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JNK signaling plays a critical role in both tumor promotion and tumor suppression. Here, we identified clustered microRNAs (miRNAs) miR-306 and miR-79 as novel tumor-suppressor miRNAs that specifically eliminate JNK-activated tumors in Drosophila. While showing only a slight effect on normal tissue growth, miR-306 and miR-79 strongly suppressed growth of multiple tumor models, including malignant tumors caused by Ras activation and cell polarity defects. Mechanistically, these miRNAs commonly target the mRNA of an E3 ubiquitin ligase ring finger protein 146 (RNF146). We found that RNF146 promotes degradation of tankyrase (Tnks), an ADP-ribose polymerase that promotes JNK activation in a noncanonical manner. Thus, downregulation of RNF146 by miR-306 and miR-79 leads to hyper-enhancement of JNK activation. Our data show that, while JNK activity is essential for tumor growth, elevation of miR-306 or miR-79 overactivate JNK signaling to the lethal level via noncanonical JNK pathway and thus eliminate tumors, providing a new miRNA-based strategy against cancer.

Breast Ultrasound (BUS) imaging has been recognized as an essential imaging modality for breast masses classification in China. Current deep learning (DL) based solutions for BUS classification seek to feed ultrasound (US) images into deep convolutional neural networks (CNNs), to learn a hierarchical combination of features for discriminating malignant and benign masses. One existing problem in current DL-based BUS classification was the lack of spatial and channel-wise features weighting, which inevitably allow interference from redundant features and low sensitivity. In this study, we aim to incorporate the instructive information provided by breast imaging reporting and data system (BI-RADS) within DL-based classification. A novel DL-based BI-RADS Vector-Attention Network (BVA Net) that trains with both texture information and decoded information from BI-RADS stratifications was proposed for the task. Three baseline models, pre-trained DenseNet-121, ResNet-50 and Residual-Attention Network (RA Net) were included for comparison. Experiments were conducted on a large scale private main dataset and two public datasets, UDIAT and BUSI. On the main dataset, BVA Net outperformed other models, in terms of AUC (area under the receiver operating curve, 0.908), ACC (accuracy, 0.865), sensitivity (0.812) and precision (0.795). BVA Net also achieved the high AUC (0.87 and 0.882) and ACC (0.859 and 0.843), on UDIAT and BUSI. Moreover, we proposed a method that integrates both BVA Net binary classification and BI-RADS stratification estimation, called integrated classification. The introduction of integrated classification helped improving the overall sensitivity while maintaining a high specificity.

In recent years, the problem of youth unemployment in China has become a great concern. Unemployed young people often find themselves under tremendous stress and vulnerable to sleep problems. The link between perceived stress and insomnia has been widely documented, but the potential mechanisms underlying this relationship have not been thoroughly revealed. The objective of this study was to examine the underlying mechanisms linking perceived stress to insomnia through testing the mediating effects of emotional dysregulation and time structure. Through a multiple-stage convenience sampling, 511 unemployed young people (38.6% women; mean age = 21.51; SD = 2.22) were measured using the 10-item Perceived Stress Scale (PSS-10), Insomnia Severity Index (ISI), 16-item Difficulties in Emotion Regulation Scale (DERS-16), and Time Structure Questionnaire (TSQ). Based on the statistical description of the sample, chi-squared tests, bivariate correlation analyses, and mediation analyses were performed. The study indicated that 53.0% (95% CI: 48.7–57.4%) of the participants reported probable insomnia, and both insomnia and perceived stress demonstrated strong associations with emotional dysregulation and time structure, which served as partial mediators between perceived stress and insomnia symptoms according to mediation analyses. Path analysis further revealed that, after controlling for age and gender, emotional dysregulation and time structure accounted for 31.8 and 17.6% of the effect of perceived stress on insomnia, respectively. This study provides empirical support for the association among perceived stress, emotional dysregulation, time structure, and insomnia symptoms. To improve the sleep quality and general wellbeing of unemployed young people, emotional dysregulation and time structure must be taken into consideration.

Evidence is limited regarding whether ambient monitoring can properly represent personal ozone exposure. We conducted a longitudinal panel study to measure personal exposure to ozone using real-time personal ozone monitors. Corresponding ambient ozone concentrations and possible influencing factors (meteorological conditions and activity patterns) were also collected. We used linear mixed-effect models to analyze personal-ambient ozone concentration associations and possible influencing factors. Ambient ozone concentrations were around two to three times higher than personal ozone (43.1 μg/m3 on average) and their correlations were weak with small slopes (0.35) and marginal R square (RM2) values (0.24). Larger RM2 values were found under high temperature (>29.5 °C), low humidity (4 h) and for individuals spent longer time outdoors (>0.6 h). In final model, personal ozone exposure was positively associated with ambient concentrations and ventilation conditions, but inversely correlated with ambient temperature and humidity. The models explained >50% of personal ozone concentration variabilities. Our results highlight that ambient ozone concentration alone is not a suitable surrogate for individual exposure assessment. Meteorological conditions (temperature and humidity) and activity patterns (windows opening and outdoor activities) that affecting personal ozone exposure should be taken into account. Keywords: Ozone, Personal exposure, Ambient concentrations, Influencing factors, Panel study

To evaluate the satisfaction, concerns, and preference for Traditional Chinese Medicine (TCM) drugs among guardians of children with acute bronchiolitis, assess the agreement between satisfaction and preference, and explore the factors associated with satisfaction.A cross-sectional study was conducted in three main tertiary hospitals in Kunming, China, from September 2012 to July 2013 by structured questionnaire interviews. The characteristics of children and their guardians and guardians' satisfaction with and preference for TCM drugs were collected and analyzed by using chi-square or Fisher exact test. The agreement of satisfaction and preference was assessed by κ and prevalence-adjusted κ coefficients. Multiple logistic regression was used to identify factors associated with satisfaction.A total of 286 guardians were enrolled in the study. Most children (97.6%) were younger than age 2 years. In total, the rates of satisfaction and preference for TCM drugs were 75.5% and 73.1%, respectively, and preference and satisfaction levels did not significantly differ between TCM and non-TCM hospitals. Guardians with higher socioeconomic status were more satisfied with TCM drugs, and the most common reason for preference for TCM drugs was that they had less toxicity or fewer adverse effects. Guardians were concerned most about safety and least concerned about cost. The agreement between satisfaction and preference was moderate in general (prevalence-adjusted κ=0.42).Three fourths of the Chinese guardians of children with acute bronchiolitis were satisfied with and preferred the TCM drugs. Moderate agreement between satisfaction and preference was shown.

Transforming growth factor beta (TGF-beta) signaling pathways regulate a wide variety of cellular processes including cell proliferation, differentiation, extracellular matrix deposition, development, and apoptosis. TGF-beta type-I receptor (TbetaRI) is the major receptor that triggers several signaling events by activating downstream targets such as the Smad proteins. The intracellular kinase domain of TbetaRI is essential for its function. In this study, we have identified a short phospho-Smad peptide, pSmad3(-3), KVLTQMGSPSIRCSS(PO4)VS as a substrate of TbetaRI kinase for in vitro kinase assays. This peptide is uniquely phosphorylated by TbetaRI kinase at the C-terminal serine residue, the phosphorylation site of its parent Smad protein in vivo. Specificity analysis demonstrated that the peptide is phosphorylated by only TbetaRI and not TGF-beta type-II receptor kinase, indicating that the peptide is a physiologically relevant substrate suitable for kinetic analysis and screening of TbetaRI kinase inhibitors. Utilizing pSmad3(-3) as a substrate, we have shown that novel pyrazole compounds are potent inhibitors of TbetaRI kinase with K(i) value as low as 15 nM. Kinetic analysis revealed that these pyrazoles act through the ATP-binding site and are typical ATP competitive inhibitors with tight binding kinetics. More importantly, these compounds were shown to inhibit TGF-beta-induced Smad2 phosphorylation in vivo in NMuMg mammary epithelial cells with potency equivalent to the inhibitory activity in the in vitro kinase assay. Cellular selectivity analysis demonstrated that these pyrazoles are capable of inhibiting activin signaling but not bone morphogenic protein or platelet-derived growth factor signal transduction pathways. Further functional analysis revealed that pyrazoles are capable of blocking the TGF-beta-induced epithelial-mesenchymal transition in NMuMg cells, a process involved in the progression of cancer, fibrosis, and other human diseases. These pyrazoles provide a foundation for future development of potent and selective TbetaRI kinase inhibitors to treat human disease.

To investigate the effect of cesarean delivery and other predisposing factors of respiratory syncytial virus (RSV)-positive acute bronchiolitis in children.The case-control study was conducted in three main tertiary hospitals in Kunming, China between September 2012 and July 2013. Children with first episode of wheezing diagnosed as bronchiolitis and testedfor RSV were included RSV was detected by real-time reverse transcription polymerase chain reaction. Mode ofdelivery and characteristics of children, parents, and household were interviewed and analyzed with RSV-positive status by multiple logistic regression.Of 265 children, RSV-positive was found in 75.5%, and the majority of children (83.3%) were younger than 12 months. Compared to vaginal delivery, the odds of RSV-positive detection were double in children born by elective cesarean delivery (adjusted odds ratio 2.32; 95% confidence interval 1.19-4.52). Children aged less than 6 months, born in the rainy season, having maternal history of asthma and living in family that smoked more than 20 cigarettes per day were more likely to be RSV-positive.Children born by elective cesarean delivery increased the risk of RSV-positive acute bronchiolitis after adjusting for age, birth season, maternal asthma, and family smoking status.

Laggera pterodonta, a traditional Chinese medicine, has been commonly used in respiratory tract infections for more than hundreds of years without any randomized controlled trials to evaluate its efficacy and safety.To evaluate the efficacy and safety of Laggera pterodonta in hospitalized children aged 3-24 months with acute bronchiolitis.A double-blind, randomized-controlled trial was conducted in three tertiary hospitals of Kunming, China. A total of 133 acute bronchiolitis children with an initial episode of wheezing were randomly assigned to a control mixture or Laggera pterodonta mixture. All recruited patients were given three doses of the mixture every 24 h for 5 days. Clinical symptoms and responses including adverse events in both groups were assessed and laboratory tests were done at enrolment and then after 120 h. Analysis was performed based on an intention-to-treat principle.Significantly more hospitalized children fulfilled the discharge criteria at 96 h and 120 h in the Laggera pterodonta mixture group compared to the control group (97% vs 75.8% P 0.001 and 98.5% vs 89.4% P = 0.03), respectively. Better responses on clinical severity score, respiratory rate, oxygen saturation, wheezing and heart rate were also detected in the Laggera pterodonta mixture group along with lower white blood cell count, platelet count and aspartate aminotransferase. Vomiting and diarrhea were more common in the control group.Laggera pterodonta mixture is effective and safe to be prescribed in hospitalized children with acute bronchiolitis.

Evaluate the clinical competency in detection and management complicated pneumonia, diarrhea, and measles cases of trainees who were village doctors in Puer city of Yunnan province, China.One hundred fifty four village doctors working in the border areas were trainedfor 5-day Integrated Management of Childhood Illness (IMCI) training, which was adapted to World Health Organization (WHO) guidelines. Pre- and post-training assessment based on a modified WHO package was carried out.Statistically significant improvements in almost allperformances were observed. However, the level of post-training achievement was still low. Correct classifications of severe pneumonia, measles, and diarrhea were found in 63.0% 54.3% and 83.5%, respectively in the post-training periodThe training package needs to be further strengthened.

Background Under-5-years child mortality remains high in rural China. Integrated management of childhood illness (IMCI) was introduced to China in 1998, but only a few rural areas have been included. This study aimed at assessing the current situation of the health system of rural health care and evaluating the clinical competency of village doctors in management of childhood illnesses prior to implementing IMCI programme in remote border rural areas. Methods The study was carried out in the border areas of Puer prefecture of Yunnan province. There were 182 village doctors in the list of the health bureau in these border areas. Of these, 154 (84.6%) were recruited into the study. The local health system components were investigated using a qualitative approach and analyzed with triangulation of information from different sources. The clinical component was assessed objectively and quantitatively presented using descriptive statistics. Results The study found that the New Rural Cooperative Medical Scheme (NRCMS) coordinated the health insurance system and the provider service through 3 tiers: village doctor, township and county hospitals. The 30 RMB per person per year premium did not cover the referral cost, and thereby decreased the number of referrals. In contrast to available treatment facilities and drug supply, the level of basic medical education of village doctors and township doctors was low. Discontent among village doctors was common, especially concerning low rates of return from the service, exceptions being procedures such as injections, which in fact may create moral hazards to the patients. Direct observation on the assessment and management of paediatric patients by village doctors revealed inadequate history taking and physical examination, inability to detect potentially serious complications, overprescription of injection and antibiotics, and underprescription of oral rehydration salts and poor quality of counseling. Conclusion There is a need to improve health finance and clinical competency of the village doctors in the study area.

The multidrug resistance-associated protein 1 (ABCC1) gene from human (hMRP1), dog (canMRP1), and mouse (muMRP1) all encode proteins that efficiently transport the endogenous MRP1 substrate glutathione-S-leukotriene C(4) and confer resistance to anticancer agents, including vincristine and etoposide. hMRP1 also confers resistance to anthracyclines, whereas this is not true of canMRP1 or muMRP1. To determine whether MRP1 from another animal species used in toxicological studies would be more functionally similar to hMRP1, we cloned and characterized two alleles of the MRP1 homologue from the cynomolgus monkey Macaca fascicularis (monMRP1). The monMRP1 cDNAs encode proteins of 1531 residues that are 98, 90, and 88% identical to hMRP1, canMRP1, and muMRP1, respectively. Stable overexpression of both monMRP1 alleles and hMRP1 in transformed human embryonic kidney cells was achieved using an episomal expression vector. Transporters encoded by both monMRP1 alleles were functionally very similar to hMRP1. monMRP1 conferred an increased resistance to vincristine and etoposide and transported glutathione-S-leukotriene C(4) into membrane vesicles. In addition, MRP1-mediated drug resistance was effectively reversed in monMRP1 and hMRP1 transfectants by LY402913, a new MRP1-selective inhibitor in the class of tricyclic isoxazoles. However, monMRP1 transporters conferred a reduced level of resistance to the anthracyclines doxorubicin, daunorubicin, and epirubicin relative to hMRP1, although resistance levels were significant relative to vector control cells. These functional differences between human and monkey MRP1 transporters will need to be considered when designing pharmacokinetic and toxicological studies for the preclinical evaluation of MRP1 modulators.