Pan-squamous genomic profiling stratified by anatomic tumor site and viral association

Background: Squamous cell carcinomas (SCC) have diverse anatomic etiologies but may share common genomic biomarkers. We profiled 7,871 unique SCCs across nine anatomic sites to investigate commonality in genomic alterations (GA), tumor mutational burden (TMB), human papillomavirus (HPV) association, and mutational signatures. Methods: Tissue from over 8,100 unique SCC samples originating from nine anatomic sites (anogenital (anus, cervix, penis, vagina, vulva), esophagus, head and neck, lung, and skin) were sequenced by hybrid capture-based comprehensive genomic profiling to evaluate GA and TMB. About 3% of non-cutaneous SCC samples had UV signatures, indicative of potential primary site misdiagnoses, and were filtered from the analysis. Detection of HPV, including high-risk strains 16, 18, 31, 33, and 45, was implemented through de novo assembly of non-human sequencing reads and BLASTn comparison against all viral nucleotide sequences in the NCBI database. Results: The proportion of HPV+ patients by anatomic site varied, with the highest being anal (91%) and cervical (83%). The mutational landscape of each cohort was similar, regardless of anatomic origin, but clustered based on HPV status. The largest differences in GA frequency as stratified by HPV- vs. HPV+ were TP53 (87% vs. 12%), CDKN2A (45% vs. 6%), and PIK3CA (22% vs. 33%). The median TMB in cases originating from HPV-associated sites was similar, regardless of HPV status. Higher median TMB was observed in lung and skin cases, which exhibited significant enrichment of mutational signatures indicative of tobacco- and UV-induced DNA damage, respectively. Conclusions: HPV+ and HPV- SCC populations have distinct genomic profiles and, for the latter, anatomic site is correlated with TMB distribution, secondary to associated carcinogen exposure. As such, biomarkers such as TMB and UV signature can provide unexpected insight into site of origin misdiagnoses and may correlate with benefit from immune checkpoint inhibitors

Penrose Limits, Deformed pp-Waves and the String Duals of N=1 Large n Gauge Theory

A certain conformally invariant N=1 supersymmetric SU(n) gauge theory has a description as an infra-red fixed point obtained by deforming the N=4 supersymmetric Yang-Mills theory by giving a mass to one of its N=1 chiral multiplets. We study the Penrose limit of the supergravity dual of the large n limit of this N=1 gauge theory. The limit gives a pp-wave with R-R five-form flux and both R-R and NS-NS three-form flux. We discover that this new solution preserves twenty supercharges and that, in the light-cone gauge, string theory on this background is exactly solvable. Correspondingly, this latter is the stringy dual of a particular large charge limit of the large n gauge theory. We are able to identify which operators in the field theory survive the limit to form the string's ground state and some of the spacetime excitations. The full string model, which we exhibit, contains a family of non-trivial predictions for the properties of the gauge theory operators which survive the limit.Comment: 39 pages, Late

Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice

<p>Abstract</p> <p>Background</p> <p>Mast cells are implicated in the pathogenesis of obesity and insulin resistance. Here, we explored the effects of leptin deficiency-induced obesity on the density of mast cells in metabolic (abdominal fat depots, skeletal muscle, and liver) and lymphatic (abdominal lymph nodes, spleen, and thymus) organs. Fourteen-week-old male leptin-deficient <it>ob/ob </it>mice and their controls fed a standard chow were studied. Tissue sections were stained with toluidine blue to determine the density of mast cells. CD117/c-kit protein expression analysis was also carried out. Furthermore, mast cells containing immunoreactive tumor necrosis factor-α (TNF-α), a proinflammatory cytokine involved in obesity-linked insulin resistance, were identified by immunostaining.</p> <p>Results</p> <p><it>ob/ob </it>mice demonstrated adiposity and insulin resistance. In abdominal fat depots, mast cells were distributed differentially. While most prevalent in subcutaneous fat in controls, mast cells were most abundant in epididymal fat in <it>ob/ob </it>mice. Leptin deficiency-induced obesity was accompanied by a 20-fold increase in the density of mast cells in epididymal fat, but a 13-fold decrease in subcutaneous fat. This finding was confirmed by CD117/c-kit protein expression analysis. Furthermore, we found that a subset of mast cells in epididymal and subcutaneous fat were immunoreactive for TNF-α. The proportion of mast cells immunoreactive for TNF-α was higher in epididymal than in subcutaneous fat in both <it>ob/ob </it>and control mice. Mast cells were also distributed differentially in retroperitoneal, mesenteric, and inguinal lymph nodes. In both <it>ob/ob </it>mice and lean controls, mast cells were more prevalent in retroperitoneal than in mesenteric and inguinal lymph nodes. Leptin deficiency-induced obesity was accompanied by increased mast cell density in all lymph node stations examined. No significant difference in the density of mast cells in skeletal muscle, liver, spleen, and thymus was noted between <it>ob/ob </it>and control mice.</p> <p>Conclusions</p> <p>This study demonstrates that leptin deficiency-induced obesity is accompanied by alterations in the density of mast cells in abdominal fat depots. The divergent distribution of mast cells in subcutaneous versus visceral fat might partially account for their differential biological behavior. Mast cells might also play a role in adaptive immune response occurring in regional lymph nodes in obesity.</p

Coherent control of low loss surface polaritons

We propose fast all-optical control of surface polaritons (SPs) by placing an electromagnetically induced transparency (EIT) medium at an interface between two materials. EIT provides longitudinal compression and a slow group velocity while matching properties of the two materials at the interface provides strong transverse confinement. In particular we show that an EIT medium near the interface between a dielectric and a negative-index metamaterial can establish tight longitudinal and transverse confinement plus extreme slowing of SPs, in both transverse electric and transverse magnetic polarizations, while simultaneously avoiding losses.Comment: 4 pages, 5 figure

Inside the Horizon with AdS/CFT

Using the eternal BTZ black hole as a concrete example, we show how spacelike singularities and horizons can be described in terms of AdS/CFT amplitudes. Our approach is based on analytically continuing amplitudes defined in Euclidean signature. This procedure yields finite Lorentzian amplitudes. The naive divergences associated with the Milne type singularity of BTZ are regulated by an $i\epsilon$ prescription inherent in the analytic continuation and a cancellation between future and past singularities. The boundary description corresponds to a tensor product of two CFTs in an entangled state, as in previous work. We give two bulk descriptions corresponding to two different analytic continuations. In the first, only regions outside the horizon appear explicitly, and so amplitudes are manifestly finite. In the second, regions behind the horizon and on both sides of the singularity appear, thus yielding finite amplitudes for virtual particles propagating through the black hole singularity. This equivalence between descriptions only outside and both inside and outside the horizon is reminiscent of the ideas of black hole complementarity.Comment: 31 pages, 6 figure

Coherent States and Bayesian Duality

We demonstrate how large classes of discrete and continuous statistical distributions can be incorporated into coherent states, using the concept of a reproducing kernel Hilbert space. Each family of coherent states is shown to contain, in a sort of duality, which resembles an analogous duality in Bayesian statistics, a discrete probability distribution and a discretely parametrized family of continuous distributions. It turns out that nonlinear coherent states, of the type widely studied in quantum optics, are a particularly useful class of coherent states from this point of view, in that they contain many of the standard statistical distributions. We also look at vector coherent states and multidimensional coherent states as carriers of mixtures of probability distributions and joint probability distributions

Study protocol: developing a decision system for inclusive housing: applying a systematic, mixed-method quasi-experimental design

Background Identifying the housing preferences of people with complex disabilities is a much needed, but under-developed area of practice and scholarship. Despite the recognition that housing is a social determinant of health and quality of life, there is an absence of empirical methodologies that can practically and systematically involve consumers in this complex service delivery and housing design market. A rigorous process for making effective and consistent development decisions is needed to ensure resources are used effectively and the needs of consumers with complex disability are properly met. Methods/Design This 3-year project aims to identify how the public and private housing market in Australia can better respond to the needs of people with complex disabilities whilst simultaneously achieving key corporate objectives. First, using the Customer Relationship Management framework, qualitative (Nominal Group Technique) and quantitative (Discrete Choice Experiment) methods will be used to quantify the housing preferences of consumers and their carers. A systematic mixed-method, quasi-experimental design will then be used to quantify the development priorities of other key stakeholders (e.g., architects, developers, Government housing services etc.) in relation to inclusive housing for people with complex disabilities. Stakeholders randomly assigned to Group 1 (experimental group) will participate in a series of focus groups employing Analytical Hierarchical Process (AHP) methodology. Stakeholders randomly assigned to Group 2 (control group) will participate in focus groups employing existing decision making processes to inclusive housing development (e.g., Risk, Opportunity, Cost, Benefit considerations). Using comparative stakeholder analysis, this research design will enable the AHP methodology (a proposed tool to guide inclusive housing development decisions) to be tested. Discussion It is anticipated that the findings of this study will enable stakeholders to incorporate consumer housing preferences into commercial decisions. Housing designers and developers will benefit from the creation of a parsimonious set of consumer-led housing preferences by which to make informed investments in future housing and contribute to future housing policy. The research design has not been applied in the Australian research context or elsewhere, and will provide a much needed blueprint for market investment to develop viable, consumer directed inclusive housing options for people with complex disability

Growth and development alter susceptibility to acute renal injury.

Many of the studies of acute renal injury have been conducted in young mice usually during their rapid growth phase; yet, the impact of age or growth stage on the degree of injury is unknown. To address this issue, we studied three forms of injury (endotoxemic-, glycerol-, and maleate-induced) in mice ranging in age from adolescence (3 weeks) to maturity (16 weeks). The severity of injury within each model significantly correlated with weight and age. We also noticed a progressive age-dependent reduction in renal cholesterol content, a potential injury modifier. As the animals grew and aged they also exhibited stepwise decrements in the mRNAs of HMG CoA reductase and the low density lipoprotein receptor, two key cholesterol homeostatic genes. This was paralleled by decreased amounts of RNA polymerase II and the transcription factor SREBP1/2 at the reductase and lipoprotein receptor gene loci as measured by chromatin immunoprecipitation. Our study shows that the early phase of mouse growth can profoundly alter renal susceptibility to diverse forms of experimental acute renal injury