Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC

Material condition assessment with eddy current sensors

Eddy current sensors and sensor arrays are used for process quality and material condition assessment of conducting materials. In an embodiment, changes in spatially registered high resolution images taken before and after cold work processing reflect the quality of the process, such as intensity and coverage. These images also permit the suppression or removal of local outlier variations. Anisotropy in a material property, such as magnetic permeability or electrical conductivity, can be intentionally introduced and used to assess material condition resulting from an operation, such as a cold work or heat treatment. The anisotropy is determined by sensors that provide directional property measurements. The sensor directionality arises from constructs that use a linear conducting drive segment to impose the magnetic field in a test material. Maintaining the orientation of this drive segment, and associated sense elements, relative to a material edge provides enhanced sensitivity for crack detection at edges

Using an Ice Core to Characterize the Climatic History of Antarctica

Between 20 November and 14 December 1984, a remote tent camp was operated in the Dominion Range (center point, 85° 15\u27 S 166° 10 \u27E) on an ice-covered massif located at the confluence of the heads of the Beardmore and Mill Glaciers in the Transantarctic Mountains. The camp was occupied by four members of the Glacier Research Group (University of New Hampshire) and three members of the Polar lee Coring Office (PICO) (University of Nebraska). The main task at the site was to retrieve an ice core from which chemical and physical time series will be made available to help in assessing: (1) current stability of the east antarctic ice sheet, (2) current models concerning the recent glacial history of the Transantarctic Mountains, (3) the presence of relatively high frequency (100 per 100 years) climatic signals, and (4) the possible relationships between volcanic and/or solar activities and climatic change

Glaciochemical Investigations as a Tool in the Historical Delineation of the Acid Precipitation Problem

Precipitation in the Northern Hemisphere has been recently recognized to have hydrogen ion concentrations 10 to 100 times higher than expected for natural precipitation (Likens and Bormann 1974, Cogbill and Likens 1974, Lewis and Grant 1980). However, controversy has arisen regarding the nature of the acidity of the precipitation sampled and whether, indeed, the pH of North American precipitation has increased over time (Miller and Everett 1979, Lerman 1979, Stensland 1980, Sequeria 1981, Carlson and Rodhe 1982). In most locations pH records have been constructed rather imperfectly due to differences in sampling, handling, and analytical procedures used (Galloway and Likens 1976, 1978; Galloway et al. 1979). The lower pH\u27s measured in Northern Hemisphere precipitation are thought to be due to the input of sulfur and nitrogen oxides from fossil fuel-burning (Likens and Bormann 1974) and in some cases hydrogen chloride (Gorham 1958a). Few baseline data, however, are available on the pH of precipitation in areas of the Northern Hemisphere remote from North American and European sources of anthropogenic sulfur emissions. In addition, monitoring records of pH and acidic chemical species are of rather short time duration (~ 15 to 20 years at most), limited geographic coverage, and provide little useful information prior to the early 1960’s (Hornbeck 1981). Baseline studies of pH and related chemical species as well as historical time series data are warranted if they are to understand man’s effect on the environment. The National Academy of Sciences (1978) recommends that historical studies of glacier snow and ice should be conducted. Such studies are needed to better understand the atmospheric transport of anthropogenically-introduced chemical species to remote areas. In addition, a more recent NAS report (1980) states that a major scientific goal of the 1980’s should be to “identify the significant natural and anthropogenic factors contributing to acid rain.” Detailed glacio-chemical studies should provide this type of needed information. Snow and ice cores collected from appropriately chosen glaciers provide samples of entrapped chemical species that, unlike those derived from any other medium, are nearly-to- entirely unaltered since their deposition. This technique has barely been applied to the study of acid precipitation despite the fact that it provides a very sensitive record of precipitation chemistry

Unknowable bodies, unthinkable sexualities: lesbian and transgender legal invisibility in the Toronto women's bathhouse raid

Although litigation involving sexual orientation and gender identity discrimination claims has generated considerable public attention in recent years, lesbian and transgender bodies and sexualities still remain largely invisible in Anglo-American courts. While such invisibility is generally attributed to social norms that fail to recognize lesbian and transgender experiences, the capacity to 'not see' or 'not know' queer bodies and sexualities also involves wilful acts of ignorance. Drawing from R. v Hornick (2002) a Canadian case involving the police raid of a women's bathhouse, this article explores how lesbian and transgender bodies and sexualities are actively rendered invisible via legal knowledge practices, norms and rationalities. It argues that limited knowledge and limited thinking not only regulate the borders of visibility and belonging, but play an active part in shaping identities, governing conduct and producing subjectivity

Collaborative Care for Older Adults with low back pain by family medicine physicians and doctors of chiropractic (COCOA):study protocol for a randomized controlled trial

BACKGROUND: Low back pain is a prevalent and debilitating condition that affects the health and quality of life of older adults. Older people often consult primary care physicians about back pain, with many also receiving concurrent care from complementary and alternative medicine providers, most commonly doctors of chiropractic. However, a collaborative model of treatment coordination between these two provider groups has yet to be tested. The primary aim of the Collaborative Care for Older Adults Clinical Trial is to develop and evaluate the clinical effectiveness and feasibility of a patient-centered, collaborative care model with family medicine physicians and doctors of chiropractic for the treatment of low back pain in older adults. METHODS/DESIGN: This pragmatic, pilot randomized controlled trial will enroll 120 participants, age 65 years or older with subacute or chronic low back pain lasting at least one month, from a community-based sample in the Quad-Cities, Iowa/Illinois, USA. Eligible participants are allocated in a 1:1:1 ratio to receive 12 weeks of medical care, concurrent medical and chiropractic care, or collaborative medical and chiropractic care. Primary outcomes are self-rated back pain and disability. Secondary outcomes include general and functional health status, symptom bothersomeness, expectations for treatment effectiveness and improvement, fear avoidance behaviors, depression, anxiety, satisfaction, medication use and health care utilization. Treatment safety and adverse events also are monitored. Participant-rated outcome measures are collected via self-reported questionnaires and computer-assisted telephone interviews at baseline, and at 4, 8, 12, 24, 36 and 52 weeks post-randomization. Provider-rated expectations for treatment effectiveness and participant improvement also are evaluated. Process outcomes are assessed through qualitative interviews with study participants and research clinicians, chart audits of progress notes and content analysis of clinical trial notes. DISCUSSION: This pragmatic, pilot randomized controlled trial uses a mixed method approach to evaluate the clinical effectiveness, feasibility, and participant and provider perceptions of collaborative care between medical doctors and doctors of chiropractic in the treatment of older adults with low back pain. TRIAL REGISTRATION: This trial registered in ClinicalTrials.gov on 04 March 2011 with the ID number of NCT01312233

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Origin and evolution of the octoploid strawberry genome.

Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. We examined the dynamics among the four subgenomes in octoploid strawberry and uncovered the presence of a single dominant subgenome with significantly greater gene content, gene expression abundance, and biased exchanges between homoeologous chromosomes, as compared with the other subgenomes. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These findings and the reference genome should serve as a powerful platform for future evolutionary studies and enable molecular breeding in strawberry

A One Health overview, facilitating advances in comparative medicine and translational research.

Table of contentsA1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology