c-Myc Is Required for Maintenance of Glioma Cancer Stem Cells

Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells.Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G(0)/G(1) phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice.These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers

Avalanche susceptibility evaluation of the Kezhayi to Gongnaisi section of the Duku expressway

The Kezhayi to Gongnaisi section of the Duku expressway is predominantly characterized by alpine landforms, with steep terrain cutting that provides conducive conditions for avalanche development. The study on the evaluation of snow avalanche susceptibility in this area is a crucial prerequisite for the safety construction and operation of the Duku expressway. The 149 snow avalanche points were collected by employing remote sensing interpretation and field investigations. Through correlation analysis of these factors, 10 evaluation factors were selected, forming the avalanche evaluation factor system. Subsequently, the non-avalanche points and original avalanche points were extracted using the K-means clustering method and random method to create a sample set. Machine learning techniques, including multilayer perceptron (MLP) and support vector machine (SVM) algorithms, were utilized to assess avalanche susceptibility in the study area. The results show that the sample datasets extracted by the random and K-means clustering methods were used for training, the Kappa coefficient of the R-SVM, R-MLP, K-SVM, and K-MLP models were greater than 0.6. These four sets of models exhibited a high degree of consistency between the predicted results and actual values of the validation dataset. The AUC (area under curve) value trained by MLP increased from 0.762 to 0.983, while the AUC value trained by SVM increased from 0.724 to 0.951. Based on the K-MLP model partition with the highest evaluation accuracy, the snow avalanche development in the research area has a relatively minor impact on the proposed route but may pose a threat to tunnel entrances. This study provides theoretical support and methodological references for the construction, operation and mitigation of sonw avalanche disasters for the Duku expressway

Advance in Pancreatic Cancer Diagnosis and Therapy

Pancreatic carcinoma is the fourth leading cause of cancer death in the word wild. Although the advance in treatment this disease, the 5-years survival rate is still rather low. In the recent year, many new therapy and treatment avenues have been developed for pancreatic cancer. In this chapter, we mainly focus on the following aspect: 1) the treatment modality in pancreatic cancer, including chemotherapy, radiotherapy, and immunotherapy; 2) the mechanism of pancreatic cancer treatment resistance, especially in cancer stem cells and tumor microenvironment; 3) the diagnosis tools in pancreatic cancer, including serum markers, imaging methods and endoscopic ultrasonography. Novel molecular probes based on the nanotechnology in the diagnosis of pancreatic cancer are also discussed

Myocardin Marks the Earliest Cardiac Gene Expression and Plays an Important Role in Heart Development

Myocardin belongs to the SAP domain family of transcription factors and is expressed specifically in cardiac and smooth muscle during embryogenesis and in adulthood. Myocardin functions as a transcriptional coactivator of SRF and is sufficient and necessary for smooth muscle gene expression. However, the in vivo function of myocardin during cardiogenesis is not completely understood. Here we clone myocardin from chick embryonic hearts and show that myocardin protein sequences are highly conserved cross species. Detailed studies of chick myocardin expression reveal that myocardin is expressed in cardiac and smooth muscle lineage during early embryogenesis, similar to that found in mouse. Interestingly, the expression of myocardin in the heart was found enriched in the outflow tract and the sinoatrial segments shortly after the formation of linear heart tube. Such expression pattern is also maintained in later developing embryos, suggesting that myocardin may play a unique role in the formation of those cardiac modules. Similar to its mouse counterpart, chick myocardin is able to activate cardiac and smooth muscle promoter reporter genes and induce smooth muscle gene expression in nonmuscle cells. Ectopic overexpression of myocardin enlarged the embryonic chick heart. Conversely, repression of the endogenous chick myocardin using antisense oligonucleotides or a dominant negative mutant form of myocardin inhibited cardiogenesis. Together, our data place myocardin as one of the earliest cardiac marker genes for cardiogenesis and support the idea that myocardin plays an essential role in cardiac gene expression and cardiogenesis

Presence of qnr gene in Escherichia coli and Klebsiella pneumoniae resistant to ciprofloxacin isolated from pediatric patients in China

<p>Abstract</p> <p>Background</p> <p>Quinolone resistance in <it>Enterobacteriaceae </it>results mainly from mutations in type II DNA topoisomerase genes and/or changes in the expression of outer membrane and efflux pumps. Several recent studies have indicated that plasmid-mediated resistance mechanisms also play a significant role in fluoroquinolone resistance, and its prevalence is increasing worldwide. In China, the presence of the <it>qnr </it>gene in the clinical isolates of <it>Enterobacteriaceae </it>has been reported, but this transmissible quinolone resistance gene has not been detected in strains isolated singly from pediatric patients. Because quinolones associated with a variety of adverse side effects on children, they are not authorized for pediatric use. This study therefore aimed to investigate the presence of the <it>qnr </it>gene in clinical isolates of <it>E. coli </it>and <it>K. pneumoniae </it>from pediatric patients in China.</p> <p>Methods</p> <p>A total 213 of non-repetitive clinical isolates resistant to ciprofloxacin from <it>E. coli </it>and <it>K. pneumoniae </it>were collected from hospitalized patients at five children's hospital in Beijing, Shanghai, Guangzhou, and Chongqing. The isolates were screened for the plasmid-mediated quinolone resistance genes of <it>qnrA</it>, <it>qnrB</it>, and <it>qnrS </it>by PCR. Transferability was examined by conjugation with the sodium azide-resistant <it>E. coli </it>J53. All <it>qnr</it>-positive were analyzed for clonality by enterobacterial repetitive intergenic consensus (ERIC)-PCR.</p> <p>Results</p> <p>The study found that 19 ciprofloxacin-resistant clinical isolates of <it>E. coli </it>and <it>K. pneumoniae </it>were positive for the <it>qnr </it>gene, and most of the <it>qnr </it>positive strains were ESBL producers. Conjugation experiments showed that quinolone resitance could be transferred to recipients. Apart from this, different DNA banding patterns were obtained by ERIC-PCR from positive strains, which means that most of them were not clonally related.</p> <p>Conclusion</p> <p>This report on transferable fluoroquinolone resistance due to the <it>qnr </it>gene among <it>E. coli </it>and <it>K. pneumoniae </it>strains indicated that plasmid-mediated quinolone resistance has emerged in pediatric patients in China.</p

The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation

Understanding the molecular mechanisms that regulate cellular proliferation and differentiation is a central theme of developmental biology. MicroRNAs (miRNAs) are a class of regulatory RNAs of ~22 nucleotides that post-transcriptionally regulate gene expression1,2. Increasing evidence points to the potential role of miRNAs in various biological processes3–8. Here we show that miRNA-1 (miR-1) and miRNA-133 (miR-133), which are clustered on the same chromosomal loci, are transcribed together in a tissue-specific manner during development. miR-1 and miR-133 have distinct roles in modulating skeletal muscle proliferation and differentiation in cultured myoblasts in vitro and in Xenopus laevis embryos in vivo. miR-1 promotes myogenesis by targeting histone deacetylase 4 (HDAC4), a transcriptional repressor of muscle gene expression. By contrast, miR-133 enhances myoblast proliferation by repressing serum response factor (SRF). Our results show that two mature miRNAs, derived from the same miRNA polycistron and transcribed together, can carry out distinct biological functions. Together, our studies suggest a molecular mechanism in which miRNAs participate in transcriptional circuits that control skeletal muscle gene expression and embryonic development

Gut microbiome mediates the protective effects of exercise after myocardial infarction

Background: Gut microbiota plays important roles in health maintenance and diseases. Physical exercise has been demonstrated to be able to modulate gut microbiota. However, the potential role of gut microbiome in exercise protection to myocardial infarction (MI) remains unclear. Results: Here, we discovered exercise training ameliorated cardiac dysfunction and changed gut microbial richness and community structure post-MI. Moreover, gut microbiota pre-depletion abolished the protective effects of exercise training in MI mice. Furthermore, mice receiving microbiota transplants from exercised MI mice had better cardiac function compared to mice receiving microbiota transplants from non-exercised MI mice. Mechanistically, we analyzed metabolomics in fecal samples from exercised mice post-MI and identified 3-Hydroxyphenylacetic acid (3-HPA) and 4-Hydroxybenzoic acid (4-HBA), which could be applied individually to protect cardiac dysfunction post-MI and apoptosis through NRF2. Conclusions: Together, our study provides new insights into the role of gut microbiome in exercise protection to MI, offers opportunities to modulate cardiovascular diseases by exercise, microbiome and gut microbiota-derived 3-HPA and 4-HBA. [MediaObject not available: see fulltext.]

Purine synthesis promotes maintenance of brain tumor initiating cells in glioma

Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy

Epidemiology of invasive group B streptococcal disease in infants from urban area of South China, 2011–2014

YesBackground: Group B Streptococcus (GBS) is a leading cause of morbidity and mortality in infants in both developed and developing countries. To our knowledge, only a few studies have been reported the clinical features, treatment and outcomes of the GBS disease in China. The severity of neonatal GBS disease in China remains unclear. Population-based surveillance in China is therefore required. Methods: We retrospectively collected data of <3 months old infants with culture-positive GBS in sterile samples from three large urban tertiary hospitals in South China from Jan 2011 to Dec 2014. The GBS isolates and their antibiotic susceptibility were routinely identified in clinical laboratories in participating hospitals. Serotyping and multi-locus sequence typing (MLST) were also conducted for further analysis of the neonatal GBS disease. Results: Total 70 cases of culture-confirmed invasive GBS infection were identified from 127,206 live births born in studying hospitals, giving an overall incidence of 0.55 per 1000 live births (95% confidence interval [CI] 0.44–0.69). They consisted of 49 with early-onset disease (EOD, 0.39 per 1000 live births (95% CI 0.29–0.51)) and 21 with late-onset disease (LOD, 0.17 per 1000 live births (95% CI 0.11–0.25)). The incidence of EOD increased significantly over the studying period. Five infants (4 EOD and 1 LOD) died before discharge giving a mortality rate of 7.1% and five infants (7.1%, 2 EOD and 3 LOD) had neurological sequelae. Within 68 GBS isolates from GBS cases who born in the studying hospitals or elsewhere, serotype III accounted for 77.9%, followed by Ib (14.7%), V (4.4%), and Ia (2.9%). MLST analysis revealed the presence of 13 different sequence types among the 68 GBS isolates and ST-17 was the most frequent sequence type (63.2%). All isolates were susceptible to penicillin, ceftriaxone, vancomycin and linezolid, while 57.4% and 51.5% were resistant to erythromycin and clindamycin, respectively. Conclusions: This study gains the insight into the spectrum of GBS infection in south China which will facilitate the development of the guidance for reasonable antibiotics usage and will provide evidence for the implementation of potential GBS vaccines in the future.Supported by medical and health science and technology projects of Health and Family Planning Commission of Guangzhou Municipality (grant number 20151A010034) and Guangdong provincial science and technology planning projects (grant number 2014A020212520)

Targeting A20 Decreases Glioma Stem Cell Survival and Tumor Growth

The A20 protein is a known inhibitor of apoptosis that here is shown to be a novel cancer stem cell-promoting factor associated with poor glioma patient survival