotypes of Taq I site in beta fibrinogen gene and the single nucleotide sites -455 G/A, -249 C/T, -148 C/T, +1689T/G, Bsm A I G/C, 448 G/A, Bcl I G/A, Hinf I A/C in beta-fibrinogen gene are linked up with the ischemic stroke(IS).

Methods: Turbidmetric assay was used to measure the plasma fibrinogen level of one hundred and sixty cases with ischemic stroke and one hundred and thirty healthy individuals from Hainanese Han population. The polymorphisms and genotypes were characterized by PCR-RFLP.

[Nine polymorphisms of fibrinogen gene and their association with plasma fibrinogen levels in Hainan Han population].

Objective: To investigate the allelic frequencies of polymorphisms of alpha Taq I and beta Bcl I, Hinf I A/C, 448 G/A, beta BsmA I G/C, +1689T/G, -148C/T, -249C/T, -455G/A in Hainan Han population and their association with plasma fibrinogen level.

Methods: Turbidmetric assay was used to measure plasma fibrinogen level of two hundred and thirty-eight healthy individuals. The genotypes were characterized by PCR-RFLP and sequence analysis.

Inhibition of activin signaling induces pancreatic epithelial cell expansion and diminishes terminal differentiation of pancreatic beta-cells.

Activins regulate the growth and differentiation of a variety of cells. During pancreatic islet development, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. In this study, we probed the role of activin signaling during pancreatic islet cell development and regeneration.

The stromal cell-derived factor-1alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas.

The SDF-1alpha/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1alpha and CXCR4 expression in fetal pancreas. We have found that SDF-1alpha and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) gamma-nonobese diabetic mouse.

[Effect of beta-Fibrinogen-455 Gene Polymorphism on Plasma Fibrinogen Levels in Patients with Ischemic Stroke].

In large prospective studies, plasma fibrinogen levels have been shown to be an independent risk factor of vascular disease, including ischemic stroke. Elevated plasma fibrinogen in an individual could be due to the presence of predisposing genetic and/or environmental factors, such as smoking. Of the polymorphisms studies to date, the beta-fibrinogen-455 (beta-Fg-455) G-->A substitution in the 5' flanking region is associated with the most consistent difference in plasma fibrinogen levels in both case-control studies and in selected groups of healthy individuals.

[Clinical value of serum soluble Apo-1/Fas for predicting biological behaviors and prognosis of gastric carcinoma].

Background & Objective: Literatures reported that the soluble Apo-1/Fas(sApo-1/Fas) levels in serum of patients with malignant carcinoma were higher than that in normal control subject, but there were fewer studies was seldom to detect the level of sApo-1/Fas in patients with malignancy carcinoma and effect of chemotherapy; the subject is to detect the level of sApo-1/Fas in patients with gastric carcinoma and effect of chemotherapy on it, and to investigate its clinical value.

Methods: Enzyme linked immunosorbent assays(ELISA) was available to detect the level of sApo-1/Fas in 42 case of patients with gastric carcinoma before and after chemotherapy, as compared with 30 case of normal control subject.

Results: Levels of sApo-1/Fas were elevated in all subgroups of patients with gastric carcinoma as compared to the controls (P < 0.