Inhibition of nuclear factor-kappa B differentially affects thyroid cancer cell growth, apoptosis, and invasion

<p>Abstract</p> <p>Background</p> <p>Nuclear factor-κB (NF-κB) is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-κB signaling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-κB signaling in thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-κB in advanced thyroid cancer cell lines.</p> <p>Results</p> <p>Three pharmacologic inhibitors of NF-κB differentially inhibited growth in a panel of advanced thyroid cancer cell lines, suggesting that these NF-κB inhibitors may have off-target effects. We therefore used a selective genetic approach to inhibit NF-κB signaling by overexpression of a dominant-negative IκBα (mIκBα). These studies revealed decreased cell growth in only one of five thyroid cancer cell lines (8505C), which occurred through a block in the S-G2/M transition. Resistance to TNFα-induced apoptosis was observed in all cell lines, likely through an NF-κB-dependent mechanism. Inhibition of NF-κB by mIκBα sensitized a subset of cell lines to TNFα-induced apoptosis. Sensitive cell lines displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway, defining a potential mechanism of response. Finally, NF-κB inhibition by mIκBα expression differentially reduced thyroid cancer cell invasion in these thyroid cancer cell lines. Sensitive cell lines demonstrated approximately a two-fold decrease in invasion, which was associated with differential expression of MMP-13. MMP-9 was reduced by mIκBα expression in all cell lines tested.</p> <p>Conclusions</p> <p>These data indicate that selective inhibition of NF-κB represents an attractive therapeutic target for the treatment of advanced thyroid. However, it is apparent that global regulation of thyroid cancer cell growth and invasion is not achieved by NF-κB signaling alone. Instead, our findings suggest that other important molecular processes play a critical role in defining the extent of NF-κB function within cancer cells.</p

The role of the paraeducator in the general physical education environment

The use of paraeducators has increased as a main mechanism to include more students with disabilities in multiple settings in the public schools in the U.S. Research has examined the use of paraeducators in typical classroom settings but little is known about their role in physical education. Although the utilization of paraeducators is intended to be a supportive service delivery option, many concerns and challenges have resulted. The purpose of this study was to explore the particular realities of paraeducators in general physical education as experienced by the teachers and the paraeducators. The paraeducator role in physical education, standards surrounding the role, supervision, and training were all examined. Data were collected from questionnaires, interviews, and observations. Results indicate concern about the clarity of the role, the supervision and training of both paraeducators and teachers in physical education

The Intertwined Renewable Energy–Water–Environment (REWE) Nexus Challenges and Opportunities: A Case Study of California

In our built environment, societal production of energy and clean water is inextricably linked to the natural resources from which they are derived. Acknowledgement and consideration of the coupling of energy, water, and the environment (the energy–water–environment nexus) will be critical to a sustainable future. This is particularly true as we transition away from historical energy sources (e.g., coal, petroleum, natural gas) and into the widespread adaptation of renewable energy (RE) sources (e.g., solar, wind, geothermal, hydro, bioenergy) as a strategy to decrease greenhouse gas emissions and consequently slow global climate change. This transition is fraught with both challenges and opportunities at the county, state, national, and international levels, as addressing future societal needs with respect to energy and water, and the environment requires recognition of their interdependence and development of new technologies and societal practices. In this study, the focus is on the RE–water–environment (REWE) nexus. In California, the REWE nexus is becoming increasingly important in achieving 100% clean electricity from eligible RE and zero-carbon resources by 2045 and in the face of climate change and population and economic growth. In this context, California’s RE deployment and renewable electrical generation, its RE legislative information, REWE nexus, and intertwined REWE nexus challenges and opportunities in California (e.g., administrative–legal, technology development, digitalization, and end-of-life RE waste) are comprehensively discussed to identify the knowledge gaps in this nexus and solutions

Identification of microRNAs expressed in two mosquito vectors, Aedes albopictus and Culex quinquefasciatus

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression in a variety of organisms, including insects, vertebrates, and plants. miRNAs play important roles in cell development and differentiation as well as in the cellular response to stress and infection. To date, there are limited reports of miRNA identification in mosquitoes, insects that act as essential vectors for the transmission of many human pathogens, including flaviviruses. West Nile virus (WNV) and dengue virus, members of the <it>Flaviviridae </it>family, are primarily transmitted by <it>Aedes </it>and <it>Culex </it>mosquitoes. Using high-throughput deep sequencing, we examined the miRNA repertoire in <it>Ae. albopictus </it>cells and <it>Cx. quinquefasciatus </it>mosquitoes.</p> <p>Results</p> <p>We identified a total of 65 miRNAs in the <it>Ae. albopictus </it>C7/10 cell line and 77 miRNAs in <it>Cx. quinquefasciatus </it>mosquitoes, the majority of which are conserved in other insects such as <it>Drosophila melanogaster </it>and <it>Anopheles gambiae</it>. The most highly expressed miRNA in both mosquito species was miR-184, a miRNA conserved from insects to vertebrates. Several previously reported <it>Anopheles </it>miRNAs, including miR-1890 and miR-1891, were also found in <it>Culex </it>and <it>Aedes</it>, and appear to be restricted to mosquitoes. We identified seven novel miRNAs, arising from nine different precursors, in C7/10 cells and <it>Cx. quinquefasciatus </it>mosquitoes, two of which have predicted orthologs in <it>An. gambiae</it>. Several of these novel miRNAs reside within a ~350 nt long cluster present in both <it>Aedes </it>and <it>Culex</it>. miRNA expression was confirmed by primer extension analysis. To determine whether flavivirus infection affects miRNA expression, we infected female <it>Culex </it>mosquitoes with WNV. Two miRNAs, miR-92 and miR-989, showed significant changes in expression levels following WNV infection.</p> <p>Conclusions</p> <p><it>Aedes </it>and <it>Culex </it>mosquitoes are important flavivirus vectors. Recent advances in both mosquito genomics and high-throughput sequencing technologies enabled us to interrogate the miRNA profile in these two species. Here, we provide evidence for over 60 conserved and seven novel mosquito miRNAs, expanding upon our current understanding of insect miRNAs. Undoubtedly, some of the miRNAs identified will have roles not only in mosquito development, but also in mediating viral infection in the mosquito host.</p

Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a clinical practice guideline

BACKGROUND: Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. A clinical practice guideline was developed based on a systematic review investigating neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer. METHODS: A systematic review with meta-analysis was developed and clinical recommendations were drafted. External review of the practice guideline report by practitioners in Ontario, Canada was obtained through a mailed survey, and incorporated. Final approval of the practice guideline was obtained from the Practice Guidelines Coordinating Committee. RESULTS: The systematic review was developed and recommendations were drafted, and the report was mailed to Ontario practitioners for external review. Ninety percent of respondents agreed with both the evidence summary and the draft recommendations, while only 69% approved of the draft recommendations as a practice guideline. Based on the external review, a revised document was created. The revised practice guideline was submitted to the Practice Guidelines Coordinating Committee for review. All 11 members of the PGCC returned ballots. Eight PGCC members approved the practice guideline report as written and three members approved the guideline conditional on specific concerns being addressed. After these recommended changes were made, the final practice guideline report was approved. CONCLUSION: In consideration of the systematic review, external review, and subsequent Practice Guidelines Coordinating Committee revision suggestions, and final approval, the Gastrointestinal Cancer Disease Site Group recommends the following: For adult patients with resectable thoracic esophageal cancer for whom surgery is considered appropriate, surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice

Behavior change interventions: the potential of ontologies for advancing science and practice

A central goal of behavioral medicine is the creation of evidence-based interventions for promoting behavior change. Scientific knowledge about behavior change could be more effectively accumulated using "ontologies." In information science, an ontology is a systematic method for articulating a "controlled vocabulary" of agreed-upon terms and their inter-relationships. It involves three core elements: (1) a controlled vocabulary specifying and defining existing classes; (2) specification of the inter-relationships between classes; and (3) codification in a computer-readable format to enable knowledge generation, organization, reuse, integration, and analysis. This paper introduces ontologies, provides a review of current efforts to create ontologies related to behavior change interventions and suggests future work. This paper was written by behavioral medicine and information science experts and was developed in partnership between the Society of Behavioral Medicine's Technology Special Interest Group (SIG) and the Theories and Techniques of Behavior Change Interventions SIG. In recent years significant progress has been made in the foundational work needed to develop ontologies of behavior change. Ontologies of behavior change could facilitate a transformation of behavioral science from a field in which data from different experiments are siloed into one in which data across experiments could be compared and/or integrated. This could facilitate new approaches to hypothesis generation and knowledge discovery in behavioral science

Variable responses of human and non-human primate gut microbiomes to a Western diet

BACKGROUND: The human gut microbiota interacts closely with human diet and physiology. To better understand the mechanisms behind this relationship, gut microbiome research relies on complementing human studies with manipulations of animal models, including non-human primates. However, due to unique aspects of human diet and physiology, it is likely that host-gut microbe interactions operate differently in humans and non-human primates. RESULTS: Here, we show that the human microbiome reacts differently to a high-protein, high-fat Western diet than that of a model primate, the African green monkey, or vervet (Chlorocebus aethiops sabaeus). Specifically, humans exhibit increased relative abundance of Firmicutes and reduced relative abundance of Prevotella on a Western diet while vervets show the opposite pattern. Predictive metagenomics demonstrate an increased relative abundance of genes associated with carbohydrate metabolism in the microbiome of only humans consuming a Western diet. CONCLUSIONS: These results suggest that the human gut microbiota has unique properties that are a result of changes in human diet and physiology across evolution or that may have contributed to the evolution of human physiology. Therefore, the role of animal models for understanding the relationship between the human gut microbiota and host metabolism must be re-focused.P40 OD010965 - NIH HHS; P40 RR019963 - NCRR NIH HHS; P51 OD011132 - NIH HHS; R01 RR016300 - NCRR NIH HHS; 5R01RR016300 - NCRR NIH HH

Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals.

Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells

Control of telomere length by a trimming mechanism that involves generation of t-circles

Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric circles (t-circles). Telomeric DNA was observed in promyelocytic leukemia bodies, but no intertelomeric copying or telomere exchange events were identified, and there was no increase in telomere dysfunction-induced foci. These data indicate that human cells possess a mechanism to negatively regulate telomere length by trimming telomeric DNA from the chromosome ends, most likely by t-loop resolution to form t-circles. Additionally, these results indicate that some phenotypic characteristics attributed to alternative lengthening of telomeres (ALT) result from increased mean telomere length, rather than from the ALT mechanism itself