Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx.

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts

Miocene Phytolith and Diatom Dataset from 10.3Myo Diatomite Formation, Fernley, Nevada, USA

Phytoliths are opal silica particles formed within plant tissues. Diatoms are aquatic, single-celled photosynthetic algae with silica skeletons. Phytolith and diatom morphotypes vary depending on local environmental and climatic conditions and because their silicate structures preserve well, the study of phytolith and diatom morphotypes can be used to better understand paleoclimatic and paleoenvironmental dynamics and changes. This article presents original data from an 820cm-deep stratigraphy excavated at the Hazen diatomite deposits, a high-elevation desert paleolake in the Fernley District, Northern Nevada, USA. The site has been studied for an assemblage of fossilized threespine stickleback, Gasterosteus doryssus, that reveal adaptive evolution. For this study, a total of 157 samples were extracted at 20 cm intervals covering approximately 24,500 years. After extraction, the samples were mounted on slides and viewed under 400-1000x light microscopy, enabling classification of 14 phytolith and 45 diatom morphotypes. Our data support paleoenvironmental reconstructions of the Hazen Miocene paleolake

Integration of Rural Community Pharmacies into a Rural Family Medicine Practice-Based Research Network: A Descriptive Analysis

Purpose: Practice-based research networks (PBRN) seek to shorten the gap between research and application in primary patient care settings. Inclusion of community pharmacies in primary care PBRNs is relatively unexplored. Such a PBRN model could improve care coordination and community-based research, especially in rural and underserved areas. The objectives of this study were to: 1) evaluate rural Appalachian community pharmacy key informants’ perceptions of PBRNs and practice-based research; 2) explore key informants’ perceptions of perceived applicability of practice-based research domains; and 3) explore pharmacy key informant interest in PBRN participation. Methods: The sample consisted of community pharmacies within city limits of all Appalachian Research Network (AppNET) PBRN communities in South Central Appalachia. A descriptive, cross-sectional, questionnaire-based study was conducted from November 2013 to February 2014. Bivariate and multivariate analyses were conducted to examine associations between key informant and practice characteristics, and PBRN interest and perceptions. Findings: A 47.8% response rate was obtained. Most key informants (88%) were very or somewhat interested in participating in AppNET. Enrichment of patient care (82.8%), improved relationships with providers in the community (75.9%), and professional development opportunities (69.0%) were perceived by more than two-thirds of respondents to be very beneficial outcomes of PBRN participation. Respondents ranked time constraints (63%) and workflow disruptions (20%) as the biggest barriers to PBRN participation. Conclusion: Key informants in rural Appalachian community pharmacies indicated interest in PBRN participation. Integration of community pharmacies into existing rural PBRNs could advance community level care coordination and promote improved health outcomes in rural and underserved areas. Type: Original Researc

Design and Evaluation of Gemini Surfactant-Based Lipoplexes Modified with Cell-Binding Peptide for Targeted Gene Therapy

Purpose Achieving successful gene therapy requires delivery of a gene vector specifically to the targeted tissue with efficient expression and a good safety profile. The objective of this work was to develop, characterize and determine if a novel gemini surfactant-based lipoplex systems, modified with a cancer-targeting peptide p18-4, could serve this role. Methods The targeting peptide p18-4 was either chemically coupled to a gemini surfactant backbone or physically co-formulated with the lipoplexes. The influence of targeting ligand and formulation strategies on essential physicochemical properties of the lipoplexes was evaluated by dynamic light scattering and small angle X-ray scattering techniques. In vitro transfection activity and cellular toxicity of lipoplexes were assessed in a model human melanoma cell line. Results All lipoplexes zeta potential and particle size were optimal for cellular uptake and physical stability of the system. The lipoplexes adopted an inverted-hexagonal lipid arrangement. The lipoplexes modified with the peptide showed no significant changes in physicochemical properties or lipoplex assembly. The modification of the lipoplexes with the targeting peptide significantly enhanced protein expression 2-6 fold compared to non-modified lipoplexes. In addition, p18-4 modified lipoplexes significantly improved the safety of the lipoplexes. The ability of the p18-4 modified lipoplexes to selectively express the model protein was confirmed by using healthy human epidermal keratinocytes (HEKa). Conclusion The gemini surfactant-based lipoplexes modified with p18-4 peptide showed significantly higher efficiency and safety compared to the system that did not contain a cancer targeting peptide and provided evidence for their potential application to achieve targeted melanoma gene therapy

Near-field characterization of 2D disk resonator on Bloch surface wave platform

We experimentally and theoretically investigate the characteristics of a two-dimensional (2D) disk resonator, which is fabricated on a Bloch surface wave platform. Such a platform is exploited to manipulate the surface waves by patterning nano-thin 2D optical components on the to

Mindfulness and Behavior Change

Initiating and maintaining behavior change is key to the prevention and treatment of most preventable chronic medical and psychiatric illnesses. The cultivation of mindfulness, involving acceptance and nonjudgment of present-moment experience, often results in transformative health behavior change. Neural systems involved in motivation and learning have an important role to play. A theoretical model of mindfulness that integrates these mechanisms with the cognitive, emotional, and self-related processes commonly described, while applying an integrated model to health behavior change, is needed. This integrative review (1) defines mindfulness and describes the mindfulness-based intervention movement, (2) synthesizes the neuroscience of mindfulness and integrates motivation and learning mechanisms within a mindful self-regulation model for understanding the complex effects of mindfulness on behavior change, and (3) synthesizes current clinical research evaluating the effects of mindfulness-based interventions targeting health behaviors relevant to psychiatric care. The review provides insight into the limitations of current research and proposes potential mechanisms to be tested in future research and targeted in clinical practice to enhance the impact of mindfulness on behavior change

Self-stabilizing Overlays for high-dimensional Monotonic Searchability

We extend the concept of monotonic searchability for self-stabilizing systems from one to multiple dimensions. A system is self-stabilizing if it can recover to a legitimate state from any initial illegal state. These kind of systems are most often used in distributed applications. Monotonic searchability provides guarantees when searching for nodes while the recovery process is going on. More precisely, if a search request started at some node $u$ succeeds in reaching its destination $v$, then all future search requests from $u$ to $v$ succeed as well. Although there already exists a self-stabilizing protocol for a two-dimensional topology and an universal approach for monotonic searchability, it is not clear how both of these concepts fit together effectively. The latter concept even comes with some restrictive assumptions on messages, which is not the case for our protocol. We propose a simple novel protocol for a self-stabilizing two-dimensional quadtree that satisfies monotonic searchability. Our protocol can easily be extended to higher dimensions and offers routing in $\mathcal O(\log n)$ hops for any search request

Tiny Sc allows the chains to rattle: Impact of Lu and Y doping on the charge density wave in ScV6_6Sn6_6

The kagome metals display an intriguing variety of electronic and magnetic phases arising from the connectivity of atoms on a kagome lattice. A growing number of these materials with vanadium kagome nets host charge density waves (CDWs) at low temperatures including ScV$_6$Sn$_6$, CsV$_3$Sb$_5$, and V$_3$Sb$_2$. Curiously, only the Sc version of the $R$V$_6$Sn$_6$ HfFe$_6$Ge$_6$-type materials hosts a CDW ($R =$Gd-Lu, Y, Sc). In this study we investigate the role of rare earth size in CDW formation in the $R$V$_6$Sn$_6$ compounds. Magnetization measurements on our single crystals of (Sc,Lu)V$_6$Sn$_6$ and (Sc,Y)V$_6$Sn$_6$ establish that the CDW is suppressed by substitution of Sc by larger Lu or Y. Single crystal x-ray diffraction reveals that compressible Sn-Sn bonds accommodate the larger rare earth atoms within loosely packed $R$-Sn-Sn chains without significantly expanding the lattice. We propose that Sc provides the extra room in these chains crucial to CDW formation in ScV$_6$Sn$_6$. Our rattling chain model explains why both physical pressure and substitution by larger rare earths hinder CDW formation despite opposite impacts on lattice size. We emphasize the cooperative effect of pressure and rare earth size by demonstrating that pressure further suppresses the CDW in a Lu-doped ScV$_6$Sn$_6$ crystal. Our model not only addresses why a CDW only forms in the $R$V$_6$Sn$_6$ materials with tiny Sc, it also advances to our understanding of why unusual CDWs form in the kagome metals.Comment: 28 pages, 9 figures, crystallographic information files for LuV6Sn6 and YV6Sn6 along with supplemental materials in ancillary file

Malic enzyme 1 absence in synovial sarcoma shifts antioxidant system dependence and increases sensitivity to ferroptosis induction with ACXT-3102

PURPOSE: To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. EXPERIMENTAL DESIGN: ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo. RESULTS: ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls. CONCLUSIONS: These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients. See related commentary by Subbiah and Gan, p. 3408