Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer.

BackgroundHyperactivation of STAT3 via constitutive phosphorylation of tyrosine 705 (Y705) is common in most human cancers, including head and neck squamous carcinoma (HNSCC). STAT3 is rarely mutated in cancer and the (epi)genetic alterations that lead to STAT3 activation are incompletely understood. Here we used an unbiased approach to identify genomic and epigenomic changes associated with pSTAT3(Y705) expression using data generated by The Cancer Genome Atlas (TCGA).Methods and findingsMutation, mRNA expression, promoter methylation, and copy number alteration data were extracted from TCGA and examined in the context of pSTAT3(Y705) protein expression. mRNA expression levels of 1279 genes were found to be associated with pSTAT3(705) expression. Association of pSTAT3(Y705) expression with caspase-8 mRNA expression was validated by immunoblot analysis in HNSCC cells. Mutation, promoter hypermethylation, and copy number alteration of any gene were not significantly associated with increased pSTAT3(Y705) protein expression.ConclusionsThese cumulative results suggest that unbiased approaches may be useful in identifying the molecular underpinnings of oncogenic signaling, including STAT3 activation, in HNSCC. Larger datasets will likely be necessary to elucidate signaling consequences of infrequent alterations

A Method for Balancing Provider Schedules in Outpatient Specialty Clinics

Background. Variability in outpatient specialty clinic schedules contributes to numerous adverse effects including chaotic clinic settings, provider burnout, increased patient waiting times, and inefficient use of resources. This research measures the benefit of balancing provider schedules in an outpatient specialty clinic. Design. We developed a constrained optimization model to minimize the variability in provider schedules in an outpatient specialty clinic. Schedule variability was defined as the variance in the number of providers scheduled for clinic during each hour the clinic is open. We compared the variance in the number of providers scheduled per hour resulting from the constrained optimization schedule with the actual schedule for three reference scenarios used in practice at M Health Fairview’s Clinics and Surgery Center as a case study. Results. Compared to the actual schedules, use of constrained optimization modeling reduced the variance in the number of providers scheduled per hour by 92% (1.70–0.14), 88% (1.98–0.24), and 94% (1.98–0.12). When compared with the reference scenarios, the total, and per provider, assigned clinic hours remained the same. Use of constrained optimization modeling also reduced the maximum number of providers scheduled during each of the actual schedules for each of the reference scenarios. The constrained optimization schedules utilized 100% of the available clinic time compared to the reference scenario schedules where providers were scheduled during 87%, 92%, and 82% of the open clinic time, respectively. Limitations. The scheduling model’s use requires a centralized provider scheduling process in the clinic. Conclusions. Constrained optimization can help balance provider schedules in outpatient specialty clinics, thereby reducing the risk of negative effects associated with highly variable clinic settings

Effect of Ex Vivo Ionizing Radiation on Static and Fatigue Properties of Mouse Vertebral Bodies

For a variety of medical and scientific reasons, human bones can be exposed to a wide range of ionizing radiation levels. In vivo radiation therapy (0.05 kGy) is used in cancer treatment, and ex vivo irradiation (25-35 kGy) is used to sterilize bone allografts. Ionizing radiation in these applications has been shown to increase risk of fracture, decrease bone quality and degrade collagen integrity. Past studies have investigated the deleterious effects of radiation on cortical or trabecular bone specimens individually, but to date no studies have examined whole bones containing both cortical and trabecular tissue. Furthermore, a clear relationship between the dose and the mechanical and biochemical response of bone's extracellular matrix has yet to be established for doses ranging from cancer therapy to allograft sterilization (0.05-35 kGy). To gain insight into these issues, we conducted an ex vivo radiation study to investigate non-cellular (i.e. matrix) effects of ionizing radiation dose on vertebral whole bone mechanical properties, over a range of radiation doses (0.05-35 kGy), with a focus on any radiation-induced changes in collagen. With underlying mechanisms of action in mind, we hypothesized that any induced reductions in mechanical properties would be associated with changes in collagen integrity. METHODS: 20-week old female mice were euthanized and the lumbar spine was dissected using IACUC approved protocols. The lumbar vertebrae (L1- S1) were extracted from the spine via cuts through adjacent intervertebral discs, and the endplates, posterior processes, surrounding musculature, and soft tissues were removed (approx. 1.5mm diameter, approx. 2mm height). Specimens were randomly assigned to one of five groups for ex vivo radiation exposure: x-ray irradiation at 0.05, 1, 17, or 35 kGy, or a 0 kGy control. Following irradiation, the vertebrae were imaged using microcomputed tomography (micro-CT) and then subjected to either monotonic compressive loading to failure or uniform cyclic compressive loading. During cyclic testing, samples were loaded in force control to a force level that corresponded to a strain of 0.46%, as determined in advance by a linearly elastic micro-CT-based finite element analysis for each specimen. Tests were stopped at imminent fracture, defined as a rapid increase in strain. The main outcome for the monotonic test was the strength (maximum force); for cyclic testing it was the fatigue life (log of the number of cycles of loading at imminent failure). A fluorometric assay was used on the S1 vertebrae to measure the number of non-enzymatic collagen crosslinks[4]. A one-way ANOVA was performed on mechanical properties and collagen crosslinks; means were compared with controls using Dunnett's method, with a Tukey-Kramer post-hoc analysis when significance was found (p 0.05). The finite element analysis prescribed force level for cyclic loading exceeded the measured (monotonic) strength of the 17 and 35 kGy irradiated groups (mean +/- SD, 20.6 +/- 5.6 N; 13.2 +/- 3.7 N, respectively) and therefore these groups were eliminated from the fatigue study. The fatigue life for the 0.05 and 1 kGy groups were similar to each other and were not statistically significantly different from the control group (Figure 1c)

“I Got You”: Centering Identities and Humanness in Collaborations Between Mathematics Educators and Mathematicians

Existing literature widely reports on the value of collaborations between mathematicians and mathematics educators, and also how complex those collaborations can be. In this paper, we report on four collaborations that sought to address what mathematics is and who gets to do it. Drawing on the literature and from the careful and intentional work of the collaborators, we offer a framework to capture the richness of those collaborations – one that acknowledges the importance of acknowledging and welcoming the extensive personal and professional experience of each person involved in the collaboration – and a look at how collaborations built with that intentionality and acknowledgment can be impactful for students and institutions and be personally and professionally rewarding for the collaborators

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a “driver” phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine–substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.Fil: Lui, Vivian Wai Yan. University of Pittsburgh; Estados UnidosFil: Peyser, Noah D.. University of Pittsburgh; Estados UnidosFil: Ng, Patrick Kwok-Shing. University Of Texas Md Anderson Cancer Center;Fil: Hritz, Jozef. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos. Masaryk University; República ChecaFil: Zeng, Yan. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Lu, Yiling. University Of Texas Md Anderson Cancer Center;Fil: Li, Hua. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Wang, Lin. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Gilbert, Breean R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: General, Ignacio. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Bahar, Ivet. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Ju, Zhenlin. University Of Texas Md Anderson Cancer Center;Fil: Wang, Zhenghe. Case Western Reserve University; Estados UnidosFil: Pendleton, Kelsey P.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Xiao, Xiao. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Du, Yu. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Vries, John K.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Hammerman, Peter S.. Harvard Medical School; Estados UnidosFil: Garraway, Levi A.. Harvard Medical School; Estados UnidosFil: Mills, Gordon B.. University Of Texas Md Anderson Cancer Center;Fil: Johnson, Daniel E.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Grandis, Jennifer R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unido

Ionizing Radiation from Ex Vivo Sterilization Diminishes Collagen Integrity and Vertebral Body Mechanics

Clinical exposure to ionizing radiation could put cancer radiotherapy or bone allograft patients at an increased risk of fracture. In these applications, ionizing radiation levels can range from accumulative 50 Gy for radiotherapy cancer treatment, to acute 35,000 Gy for allograft sterilization. Ionizing radiation has been shown to decrease bon equality through reduced strength and post-yield properties and degrade collagen integrity through either increased crosslinks (advanced glycation end products, AGEs)or fragmentation. It is unclear which collagen structural change accounts for reduced strength. The dose-dependent effect of ionizing radiation on mechanical and biochemical properties of whole bones are not well understood, particularly for ex vivo doses ranging from 50 to 35,000 Gy

Protecting Endangered Species in the USA Requires Both Public and Private Land Conservation

Crucial to the successful conservation of endangered species is the overlap of their ranges with protected areas. We analyzed protected areas in the continental USA to assess the extent to which they covered the ranges of endangered tetrapods. We show that in 80% of ecoregions, protected areas offer equal (25%) or worse (55%) protection for species than if their locations were chosen at random. Additionally, we demonstrate that it is possible to achieve sufficient protection for 100% of the USA’s endangered tetrapods through targeted protection of undeveloped public and private lands. Our results highlight that the USA is likely to fall short of its commitments to halting biodiversity loss unless more considerable investments in both public and private land conservation are made

Unifying Community Detection Across Scales from Genomes to Landscapes

Biodiversity science encompasses multiple disciplines and biological scales from molecules to landscapes. Nevertheless, biodiversity data are often analyzed separately with discipline-specific methodologies, constraining resulting inferences to a single scale. To overcome this, we present a topic modeling framework to analyze community composition in cross-disciplinary datasets, including those generated from metagenomics, metabolomics, field ecology and remote sensing. Using topic models, we demonstrate how community detection in different datasets can inform the conservation of interacting plants and herbivores. We show how topic models can identify members of molecular, organismal and landscape-level communities that relate to wildlife health, from gut microbes to forage quality. We conclude with a future vision for how topic modeling can be used to design cross-scale studies that promote a holistic approach to detect, monitor and manage biodiversity

Exile Vol. XXXV No. 1

ARTWORK Untitled by Eric Whitney (cover) Untitled by Rory Herbster 7 Little Boy by Eric Whitney 45 FICTION Through the Window Pane by Jennifer Read 4 to whom i may concern by Chris Campi 19 For Lack of Sleep by Amy Judge 26 Jonathan by Jim Cox 39 Skin Deep by Eric Whitney 51 NON-FICTION A Theopoetic by Robert Marshall 11 POETRY Clay Pot by Christopher Collette 1 Ars Poetica by Mans Agantyr 2 Bible Thumber by Chris Rynd 6 Play by Amy Judge 9 Satellites by Andrew C. Carinston 10 Music - Love? by Shammon J. Salser 15 Allusion by Rosemary Walsh 17 Self Portrait by Margaret Dawson 18 On Our Way by Lynn Pendleton 21 They called her Mitzi... by Jen Miller 22 Storms of Illusion by Kevin Merriman 23 Beauty by Andrew C. Carington 24 Thoughts of a Husband by Kent Lambert 25 The Music of the Sum by Zach Smith 31 Don\u27t Think by Mary Forsythe 32 Aspiration by Tim Emrick 33 Where We Go Together by Man Angantyr 35 Sunset by Chris Byrd 36 The Child of my Fatalism by Jennifer Peterson 37 Untitled by Kent Lambert 38 Terribly close to being... by Michael Payne 44 Anne Frank\u27s House by Mary Forsythe 47 Invitation by Kevin Merriman 48 Height Protest by Jen Miller 49 Dancer by Bradford Cover 50 Ars Poetica by Amy Judge 55 Editorial decision is shared equally among the Editorial Board members -title page NOTE: The author of the poem Satellites is listed as Andrew C. Carinston in the published table of contents. This is likely a misspelling as there are four instances of an Andrew C. Carington elsewhere in this edition, including the attribution on the page where Satellites is published. NOTE: The author of the poem Where We Go Together is listed as Man Angantyr in the published table of contents. This is likely a misspelling as there are four instances of an Mans Angantyr elsewhere in this edition, including the attribution on the pages where Where We Go Together is published. NOTE: Chris Byrd is listed as the author of the poem Sunset in the published version. However a note in the received version indicates that the author is actually Chris Rynd, whose poem Bible Thumper is also published in this issue. No Chris Byrd is listed among the contributors to this issue. NOTE: The author of the poem Music = Love? is listed as Shammon J. Salser in the published table of contents. This is likely a misspelling. Where Music = Love? appears the author is listed as Shannon J. Salser. The same is true of the contributors section. NOTE: Though the published table of contents is followed here, the poem by Zach Smith that is published on page 31 is listed as The Music of the Sun on page 31

Solar System Exploration Research Virtual Institute: Year Three Annual Report 2016

NASA's Solar System Exploration Research Virtual Institute (SSERVI) is pleased to present the 2016 Annual Report. Each year brings new scientific discoveries, technological breakthroughs, and collaborations. The integration of basic research and development, industry and academic partnerships, plus the leveraging of existing technologies, has further opened a scientific window into human exploration. SSERVI sponsorship by the NASA Science Mission Directorate (SMD) and Human Exploration and Operations Mission Directorate (HEOMD) continues to enable the exchange of insights between the human exploration and space science communities, paving a clearer path for future space exploration. SSERVI provides a unique environment for scientists and engineers to interact within multidisciplinary research teams. As a virtual institute, the best teaming arrangements can be made irrespective of the geographical location of individuals or laboratory facilities. The interdisciplinary science that ensues from virtual and in-person interactions, both within the teams and across team lines, provides answers to questions that many times cannot be foreseen. Much of this research would not be accomplished except for the catalyzing, collaborative environment enabled by SSERVI. The SSERVI Central Office, located at NASA Ames Research Center in Silicon Valley, California, provides the leadership, guidance and technical support that steers the virtual institute. At the start of 2016, our institute had nine U.S. teams, each mid-way through their five-year funding cycle, plus nine international partnerships. However, by the end of the year we were well into the selection of four new domestic teams, selected through NASA's Cooperative Agreement Notice (CAN) process, and a new international partnership. Understanding that human and robotic exploration is most successful as an international endeavor, international partnerships collaborate with SSERVI domestic teams on a no-exchange of funds basis, but they bring a richness to the institute that is priceless. The international partner teams interact with the domestic teams in a number of ways, including sharing students, scientific insights, and access to facilities. We are proud to introduce our newest partnership with the Astrophysics and Planetology Research Institute (IRAP) in Toulouse, France. In 2016, Principal Investigator Dr. Patrick Pinet assembled a group of French researchers who will contribute scientific and technological expertise related to SSERVI research. SSERVI's domestic teams compete for five-year funding opportunities through proposals to a NASA CAN every few years. Having overlapping proposal selection cycles allows SSERVI to be more responsive to any change in direction NASA might experience, while providing operational continuity for the institute. Allowing new teams to blend with the more seasoned teams preserves corporate memory and expands the realm of collaborative possibilities. A key component of SSERVI's mission is to grow and maintain an integrated research community focused on questions related to the Moon, Near-Earth asteroids, and the moons of Mars. The strong community response to CAN-2 demonstrated the health of that effort. NASA Headquarters conducted the peer-review of 22 proposals early in 2017 and, based on recommendations from the SSERVI Central Office and NASA SSERVI program officers, the NASA selecting officials determined the new teams in the spring of 2017. We are pleased to welcome the CAN-2 teams into the institute, and look forward to the collaborations that will develop with the current teams. The new teams are: The Network for Exploration and Space Science (NESS) team (Principal Investigator (PI) Prof. Jack Burns/U. Colorado); the Exploration Science Pathfinder Research for Enhancing Solar System Observations (ESPRESSO) team (PI Dr. Alex Parker/Southwest Research Institute); the Toolbox for Research and Exploration (TREX) team (PI Dr. Amanda Hendrix/ Planetary Science Institute); and the Radiation Effects on Volatiles and Exploration of Asteroids & Lunar Surfaces (REVEALS) team (PI Prof. Thomas Orlando/ Georgia Institute of Technology). In this report, you will find an overview of the 2016 leadership activities of the SSERVI Central Office, reports prepared by the U.S. teams from CAN-1, and achievements from several of the SSERVI international partners. Reflecting on the past year's discoveries and advancements serves as a potent reminder that there is still a great deal to learn about NASA's target destinations. Innovation in the way we access, sample, measure, visualize, and assess our target destinations is needed for further discovery. At the same time, let us celebrate how far we have come, and strongly encourage a new generation that will make the most of future opportunities