Porcine Models of Pancreatic Cancer: Current Status and Future

The KRASG12D and TP53R172H mutations are the leading causes of pancreatic cancer, with the third deadliest cancer mortality rate. Majority of the pancreatic cancer research utilizes mouse models. Our lab is currently studying porcine as a suitable model to study pancreatic cancer due to the comparative anatomy and genomic similarities between humans and porcine. Our first approach to develop the porcine pancreatic cancer model was to orthotopically implant the transformed and mutated primary pig pancreatic epithelial cells into the pig pancreas. The second approach was using the Oncopig model with KRASG12D and TP53R172H genetic mutations. The mutated genes were expressed by injecting adenovirus with Cre recombinase to develop tumors. Hematoxylin and Eosin staining, immunohistochemistry, plasmid, and RNA isolation were used to study the porcine pancreas before and after the tumor induction. Results showed that humans and porcine have similar histological characteristics showing comprising islets, ducts, and acinar cells. For the orthotopic model, after two weeks of orthotopic implantation, there were signs of pancreatitis and some evidence of tumor-like cells, but not tumors. Some signs were the formation of acinar to ductal metaplasia, massive immune cell responses, and vimentin expression in the regions of desmoplasia. Our results showed that the Oncopigs did generate pancreatic tumors successfully and are currently being characterized for future use, and the orthotopic model showed promising results. However, implanted tumor cells will be given additional help to allow them to survive from host immune response by over-expressing PD-L1 on the implanted tumor cells surface.https://digitalcommons.unmc.edu/surp2022/1041/thumbnail.jp

Topological surface states above the Fermi level in Hf2Te2 P

We report a detailed experimental study of the band structure of the recently discovered topological material Hf2Te2P. Using the combination of scanning tunneling spectroscopy and angle-resolved photoemission spectroscopy with surface K doping, we probe the band structure of Hf2Te2P with energy and momentum resolution above the Fermi level. Our experiments show the presence of multiple surface states with a linear Dirac-like dispersion, consistent with the predictions from previously reported band-structure calculations. In particular, scanning tunneling spectroscopy measurements provide experimental evidence for the strong topological surface state predicted at 460meV, which stems from the band inversion between Hf-d and Te-p orbitals. This band inversion comprised of more localized d states could result in a better surface-to-bulk conductance ratio relative to more traditional topological insulators

New evidence on Allyn Young's style and influence as a teacher

This paper publishes the hitherto unpublished correspondence between Allyn Abbott Young's biographer Charles Blitch and 17 of Young's former students or associates. Together with related biographical and archival material, the paper shows the way in which this adds to our knowledge of Young's considerable influence as a teacher upon some of the twentieth century's greatest economists. The correspondents are as follows: James W Angell, Colin Clark, Arthur H Cole, Lauchlin Currie, Melvin G de Chazeau, Eleanor Lansing Dulles, Howard S Ellis, Frank W Fetter, Earl J Hamilton, Seymour S Harris, Richard S Howey, Nicholas Kaldor, Melvin M Knight, Bertil Ohlin, Geoffrey Shepherd, Overton H Taylor, and Gilbert Walker

Microarray analysis of Foxa2 mutant mouse embryos reveals novel gene expression and inductive roles for the gastrula organizer and its derivatives

<p>Abstract</p> <p>Background</p> <p>The Spemann/Mangold organizer is a transient tissue critical for patterning the gastrula stage vertebrate embryo and formation of the three germ layers. Despite its important role during development, there are still relatively few genes with specific expression in the organizer and its derivatives. Foxa2 is a forkhead transcription factor that is absolutely required for formation of the mammalian equivalent of the organizer, the node, the axial mesoderm and the definitive endoderm (DE). However, the targets of Foxa2 during embryogenesis, and the molecular impact of organizer loss on the gastrula embryo, have not been well defined.</p> <p>Results</p> <p>To identify genes specific to the Spemann/Mangold organizer, we performed a microarray-based screen that compared wild-type and <it>Foxa2 </it>mutant embryos at late gastrulation stage (E7.5). We could detect genes that were consistently down-regulated in replicate pools of mutant embryos versus wild-type, and these included a number of known node and DE markers. We selected 314 genes without previously published data at E7.5 and screened for expression by whole mount <it>in situ </it>hybridization. We identified 10 novel expression patterns in the node and 5 in the definitive endoderm. We also found significant reduction of markers expressed in secondary tissues that require interaction with the organizer and its derivatives, such as cardiac mesoderm, vasculature, primitive streak, and anterior neuroectoderm.</p> <p>Conclusion</p> <p>The genes identified in this screen represent novel Spemann/Mangold organizer genes as well as potential Foxa2 targets. Further investigation will be needed to define these genes as novel developmental regulatory factors involved in organizer formation and function. We have placed these genes in a Foxa2-dependent genetic regulatory network and we hypothesize how Foxa2 may regulate a molecular program of Spemann/Mangold organizer development. We have also shown how early loss of the organizer and its inductive properties in an otherwise normal embryo, impacts on the molecular profile of surrounding tissues.</p

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

Projected WIMP sensitivity of the LUX-ZEPLIN dark matter experiment

LUX-ZEPLIN (LZ) is a next-generation dark matter direct detection experiment that will operate 4850 feet underground at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. Using a two-phase xenon detector with an active mass of 7 tonnes, LZ will search primarily for low-energy interactions with weakly interacting massive particles (WIMPs), which are hypothesized to make up the dark matter in our galactic halo. In this paper, the projected WIMP sensitivity of LZ is presented based on the latest background estimates and simulations of the detector. For a 1000 live day run using a 5.6-tonne fiducial mass, LZ is projected to exclude at 90% confidence level spin-independent WIMP-nucleon cross sections above 1.4×10-48 cm2 for a 40 GeV/c2 mass WIMP. Additionally, a 5σ discovery potential is projected, reaching cross sections below the exclusion limits of recent experiments. For spin-dependent WIMP-neutron(-proton) scattering, a sensitivity of 2.3×10-43 cm2 (7.1×10-42 cm2) for a 40 GeV/c2 mass WIMP is expected. With underground installation well underway, LZ is on track for commissioning at SURF in 2020

Predicting healthcare employees' participation in an office redesign program: Attitudes, norms and behavioral control

<p>Abstract</p> <p>Background</p> <p>The study examined the extent to which components based on a modified version of the theory of planned behavior explained employee participation in a new clinical office program designed to reduce patient waiting times in primary care clinics.</p> <p>Methods</p> <p>We regressed extent of employee participation on attitudes about the program, group norms, and perceived behavioral control along with individual and clinic characteristics using a hierarchical linear mixed model.</p> <p>Results</p> <p>Perceived group norms were one of the best predictors of employee participation. Attitudes about the program were also significant, but to a lesser degree. Behavioral control, however, was not a significant predictor. Respondents with at least one year of clinic tenure, or who were team leaders, first line supervisor, or managers had greater participation rates. Analysis at the clinic level indicated clinics with scores in the highest quartile clinic scores on group norms, attitudes, and behavioral control scores were significantly higher on levels of overall participation than clinics in the lowest quartile.</p> <p>Conclusion</p> <p>Findings suggest that establishing strong norms and values may influence employee participation in a change program in a group setting. Supervisory level was also significant with greater responsibility being associated with greater participation.</p

CXCL1 can be regulated by IL-6 and promotes granulocyte adhesion to brain capillaries during bacterial toxin exposure and encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Granulocytes generally exert protective roles in the central nervous system (CNS), but recent studies suggest that they can be detrimental in experimental autoimmune encephalomyelitis (EAE), the most common model of multiple sclerosis. While the cytokines and adhesion molecules involved in granulocyte adhesion to the brain vasculature have started to be elucidated, the required chemokines remain undetermined.</p> <p>Methods</p> <p>CXCR2 ligand expression was examined in the CNS of mice suffering from EAE or exposed to bacterial toxins by quantitative RT-PCR and <it>in situ </it>hybridization. CXCL1 expression was analyzed in IL-6-treated endothelial cell cultures by quantitative RT-PCR and ELISA. Granulocytes were counted in the brain vasculature after treatment with a neutralizing anti-CXCL1 antibody using stereological techniques.</p> <p>Results</p> <p>CXCL1 was the most highly expressed ligand of the granulocyte receptor CXCR2 in the CNS of mice subjected to EAE or infused with lipopolysaccharide (LPS) or pertussis toxin (PTX), the latter being commonly used to induce EAE. IL-6 upregulated CXCL1 expression in brain endothelial cells by acting transcriptionally and mediated the stimulatory effect of PTX on CXCL1 expression. The anti-CXCL1 antibody reduced granulocyte adhesion to brain capillaries in the three conditions under study. Importantly, it attenuated EAE severity when given daily for a week during the effector phase of the disease.</p> <p>Conclusions</p> <p>This study identifies CXCL1 not only as a key regulator of granulocyte recruitment into the CNS, but also as a new potential target for the treatment of neuroinflammatory diseases such as multiple sclerosis.</p

Alterations in cognitive performance during passive hyperthermia are task dependent

The objectives of this study were to (1) assess the effect of passive heating upon attention and memory task performance, and (2) evaluate the effectiveness of the application of cold packs to the head on preserving these functions. Using a counterbalance design 16 subjects underwent three trials: a control (CON, 20°C, 40% rH), hot (HOT, 50°C, 50% rH) and hot with the head kept cool (HHC). In each condition, three attention tests and two memory tests were performed. Mean core, forehead and tympanic temperatures were all significantly higher (p< 0.05) during HOT (38.6° ±0.1°, 39.6° ±0.2° and 38.8°±0.1°C, respectively) and HHC (38°±0.2, 37.7°±0.3° and 37.7°C, respectively) than in CON (37.1°±0.6°, 33.3° ±0.2° and 35.9°±0.3°C, respectively). Results indicate that there was impairment in working memory with heat exposure (p < 0.05) without alteration in attentional processes. The regular application of cold packs only prevented the detrimental effect of hyperthermia on short-term memory. Our results show that impairments in cognitive function with passive hyperthermia and the beneficial effect of head cooling are task dependent and suggests that exposure to a hot environment is a competing variable to the cognitive processes