It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.

Objective Bismuth‐containing quadruple therapy for Helicobacter pylori (H. pylori) eradication has a relatively high rate of side effects and high cost, thus the option of a high‐dose dual therapy with a high eradication rate and fewer adverse events is a consideration. However, studies of dual therapy are still scarce and are mostly single‐center studies with limited generalizability. Large‐scale, multicenter studies are required. Our study investigated and compared the effectiveness, adverse events, patient compliance, and costs of high‐dose dual therapy with those of bismuth‐containing quadruple therapy in H. pylori‐infected treatment‐naive patients in a prospective, multicenter, open‐label, randomized controlled trial. Method Treatment‐naive patients infected with H. pylori were randomly assigned to receive high‐dose dual therapy (esomeprazole 20 mg 4 times daily and amoxicillin 1000 mg 3 times daily, for 14 days) or bismuth‐containing quadruple therapy (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg, all twice daily for 14 days). The effectiveness, adverse events, patient compliance, and costs of both groups were compared. Results A total of 700 patients were enrolled. The high‐dose dual therapy group (N = 350) achieved eradication rates of 89.4% (intention‐to‐treat), 90.4% (modified intention‐to‐treat), and 90.6% (per‐protocol), which were similar to rates in the bismuth‐containing quadruple therapy group (N = 350), 84.6%, 88.0%, and 88.2%, respectively (p > 0.05). The high‐dose dual therapy group had a lower rate of adverse events (12.9% vs. 28.1%, p < 0.001) and lower costs (¥590.2 vs. ¥723.22) compared with the quadruple therapy group, respectively. The compliance of both groups was satisfactory (97.7% high‐dose dual vs. 96.8% quadruple, p > 0.05). Conclusion High‐dose dual therapy for H. pylori eradication had similar efficacy and compliance, fewer adverse events, and lower costs than bismuth‐containing quadruple therapy for treatment‐naive patients.

BackgroundStreptococcus pneumoniae is the main pathogen that causes respiratory infections in children younger than five years. The increasing incidence of macrolide- and tetracycline-resistant pneumococci among children has been a serious problem in China for many years. The molecular characteristics of erythromycin-resistant pneumococcal isolates that were collected from pediatric patients younger than five years in Beijing in 2010 were analyzed in this study.ResultsA total of 140 pneumococcal isolates were collected. The resistance rates of all isolates to erythromycin and tetracycline were 96.4% and 79.3%, respectively. Of the 135 erythromycin-resistant pneumococci, 91.1% were non-susceptible to tetracycline. In addition, 30.4% of the erythromycin-resistant isolates expressed both the ermB and mef genes, whereas 69.6% expressed the ermB gene but not the mef gene. Up to 98.5% of the resistant isolates exhibited the cMLSB phenotype, and Tn6002 was the most common transposon present in approximately 56.3% of the resistant isolates, followed by Tn2010, with a proportion of 28.9%. The dominant sequence types (STs) in all erythromycin-resistant S. pneumoniae were ST271 (11.9%), ST81 (8.9%), ST876 (8.9%), and ST320 (6.7%), whereas the prevailing serotypes were 19F (19.3%), 23F (9.6%), 14 (9.6%), 15 (8.9%), and 6A (7.4%). The 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) coverage of the erythromycin-resistant pneumococci among the children younger than five years were 45.2% and 62.2%, respectively. ST320 and serotype 19A pneumococci were common in children aged 0 to 2 years. CC271 was the most frequent clonal complex (CC), which accounts for 24.4% of all erythromycin-resistant isolates.ConclusionsThe non-invasive S. pneumoniae in children younger than five years in Beijing presented high and significant resistance rates to erythromycin and tetracycline. The expressions of ermB and tetM genes were the main factors that influence pneumococcal resistance to erythromycin and tetracycline, respectively. Majority of the erythromycin-resistant non-invasive isolates exhibited the cMLSB phenotype and carried the ermB, tetM, xis, and int genes, suggesting the spread of the transposons of the Tn916 family. PCV13 provided higher serotype coverage in the childhood pneumococcal diseases caused by the erythromycin-resistant isolates better than PCV7. Further long-term surveys are required to monitor the molecular characteristics of the erythromycin-resistant S. pneumoniae in children.

Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FceRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P¼8.8Â10 À5 ) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P¼0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P¼0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P¼0.016), and replicated among the Brazilian families (P¼0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6¢-sulfo-sLe x , a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.