Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.

Effects of experimental liver injury on the intestinal barrier in rats / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the effects of experimental liver injury on the intestinal barrier, and to evaluate the significance of plasma D(-)-lactate, diamine oxidase (DAO) and endotoxin in live injury.</p><p><b>METHODS</b>Fifty-five rats were randomized into the acute liver failure group (group C, n = 25), acute liver injury group (group B, n = 15), and control group (group A, n = 15). The concentrations of D(-)-lactate, DAO and endotoxin in plasma were detected by spectrophotograph. The morphology and subcellular structure were observed under optical microscope and transmission electron microscope.</p><p><b>RESULTS</b>Acute liver failure and acute liver injury models were established successfully. The concentrations of D(-)-lactate and DAO in the plasma of experimental groups (group B and C) were significantly higher than those in the control group (P less than 0.05); the concentration of intestinal DAO in experimental groups were significantly lower than that in the control group (P less than 0.05); the level of endotoxin in C group was significantly higher than that in group A and group B (P less than 0.05).</p><p><b>CONCLUSION</b>Liver injury induces hyperpermeability of the rat intestinal mucosal barrier, plasma D(-)-lactate and DAO are sensitive markers for early diagnosis of liver injury, plasma endotoxin may accelerate deterioration of liver function.</p>

Liver histopathology, clinical features and prognostic factors of primary biliary cirrhosis: an analysis of 60 cases / 中华肝脏病杂志

<p><b>OBJECTIVE</b>Clinical and liver pathological features of 60 primary biliary cirrhosis (PBC) patients were reviewed to identify prognostic factors in order to improve the diagnosis and treatment of the disease.</p><p><b>METHODS</b>The general conditions, clinical manifestations, serum biochemical and immunological changes, and liver pathological findings were assessed in 60 PBC patients. All cases were followed up and 5 variables were studied by univariate analysis; the variables linked with survival were included in a Cox model.</p><p><b>RESULTS</b>Forty-eight patients were females (80%), 12 were males (20%), and the mean age at their diagnoses was (52.5+/-9.4). The symptoms most frequently complained about were jaundice (61.6%), fatigue (51.6%), anorexia (43.3%) and pruritus (25%). Serum alkaline phosphatase (ALP) and glutamyl transpeptidase (GGT) levels were markedly elevated in the majority of the patients [(242.3+/-137.1) U/L and (250.6+/-216.1) U/L, respectively], whereas ALT and AST levels were mildly to moderately elevated [(185.8+/-269.1) U/L and (172.5+/-163.6) U/L, respectively]. Thirty-two patients (53.3%) had a total bilirubin level of > or = 34.2 micromol/L. Twenty-eight patients (59.5%) had elevated serum IgM and 41 patients (68.3%) were anti-mitochondrial antibody AMA/AMA-M2 positive. Forty-two of the 60 patients had liver biopsies. The liver pathological changes: 33.3% of the cases were in I or II stage and 66.6% in III or IV stage. The follow up results: Five patients died of liver failure or massive upper gastrointestinal bleeding; 45 were still alive; the average survival period was 3.92 years; 10 patients were lost in the follow-up. With multivariate analysis (Cox model), age, level of total bilirubin and the stage of the liver pathological changes were found to be independent factors linked to the survival of the patients.</p><p><b>CONCLUSION</b>PBC may not be a rare liver disease in China. The awareness to recognize PBC is important in making an early diagnosis and treatment.</p>