pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner

Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel–Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance

Enterovirus 71-induced acute flaccid paralysis: two case reports with review of literatures

Objective To investigate the clinical characteristics and prognosis of hand⁃foot⁃and⁃mouth disease (HFMD) complicated with acute flaccid paralysis (AFP). Methods The clinical features, MRI, electroencephalogram (EEG), neurophysiological examination and prognosis of 2 cases of HFMD complicated with AFP were analyzed retrospectively. Functional recovery was followed up for 9 weeks. Related literatures were reviewed. Results Both of the two cases are infants. AFP occurred at the 7 th day, and advanced to severe degree at 1-2 d after onset. Paralysis affected one limb in one case and 3 limbs in another case. Muscle strength ranged from 0 to 3 degree. Cranial MRI indicated broadened extracerebral lacuna. Cervical MRI presented long T2 lesion in the spinal cord. EEG recorded symmetrical slow background waves. Neurophysiological examination showed minor or moderate spontaneous potential at the paralytic limb. The duration of motor unit potential was prolonged, but the amplitude declined. Motor nerve conduction velocity was normal. Terminal latent period was intact. The amplitude of muscle motor potential declined. Sensory nerve conduction velocity was normal. F wave disappeared. Both of the 2 patients began to recover 2-3 weeks later. Conclusion HFMD complicated with AFP usually affects infant. Paralysis usually occurs around 1 week during the course of HFMD and progresses rapidly to peak 1-2 days after onset. Unique or multi limbs can be affected and the paralysis can recover rapidly. MRI, EEG, and neurophysiological examination are valuable for diagnosis and predicting prognosis. DOI：10.3969/j.issn.1672-6731.2011.06.01

Analysis of the predicting factors of recurrent wheezing in infants

Abstract Background Clinically, asthma in children under 5 years old is under estimated because lack of diagnostic criteria. The current study was, therefore, designed to identify the predicting factors for recurrent wheezing in infants. Methods One hundred forty-five infants under 3-year old hospitalized with respiratory diseases were enrolled into this study. Patients were followed up for one-year period after being discharged from the hospital and were, then, divided into recurrent wheezing group and non-recurrent wheezing group based on whether there was recurrent wheezing or not. Wheezing or recurrent wheezing was specifically monitored in addition to blood tests for allergic and respiratory diseases. Results The prevalence of eczema and respiratory syncytial virus (RSV) infection were significantly higher in recurrent wheezing group than in control group (74.2% vs 45.8%; 32.3% vs. 13.3%, respectively, both P < 0.05); the percentage of blood eosinophil and serum eosinophil-derived neurotoxin (EDN) concentration at admission were also higher in recurrent wheezing group than in control group (3.10 ± 2.54% vs. 1.31 ± 1.15%; 68.67 ± 55.05 ng/mL vs. 27. 36 ± 19.51 ng/mL; respectively, both P < 0.001). Multivariate logistic regression analysis on eosinophil count and serum EDN concentration in predicting recurrent wheezing revealed that the eosinophil count showed the lowest sensitivity (51.6%) and highest specificity (90.4%), with the area under the ROC curve (AUC) of 0.752 ± 0.041; and that, in contrast, the serum EDN showed the highest sensitivity (88.7%) and lowest specificity (56.6%), with AUC of 0.795 ± 0.037. Conclusion Combination of eosinophil count and serum EDN measurement may be better to predict the risk of recurrent wheezing in early life of childhood

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.Methods: We constructed a polygenic risk score using a genome wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75 0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.</div