A call for the aggressive treatment of oligometastatic and oligo-recurrent non-small cell lung cancer.

Metastatic non-small cell lung cancer (NSCLC) carries a dismal prognosis. Clinical evidence suggests the existence of an intermediate, or oligometastatic, state when metastases are limited in number and/or location. In addition, following initial curative therapy, many patients present with limited metastatic disease, or oligo-recurrence. Metastasis-directed, anti-cancer therapies may benefit these patients. A growing evidence-base supports the use of hypofractionated, image-guided radiotherapy (HIGRT) for a variety of malignant conditions including inoperable stage I NSCLC and many metastatic sites. When surgical resection is not possible, HIGRT offers an effective alternative for local treatment of limited metastatic disease. Early studies have produced promising results when HIGRT was delivered to all known sites of disease in patients with oligometastatic/oligo-recurrent NSCLC. In a population of patients formerly considered rapidly terminal, these studies report five year overall survival rates of 13-22%. HIGRT for metastatic NSCLC warrants further study. We call for large, intergroup, and even international randomized trials incorporating HIGRT and other metastasis-directed therapies into the treatment of patients with oligometastatic/oligo-recurrent NSCLC

Hedgehog signaling is required at multiple stages of zebrafish tooth development

Background. The accessibility of the developing zebrafish pharyngeal dentition makes it an advantageous system in which to study many aspects of tooth development from early initiation to late morphogenesis. In mammals, hedgehog signaling is known to be essential for multiple stages of odontogenesis; however, potential roles for the pathway during initiation of tooth development or in later morphogenesis are incompletely understood. Results. We have identified mRNA expression of the hedgehog ligands shha and the receptors ptc1 and ptc2 during zebrafish pharyngeal tooth development. We looked for, but did not detect, tooth germ expression of the other known zebrafish hedgehog ligands shhb, dhh, ihha, or ihhb, suggesting that as in mammals, only Shh participates in zebrafish tooth development. Supporting this idea, we found that morphological and gene expression evidence of tooth initiation is eliminated in shha mutant embryos, and that morpholino antisense oligonucleotide knockdown of shha, but not shhb, function prevents mature tooth formation. Hedgehog pathway inhibition with the antagonist compound cyclopamine affected tooth formation at each stage in which we applied it: arresting development at early stages and disrupting mature tooth morphology when applied later. These results suggest that hedgehog signaling is required continuously during odontogenesis. In contrast, over-expression of shha had no effect on the developing dentition, possibly because shha is normally extensively expressed in the zebrafish pharyngeal region. Conclusion. We have identified previously unknown requirements for hedgehog signaling for early tooth initiation and later morphogenesis. The similarity of our results with data from mouse and other vertebrates suggests that despite gene duplication and changes in the location of where teeth form, the roles of hedgehog signaling in tooth development have been largely conserved during evolution. © 2010 Jackman et al; licensee BioMed Central Ltd

Flavour capsule cigarettes continue to experience strong global growth

First paragraph: Cigarettes with flavour-changing capsules in the filter, a continuing success story for tobacco companies, have grown exponentially since being introduced in 2007. The global capsule market is estimated to be 150 billion sticks in 2017. We provide an update on the capsule market since 2014. From this time capsule cigarettes have been introduced in new markets in Europe (Croatia, Spain), Africa (Tunisia), Latin America (Bolivia, Ecuador, Uruguay) and Asia (China, India, Philippines, Thailand, Vietnam). They are the fastest growing segment of the combustible market, with market share increasing between 2014 and 2017 in 52 of the 67 countries where they are sold and monitored by tobacco analyst Euromonitor. These products now have market share greater than 10% in four European countries (UK, Hungary, Ireland, Poland), and have increased 12% in the Middle East and Africa. The five most popular capsule markets remain in Latin America (see Figure 1), with market share increasing by at least 40% in each of these countries since 2014

Response to Questions in the First White Paper, \u27Modernizing the Communications Act\u27

The House Energy and Commerce Committee has begun a process to review and update the Communications Act of 1934, last revised in any material way in 1996. As the Committee begins the review process, this paper responds to questions posed by the Committee that all relate, in fundamental ways, to the question: What should a modern Communications Act look like? The Response advocates a clean slate approach under which the regulatory silos that characterize the current statute would be eliminated, along with almost all of the ubiquitous \u27public interest\u27 delegation of authority found throughout the Communications Act. The replacement regime would have at its core a new competition-based standard that, except in limited circumstances, would require that the FCC\u27s regulatory activities be tied to findings of consumer harm resulting from lack of sufficient competition. The FCC\u27s authority to adopt broad anticipatory rules on an ex ante basis would be substantially circumscribed, and the agency would be required to rely more heavily than is presently the case on ex post adjudication of individual complaints alleging specific abuses of market power and consumer harm. Some aspects of the FCC\u27s current jurisdiction, such as privacy and data security regulation, might be transferred to the FTC in light of the FTC\u27s institutional competence in these areas

Response to Questions in the First White Paper, \u27Modernizing the Communications Act\u27

The House Energy and Commerce Committee has begun a process to review and update the Communications Act of 1934, last revised in any material way in 1996. As the Committee begins the review process, this paper responds to questions posed by the Committee that all relate, in fundamental ways, to the question: What should a modern Communications Act look like? The Response advocates a clean slate approach under which the regulatory silos that characterize the current statute would be eliminated, along with almost all of the ubiquitous \u27public interest\u27 delegation of authority found throughout the Communications Act. The replacement regime would have at its core a new competition-based standard that, except in limited circumstances, would require that the FCC\u27s regulatory activities be tied to findings of consumer harm resulting from lack of sufficient competition. The FCC\u27s authority to adopt broad anticipatory rules on an ex ante basis would be substantially circumscribed, and the agency would be required to rely more heavily than is presently the case on ex post adjudication of individual complaints alleging specific abuses of market power and consumer harm. Some aspects of the FCC\u27s current jurisdiction, such as privacy and data security regulation, might be transferred to the FTC in light of the FTC\u27s institutional competence in these areas

ELF3 controls thermoresponsive growth in Arabidopsis

Plant development is highly responsive to ambient temperature, and this trait has been linked to the ability of plants to adapt to climate change [1]. The mechanisms by which natural populations modulate their thermoresponsiveness are not known [2]. To address this, we surveyed Arabidopsis accessions for variation in thermal responsiveness of elongation growth and mapped the corresponding loci. We find that the transcriptional regulator EARLY FLOWERING3 (ELF3) controls elongation growth in response to temperature. Through a combination of modeling and experiments, we show that high temperature relieves the gating of growth at night, highlighting the importance of temperature-dependent repressors of growth. ELF3 gating of transcriptional targets responds rapidly and reversibly to changes in temperature. We show that the binding of ELF3 to target promoters is temperature dependent, suggesting a mechanism where temperature directly controls ELF3 activity

A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases.

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure

Cloned, CD117 Selected Human Amniotic Fluid Stem Cells Are Capable of Modulating the Immune Response

Amniotic fluid stem (AFS) cells are broadly multipotent, can be expanded extensively in culture, are not tumorigenic and can be readily cryopreserved for cell banking. Mesenchymal stem cells (MSC) show immunomodulatory activity and secrete a wide spectrum of cytokines and chemokines that suppress inflammatory responses, block mixed lymphocyte reactions (MLR) and other immune reactions, and have proven therapeutic against conditions such as graft-versus-host disease. AFS cells resemble MSCs in many respects including surface marker expression and differentiation potential. We therefore hypothesized that AFS cells may exhibit similar immunomodulatory capabilities. We present data to demonstrate that direct contact with AFS cells inhibits lymphocyte activation. In addition, we show that cell-free supernatants derived from AFS cells primed with total blood monocytes or IL-1β, a cytokine released by monocytes and essential in mediation of the inflammatory response, also inhibited lymphocyte activation. Further investigation of AFS cell-free supernatants by protein array revealed secretion of multiple factors in common with MSCs that are known to be involved in immune regulation including growth related oncogene (GRO) and monocyte chemotactic protein (MCP) family members as well as interleukin-6 (IL-6). AFS cells activated by PBMCs released several additional cytokines as compared to BM-MSCs, including macrophage inflammatory protein-3α (MIP-3α), MIP-1α and Activin. AFS cells also released higher levels of MCP-1 and lower levels of MCP-2 compared to BM-MSCs in response to IL-1β activation. This suggests that there may be some AFS-specific mechanisms of inhibition of lymphocyte activation. Our results indicate that AFS cells are able to suppress inflammatory responses in vitro and that soluble factors are an essential component in the communication between lymphocytes and AFS cells. Their extensive self-renewal capacity, possibility for banking and absence of tumorigenicity may make AFS cells a superior source of stable, well characterized “off the shelf” immunomodulatory cells for a variety of immunotherapies