ROLE OF MACROPHAGES IN ADAPTIVE RESISTANCE TO ANTI-VEGF THERAPY

Background: The clinical implementation of therapies targeting the VEGF pathway in cancer has been limited by acquired resistance; yet, the mechanisms by which this occurs is unclear. We investigated the role of macrophages in the development of acquired resistance to anti-VEGF antibody (AVA) therapy. Materials and Methods: We first established a murine ovarian cancer model of resistance to anti-VEGF therapy. Using this model we investigated changes in macrophage infiltration during AVA sensitive and resistant phases. We also investigated the in vivo effects of macrophage depletion at the emergence of anti-VEGF resistance and in upfront combination with AVA therapy. In vitro, we assessed differences in viability and invasion/migration in AVA sensitive and resistant macrophages. We also investigated macrophage VEGF receptor expression in response to AVA therapy. Finally, we performed high throughput analyses to determine pathways important in modulating macrophage response to AVA. Results: We show that macrophages are actively recruited to the tumor microenvironment, where their accumulation correlates with the emergence of anti-VEGF resistance. Importantly, depletion of macrophages at the emergence of anti-VEGF resistance halts tumor growth and significantly prolongs survival in murine models. Additionally, the upfront combination of anti-VEGF therapy with macrophage depletion is synergistic, decreasing tumor growth in vivo. We found downregulation of macrophage VEGFR-1 expression in conjunction with upregulation of alternative angiogenic and anti-apoptotic pathways at the emergence of resistance, possibly facilitating escape from VEGF-directed therapies. Conclusions: After establishing murine ovarian cancer models of anti-VEGF resistance, we demonstrate a previously unrecognized role for macrophages in adaptive resistance to anti-VEGF therapy. Depletion of macrophages restores sensitivity to AVA therapy and reduces tumor growth in combination with VEGF blockade. Collectively, this study highlights macrophages as catalysts in the development of anti-VEGF resistance and offers strategies to modulate the influence of macrophages, thus improving the effectiveness of anti-VEGF therapy

Do Open Access Electronic Theses and Dissertations Diminish Publishing Opportunities in the Sciences?

In academia, there is a growing acceptance of sharing the final electronic version of graduate work, such as a thesis or dissertation, in an online university repository. Though previous studies have shown that journal editors are willing to consider manuscripts derived from electronic theses and dissertations (ETDs), faculty advisors and graduate students continue to raise concerns that online discoverability of ETDs negatively impact future opportunities to publish those findings. The current study investigated science journal policies on open access ETDs and found that more than half of the science journals responding (51.4%) reported that manuscripts derived from openly accessible ETDs are welcome for submission and an additional 29.1 percent would accept revised ETDs under certain conditions

Frederick II of Hohenstaufen's Australasian Cockatoo: Symbol of Detente between East and West and Evidence of the Ayyubids' Global Reach

Frederick II of Sicily made contact with the Kurdish al-Malik Muhammad al-Kamil in 1217-a year before al-Malik became sultan of Egypt. The two rulers communicated regularly over the following twenty years, exchanging letters, books and rare and exotic animals. The focus of this article is the Sulphur-crested or Yellow-crested Cockatoo the sultan sent Frederick. A written description and four sketches of this parrot survive in a mid thirteenth-century manuscript in the Vatican Library. This article reviews these images, revealing that Australasian cockatoos were present in the Middle East in the medieval period and exploring how and why one reached Europe in the mid thirteenth century

Pharmacologic activation of estrogen receptor α increases mitochondrial function, energy expenditure, and brown adipose tissue

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154285/1/fsb2fj201600787rr.pd

Fasciola hepatica is refractory to complement killing by preventing attachment of mannose binding lectin (MBL) and inhibiting MBL-associated serine proteases (MASPs) with serpins

The complement system is a first-line innate host immune defence against invading pathogens. It is activated via three pathways, termed Classical, Lectin and Alternative, which are mediated by antibodies, carbohydrate arrays or microbial liposaccharides, respectively. The three complement pathways converge in the formation of C3-convertase followed by the assembly of a lethal pore-like structure, the membrane attack complex (MAC), on the pathogen surface. We found that the infectious stage of the helminth parasite Fasciola hepatica, the newly excysted juvenile (NEJ), is resistant to the damaging effects of complement. Despite being coated with mannosylated proteins, the main initiator of the Lectin pathway, the mannose binding lectin (MBL), does not bind to the surface of live NEJ. In addition, we found that recombinantly expressed serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively prevent activation of the complement via the Lectin pathway. Our experiments demonstrate that rFhSrp1 and rFhSrp2 inhibit native and recombinant MBL-associated serine proteases (MASPs), impairing the primary step that mediates C3b and C4b deposition on the NEJ surface. Indeed, immunofluorescence studies show that MBL, C3b, C4b or MAC are not deposited on the surface of NEJ incubated in normal human serum. Taken together, our findings uncover new means by which a helminth parasite prevents the activation of the Lectin complement pathway to become refractory to killing via this host response, in spite of presenting an assortment of glycans on their surface.</jats:p

The Nihoku Ecosystem Restoration Project: A case study in predator exclusion fencing, ecosystem restoration, and seabird translocation

Reports were scanned in black and white at a resolution of 600 dots per inch and were converted to text using Adobe Paper Capture Plug-in.Newell’s Shearwater (Puffinus auricularis newelli; NESH) and Hawaiian Petrel (Pterodroma sandwichensis; HAPE) are both listed under the Endangered Species Act of 1973 and are declining due to collisions with power lines and structures, light attraction, predation by feral cats, pigs, rats, and introduced Barn Owls, habitat degradation by feral ungulates (pigs, goats) and invasive exotic plants. Protection of NESH and HAPE on their nesting grounds and reduction of collision and lighting hazards are high priority recovery actions for these species. Given the challenges in protecting nesting birds in their rugged montane habitats, it has long been desirable to also create breeding colonies of both species in more accessible locations that offer a higher level of protection. Translocation of birds to breeding sites within predator exclusion fences was ranked as priority 1 in the interagency 5-year Action Plan for Newell’s Shearwater and Hawaiian Petrel. In 2012, funding became available through several programs to undertake this action at Kilauea Point National Wildlife Refuge (KPNWR), which is home to one of the largest seabird colonies in the main Hawaiian Islands. The project was named the “Nihoku Ecosystem Restoration Project” after the area on the Refuge where the placement of the future colony was planned. The Nihoku Ecosystem Restoration Project is a result of a large partnership between multiple government agencies and non-profit groups who have come together to help preserve the native species of Hawaii. There were four stages to this multi-faceted project: permitting and biological monitoring, fence construction, restoration and predator eradication, followed by translocation of the birds to the newly secured habitat. The translocation component is expected to last five years and involve up to 90 individuals each of NESH and HAPE. Prior to fence construction, baseline monitoring data were collected in order to provide a record of initial site conditions and species diversity. Surveys were conducted quarterly from 2012-2014, investigating diversity and richness of plant, invertebrate, mammalian, and avian species. A 650 m (2130 ft) long predator proof fence was completed at Nihoku in September 2014, enclosing 2.5 ha (6.2 ac), and all mammalian predators were eradicated by March 2015. From 2015-2017, approximately 40% of the fenced area (~1 ha) was cleared of non-native vegetation using heavy machinery and herbicide application. A water catchment and irrigation system was installed, and over 18,000 native plants representing 37 native species were outplanted in the restoration area. The plant species selected are low-in-stature, making burrow excavation easier for seabirds while simultaneously providing forage for Nene (Branta sandvicensis). Habitat restoration was done in phases (10-15% of the project per year) and will be continued until the majority of the area has been restored. In addition to habitat restoration, 50 artificial burrows were installed in the restoration to facilitate translocation activities. From 2012-2017 potential source colonies of NESH and HAPE were located by the Kauai Endangered Seabird Recovery Project (KESRP) with visual, auditory, and ground searching methods at locations around Kauai. The sites that were selected as source colonies for both species were Upper Limahuli Preserve (owned by the National Tropical Botanical Garden; NTBG) and several sites within the Hono o Na Pali Natural Area Reserve system. These sites had high call rates, high burrow densities to provide an adequate source of chicks for the translocation, and had active predator control operations in place to offset any potential impacts of the monitoring. Translocation protocols were developed based on previous methods developed in New Zealand; on the ground training was done by the translocation team by visiting active projects in New Zealand. In year one, 10 HAPE and eight NESH were translocated, and the goal is to translocate up to 20 in subsequent years for a cohort size of 90 birds of each species over a five year period. Post-translocation monitoring has been initiated to gauge the level of success, and social attraction has been implemented in an attempt to attract adults to the area. It is anticipated that the chicks raised during this project will return to breed at Nihoku when they are 65-6 years old; for the first cohort released in 2015 this would be starting in 2020. Once this occurs, Nihoku will be the first predator-free breeding area of both species in Hawaii.This project and manuscript are part of a large collaboration that spans beyond the agencies mentioned. Many individuals were consulted for advice and input along the way. For botanical and invertebrate advice, we thank: David Burney, Lida Burney, Natalia Tangalin, Emory Griffin‐Noyes, Kawika Winter, Kim Starr, Forest Starr, Sheldon Plentovich and Keren Gunderson. For assistance with translocation training and predator exclusion fence technical advice we thank Helen Gummer, John McLennan, Lindsay Wilson, and Darren Peters. For reviewing documents related to this project, and for feedback on techniques we thank the seabird hui, particularly Fern Duvall, Jay Penniman, Megan Laut, Darcy Hu and Cathleen Bailey. For their on the ground assistance at KPNWR, we thank: Shannon Smith, Chadd Smith, Warren Madeira, Rob Petersen, Jennifer Waipa, Padraic Gallagher, Carolyn Rushforth, Kristina Macaulay, Jimmy Macaulay, and Jillian Cosgrove. We would also like to thank Chris Mottley, Kyle Pias and the entire predator control team in Hono o Na Pali NAR and Kawika Winter, Chiemi Nagle, Merlin Edmonds and the entire predator control team in Upper Limahuli Preserve. We would also like to thank the Kaua‘i Island Utility Co‐operative (KIUC) for the funding that they provide – through a Habitat Conservation Plan – to provide predator control and seabird monitoring at several of the sites used for translocation. Lastly, we would like to thank all of the endangered seabird technicians within the Kauaʻi Endangered Seabird Recovery Project for all of their hard work in montane colonies. Mahalo

The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes.

OBJECTIVE: Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR(cystatin). Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors. METHODS: Urine and serum cytokines/chemokines (Luminex platform) and GFR(cystatin) were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m(2)) and hyperfiltering (n = 31, T1D-H, GFR ≥ 135 ml/min/1.73 m(2)) adolescents with T1D (ages 10-16), and in age and sex matched healthy control subjects (HC, n = 59). RESULTS: We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076). CONCLUSIONS: Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study

Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments.

BACKGROUND: The COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment. This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within approximately 24-48 h of their test result. METHODS: A multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (approximately within 24-48 h of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology. RESULTS: Prior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1013 recruits to PRINCIPLE at the start of October 2020 to 2802 recruits by 20 December 2020. Whilst procedural caveats were identified by the public consultation, out of 2639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached. CONCLUSIONS: This paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness. This approach increased recruitment and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions. TRIAL REGISTRATION: PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research. EudraCT number: 2020-001209-22 . 26/03/2020 ISRCTN registry: ISRCTN86534580 . 20/03/2020 REC number: 20/SC/058 IRAS number: 281958