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Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3′ UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.

Glioblastoma (GBM) is one of the most deadly cancers and poorly responses to chemotherapies, such as temozolomide (TMZ). Dysregulation of intrinsic signaling pathways in cancer cells are often resulted by dysregulated tumor suppressive microRNAs (miRNAs). Previously, we found miR-138 as one of tumor suppressive miRNAs that were significantly down-regulated in GBM. In this study, we demonstrated that ectopic over-expression of miR-138 sensitizes GBM cells to the treatment of TMZ and increased apoptotic cell death. Mechanistically, miR-138 directly repressed the expression of Survivin, an anti-apoptotic protein, to enhance caspase-induced apoptosis upon TMZ treatment. Using an intracranial GBM xenograft mice model, we also showed that combination of miR-138 with TMZ increases survival rates of the mice compared to the control mice treated with TMZ alone. This study provides strong preclinical evidence of the therapeutic benefit from restoration of miR-138 to sensitize the GBM tumor to conventional chemotherapy.

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including ImlygicTM, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.

This dissertation examined the role of maternal input in word order acquisition of Mandarin-speaking children from the one-word to multi-word stages. Four questions about the role of maternal input were addressed: frequency effects, age-related changes, utterance type effects, and verb diversity effects. Predictions for each question were made based on the generativist and constructivist accounts. Spontaneous speech of 40 Mandarin-speaking mother-child dyads selected from CHILDES Zhou corpus, with 10 dyads in each of four age groups: 14-, 20-, 26-, and 32-month-olds, were coded for word order, utterance type, and verb type. Both maternal and child distributions were compared for analyses. Mothers across all four age groups produced a variety of word orders and constructions in their speech. Frequency effects were found in most child word order uses but not in the Ba and different multiple-verb constructions. Most child word order uses reached adult levels of frequency at either 26 or 32 months. Maternal speech did not show age-related changes as child production grew from one word to multi words. No significant relationship was found between mothers and children in most word orders. Utterance type effects were not found because mothers used different word orders for different utterance types while child production did not reflect this tendency. The distribution of verb diversity within maternal and child word orders shared a similar pattern. Word orders with greater verb diversity tended to be acquired earlier. The findings that frequency effects and verb diversity effects were found in early word order acquisition support both generativist and constructivist claims. The lack of age-related changes and utterance type effects in maternal word order uses is contrary to the constructivist view. Although maternal input (e.g., frequency and verb diversity) may play a role in acquisition of Mandarin word order, there are possible influences other than input. These influences may include child linguistic competence, linguistic complexity of constructions being learned, and semantic/pragmatic factors that constrain the choice of word order.

In the United States, more than 780,000 people annually suffer a new or recurrent stroke, which has emerged as one of the leading causes of severe and long-term disability (American Heart Association, 2008). This health crisis refl ects considerable human suffering as well as an enormous economic burden. According to the American Heart Association (2008), the health care costs of caring for stroke victims is estimated to cost about $65.5 billion in 2008 alone. The poststroke disability manifests itself in functional impairments such as diffi culty in handling multiple activities of daily living (e.g., dressing, preparing and eating a meal, bathing, etc.). Quality of life tends to be severely impacted by stroke (Jonsson, Lindgren, Hallstrom, Norrving, & Lindgren, 2005; Mayo, Wood-Dauphinee, Cote, Durcan, & Carlton, 2002).

Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island-dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations.

Tsunami hazards have been observed to cause soil instability resulting in substantial damage to coastal infrastructure. Studying this problem is difficult owing to tsunamis’ transient, non-uniform and large loading characteristics. To create realistic tsunami conditions in a laboratory environment, we control the body force using a centrifuge facility. With an apparatus specifically designed to mimic tsunami inundation in a scaled-down model, we examine the effects of an embedded impermeable layer on soil instability: the impermeable layer represents a man-made pavement, a building foundation, a clay layer and alike. The results reveal that the effective vertical soil stress is substantially reduced at the underside of the impermeable layer. During the sudden runup flow, this instability is caused by a combination of temporal dislocation of soil grains and an increase in pore pressure under the impermeable layer. The instability during the drawdown phase is caused by the development of excess pore-pressure gradients, and the presence of the impermeable layer substantially enhances the pressure gradients leading to greater soil instability. The laboratory results demonstrate that the presence of an impermeable layer plays an important role in weakening the soil resistance under tsunami-like rapid runup and drawdown processes.

Objectives Advanced tools and resources are needed to efficiently and sustainably produce food for an increasing world population in the context of variable environmental conditions. The maize genomes to fields (G2F) initiative is a multi-institutional initiative effort that seeks to approach this challenge by developing a flexible and distributed infrastructure addressing emerging problems. G2F has generated large-scale phenotypic, genotypic, and environmental datasets using publicly available inbred lines and hybrids evaluated through a network of collaborators that are part of the G2F’s genotype-by-environment (G × E) project. This report covers the public release of datasets for 2014–2017. Data description Datasets include inbred genotypic information; phenotypic, climatic, and soil measurements and metadata information for each testing location across years. For a subset of inbreds in 2014 and 2015, yield component phenotypes were quantified by image analysis. Data released are accompanied by README descriptions. For genotypic and phenotypic data, both raw data and a version without outliers are reported. For climatic data, a version calibrated to the nearest airport weather station and a version without outliers are reported. The 2014 and 2015 datasets are updated versions from the previously released files [ 1 ] while 2016 and 2017 datasets are newly available to the public.

Objectives Crop improvement relies on analysis of phenotypic, genotypic, and environmental data. Given large, well-integrated, multi-year datasets, diverse queries can be made: Which lines perform best in hot, dry environments? Which alleles of specific genes are required for optimal performance in each environment? Such datasets also can be leveraged to predict cultivar performance, even in uncharacterized environments. The maize Genomes to Fields (G2F) Initiative is a multi-institutional organization of scientists working to generate and analyze such datasets from existing, publicly available inbred lines and hybrids. G2F’s genotype by environment project has released 2014 and 2015 datasets to the public, with 2016 and 2017 collected and soon to be made available. Data description Datasets include DNA sequences; traditional phenotype descriptions, as well as detailed ear, cob, and kernel phenotypes quantified by image analysis; weather station measurements; and soil characterizations by site. Data are released as comma separated value spreadsheets accompanied by extensive README text descriptions. For genotypic and phenotypic data, both raw data and a version with outliers removed are reported. For weather data, two versions are reported: a full dataset calibrated against nearby National Weather Service sites and a second calibrated set with outliers and apparent artifacts removed.

ObjectiveThe Appropriate Use Criteria (AUC) has been used to identify individuals who are likely to benefit from percutaneous coronary intervention (PCI) for stable ischaemic heart disease. However, whether physicians reliably grade PCI appropriateness and whether AUC categories stratify symptomatic improvement in real-world practice are unclear.MethodsPatient-reported outcomes measures (PROMs) for angina (Seattle Angina Questionnaire (SAQ-7)), dyspnoea (Rose Dyspnea Scale (RDS)) and depression (Patient Health Questionnaire-2 (PHQ-2)) were collected on patients undergoing elective coronary angiography at an academic medical centre. Retrospectively, two physicians independently determined PCI appropriateness by the AUC criteria.ResultsInter-rater agreement on appropriateness was moderate (κ=0.48, 95% CI 0.32 to 0.63). Of PCI procedures evaluated, 57 (47.1%) were appropriate (A-PCI), 62 (51.2%) were maybe appropriate (MA-PCI) and 2 (1.6%) were rarely appropriate. At baseline, A-PCI compared with MA-PCI patients had worse RDS scores (2.0 vs 1.2, p=0.01). At 30 days, the change in SAQ-7 summary score was similar between groups (A-PCI vs MA-PCI, +27.1 vs +20.7, p=0.11). The mean change in RDS score was greater in A-PCI than MA-PCI (−1.0 vs −0.5, p for group by time interaction=0.03). PHQ-2 scores were similar and did not improve at 30 days.ConclusionIn patients undergoing PCI with PROMs collected before and 30 days after PCI, similar improvements in angina were observed regardless of appropriateness. Inter-rater agreement on PCI appropriateness was only moderate. Use of PROMs may improve reliability of physician assessments of PCI appropriateness.