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We performed 3D hydrodynamic simulations of the inner $\approx 50\%$ radial extent of a $25\ \mathrm{M_\odot}$ star in the early phase of the main sequence and investigate core convection and internal gravity waves in the core-envelope boundary region. Simulations for different grid resolutions and driving luminosities establish scaling relations to constrain models of mixing for 1D applications. As in previous works, the turbulent mass entrainment rate extrapolated to nominal heating is unrealistically high ($1.58\times 10^{-4}\ \mathrm{M_\odot/yr}$), which is discussed in terms of the non-equilibrium response of the simulations to the initial stratification. We measure quantitatively the effect of mixing due to internal gravity waves excited by core convection interacting with the boundary in our simulations. The wave power spectral density as a function of frequency and wavelength agrees well with the GYRE eigenmode predictions based on the 1D spherically averaged radial profile. A diffusion coefficient profile that reproduces the spherically averaged abundance distribution evolution is determined for each simulation. Through a combination of eigenmode analysis and scaling relations it is shown that in the $N^2$-peak region, mixing is due to internal gravity waves and follows the scaling relation $D_\mathrm{IGW-hydro} \propto L^{4/3}$ over a $\gtrapprox 2\ \mathrm{dex}$ range of heating factors. Different extrapolations of the mixing efficiency down to nominal heating are discussed. If internal gravity wave mixing is due to thermally-enhanced shear mixing, an upper limit is $D_\mathrm{IGW} \lessapprox 2$ to $3\times 10^4\ \mathrm{cm^2/s}$ at nominal heating in the $N^2$-peak region above the convective core., MNRAS. Clarifications and improvements following referee recommendations. Movies and data access https://www.ppmstar.org. 38 Figs. In v2 the bottom panel of Fig 28 is showing the wrong case (M116 instead of M114). Corrected in v3

Despite some impressive clinical results with immune checkpoint inhibitors, the majority of patients with cancer do not respond to these agents, in part due to immunosuppressive mechanisms in the tumor microenvironment. High levels of adenosine in tumors can suppress immune cell function, and strategies to target the pathway involved in its production have emerged. CD73 is a key enzyme involved in adenosine production. This led us to identify a novel humanized antagonistic CD73 antibody, mAb19, with distinct binding properties. mAb19 potently inhibits the enzymatic activity of CD73 in vitro, resulting in an inhibition of adenosine formation and enhanced T-cell activation. We then investigated the therapeutic potential of combining CD73 antagonism with other immune modulatory and chemotherapeutic agents. Combination of mAb19 with a PD-1 inhibitor increased T-cell activation in vitro. Interestingly, this effect could be further enhanced with an agonist of the adenosine receptor ADORA3. Adenosine levels were found to be elevated upon doxorubicin treatment in vivo, which could be blocked by CD73 inhibition. Combining CD73 antagonism with doxorubicin resulted in superior responses in vivo. Furthermore, a retrospective analysis of rectal cancer patient samples demonstrated an upregulation of the adenosine pathway upon chemoradiation, providing further rationale for combining CD73 inhibition with chemotherapeutic agents. This study demonstrates the ability of a novel CD73 antibody to enhance T-cell function through the potent suppression of adenosine levels. In addition, the data highlight combination opportunities with standard of care therapies as well as with an ADORA3 receptor agonist to treat patients with solid tumors.

Aligning development and climate goals means Africa’s energy systems will be based on clean energy technologies in the long term, but pathways to get there are uncertain and variable across countries. Although current debates about natural gas and renewables in Africa are heated, they largely ignore the substantial context specificity of the starting points, development objectives and uncertainties of each African country’s energy system trajectory. Here we—an interdisciplinary and majority African group of authors—highlight that each country faces a distinct solution space and set of uncertainties for using renewables or fossil fuels to meet its development objectives. For example, Ethiopia is headed for an accelerated green-growth pathway, but Mozambique is at a crossroads of natural gas expansion with implicit large-scale technological, economic, financial and social risks and uncertainties. We provide geopolitical, policy, finance and research recommendations to create firm country-specific evidence to identify adequate energy system pathways for development and to enable their implementation.

Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand–neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, and PC-3) using established in vitro assays, and in vivo, using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. Xentuzumab + enzalutamide reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased antiproliferative activity and apoptosis induction in VCaP. Xentuzumab or xentuzumab + enzalutamide inhibited IGF type 1 receptor and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; xentuzumab had no effect on AKT phosphorylation and proliferation in PTEN-null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of antiproliferative activity of xentuzumab and reduced activity of xentuzumab + enzalutamide in VCaP cells. Xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo. The data suggest that xentuzumab + enzalutamide combination therapy may overcome castration resistance and could be effective in patients who are resistant to enzalutamide alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.

T-cell engagers redirect T cells to a tumor specific target leading to lysis of tumor cells with demonstrated therapeutic benefit in hematological and solid tumors. Most T-cell engagers in development focus on surface exposed tumor antigens as targets. However, HLA/peptide complex directed (TCR mimic) T cell engagers enable targeting of tumour associated intracellular proteins and therefore broaden the cancer antigen space for T cell engagers. Potency and specificity are key attributes for the design of TCR mimic T cell engagers. Here, we employed a three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs: i) innovative bispecific formats employing avidity effect ii) TCRm affinity maturation by pHLA-Fv model based library design and phage display iii) pHLA-Fv crystal structure based affinity maturation in silico. The different strategies and combinations thereof enabled and improved lysis of tumor cells by T cell engager and informed on the structure-function relation of TCR mimic T cell engager. Citation Format: Nicolas Sabarth, Paul Adam, Sandeep Kumar, Yanyun Liu, Renate Konopitzky, Jark Boettcher, Tadas Panavas. Three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A62.

Saltmarshes provide many valuable ecosystem services including storage of a large amount of ‘blue carbon’ within their soils. To date, up to 50% of the world’s saltmarshes have been lost or severely degraded primarily due to a variety of anthropogenic pressures. Previous efforts have aimed to restore saltmarshes and their ecosystem functions, but the success of these efforts is rarely evaluated. To fill this gap, we used a range of metrics, including organic carbon stocks, root production, soil respiration and microbial communities to compare natural and a 20-year restoration effort in saltmarsh habitats within the Sydney Olympic Park in New South Wales, Australia. We addressed four main questions: (1) Have above- and belowground plant biomass recovered to natural levels? (2) Have organic carbon stocks of soils recovered? (3) Are microbial communities similar between natural and regenerated saltmarshes? and (4) Are microbial communities at both habitats associated to ecosystem characteristics? For both soil organic carbon stocks and belowground biomass, we found no significant differences between natural and regenerated habitats (F(1,14) = 0.47, p = 0.5; F(1,42) = 0.08, p = 0.76). Aboveground biomass was higher in the natural habitat compared to the regenerated habitat (F(1,20) = 27.3, p

Although some green housing elements have become more commonplace in residential renovations in Canada, the undertaking of complete green retrofits is relatively uncommon. This paper explores the barriers to green retrofits, such as affordability and bureaucracy, in the urban context of the City of Toronto. The research was informed by one main case study, one supplementary case study, and six interviews with sustainable housing experts. The research has yielded nine recommendations that are directed towards three levels of government and related public and private housing organizations. These recommendations have been made in the hopes of making sustainable housing more ubiquitous in Toronto.

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.

Purpose: Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. Experimental Design: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells. Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. Conclusions: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related deaths worldwide with only a minority of patients responding to immune checkpoint targeting therapies. To effectively treat mCRC, we have developed a novel B7-H6/CD3 IgG-like T cell Engager (ITE) that mediates cytolytic synapse formation between T cells and tumor cells, re-directs their cytolytic activity selectively to B7-H6 (B7 homolog 6, NCR3LG1) expressing CRC cells, and increases infiltration of immune cells into the tumor tissue. B7-H6 is a member of the B7 family of immune receptors. We have identified B7-H6 as a novel antigen which is expressed in several solid tumor indications. In CRC tissues B7-H6 is expressed in >95 % of cases, while no to very little expression could be detected in normal tissues, thus making B7-H6 a promising antigen to re-direct cytolytic T cells to B7-H6-expressing CRC cells. The bispecific monovalent B7-H6/CD3 ITE is designed to bind simultaneously to CD3 on T cells and B7-H6 on CRC cells resulting in formation of a cytolytic synapse without interfering with the natural function of B7-H6 and has sustained serum exposure. In vitro, unstimulated T cells were co-cultured with B7-H6 expressing CRC cell lines and increasing concentrations of the B7-H6/CD3 ITE. The B7-H6/CD3 ITE induced dose-dependent lysis of CRC cell lines with EC50 values ranging from 0.9 to 25 ng/mL, whereas viability of B7-H6-negative cells was not affected, demonstrating the selectivity of the B7-H6/CD3 ITE for the B7-H6 antigen. In addition, the B7-H6/CD3 ITE induced B7-H6-dependent activation and proliferation of T cells, and granzyme B and cytokine secretion. In vivo, the B7-H6/CD3 ITE induced dose-dependent anti-tumor activity in subcutaneous CRC (NCI-H716, HCT-15, HT-29) xenograft tumor bearing immunodeficient mice which were reconstituted with human PBMCs or T cells. Tumor regressions were observed with single doses of < 0.5 mg/kg of B7-H6/CD3 ITE administered as i.v. injection, and anti-tumor activity could be further enhanced by q7d dosing. Consistent with the mode-of-action, the B7-H6/CD3 ITE led to a profound infiltration of both CD4+ and CD8+ T cell subsets into the tumor, which correlated with cleaved caspase 3 expression on tumor cells and tumor shrinkage. The inflammatory tumor microenvironment that was created by treatment with the B7-H6/CD3 ITE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells. The B7-H6/CD3 ITE shows cross-reactivity to both B7-H6 and CD3 of human and non-human primate origin respectively, and demonstrates antibody-like pharmacokinetic properties in a single dose study in cynomolgus monkeys. Our pre-clinical data demonstrate that the B7-H6/CD3 ITE is a highly B7-H6-selective and efficacious T cell engaging antibody with the ability to convert a non-inflamed into an inflamed tumor environment which supports clinical development. Citation Format: Susanne Hipp, Wei Zhang, Xiaoyun Liao, Aurelie Auguste, Annika Osswald, Kathrin Bauer, Christian Walterskirchen, Farzaneh H. Sayedian, Manuela Kellner, Craig Giragossian, Vladimir Voynov, Andrew E. Nixon, Paul J. Adam. A novel B7-H6/CD3 bispecific IgG-like T cell engaging antibody for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 56.

Science thrives on ideas, and within its domain no idea is inherently dangerous. However, interpretations of science, and applications of misinterpretations in policies have potential to b...

The thirtieth anniversary of the nomination of New South Wales rainforests for World Heritage listing provided an opportunity to reflect on the process by which the nomination came about. I discuss the development of ideas about ‘heritage’, as it applies to the natural environment, the development of the World Heritage List and changing perceptions about the values and importance of rainforest in subtropical and temperate Australia. The concept of a serial nomination and its relevance to a geographically widespread collection of sites is considered. The nomination included sites which contained a range of vegetation, not just rainforest. The significance of the interactions between rainforest and wet sclerophyll forest displayed in New South Wales rainforest is recognised as one of the outstanding values in the nomination.

Description of the females of Australophlebotomus notteghemae and A. maduloae, and redescription of the males (Diptera, Psychodidae). Females of Australophlebotomus notteghemae Léger & Pesson, 1993, and A. maduloae Léger & Pesson, 1993, are described and illustrated ; males are redescribed. For these two species endemic from New Caledonia, emphasis is put on the peculiar characteristics of their male and female genitalia., Les femelles d’Australophlebotomus notteghemae Léger & Pesson, 1993, et A. maduloae Léger & Pesson, 1993, sont décrites, les mâles redécrits. L’accent est mis, pour ces deux espèces de Phlébotomes endémiques de Nouvelle-Calédonie, sur les caractères originaux de leurs genitalia mâles et femelles., Le Pont François, Adam Jean-Paul, Jezek Jan. Description des femelles d’Australophlebotomus notteghemae et Australophlebotomus maduloae, et redescription des mâles (Diptera, Psychodidae). In: Bulletin de la Société entomologique de France, volume 122 (2),2017. pp. 179-190.

B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

Salt marsh restoration and rehabilitation projects have been initiated at many locations around the world as a means of addressing past habitat loss as well as future threats. Planning for restoration requires making decisions between various options, and recognition of those values of salt marsh which we seek to replicate or protect. A range of threats is discussed, the chief amongst them are those related to climate change and the impacts of the growing human population. Climate change is a driver of sea level rise, but the viability of restoration projects is determined by relative sea level rise which will vary between and within wetlands; generalisations about the effect of sea level rise are not useful and there needs to be site-by-site consideration of relative sea level rise at the local scale. The concept of coastal squeeze is discussed and managed realignment as a restoration option is explored. The importance of monitoring and the use of feedback from monitoring for adaptive management stressed. Disturbance arising from human activity will need to be addressed at a range of scales, from global to local, and will often require cooperation between regulatory agencies in both setting and implementing policy. There is uncertainty associated with many of our predictions about the future of individual sites so we will need to treat restorations as field experiments.

Purpose: To report a case of epibulbar nodular fasciitis in a 32-year-old female and provide context by reviewing the current literature. Results: Using excisional biopsy, the patient was successfully diagnosed and treated for epibulbar nodular fasciitis. Upon follow-up, there has been no recurrence, consistent with the typical course for nodular fasciitis. Conclusions: Epibulbar nodular fasciitis is a rare process that can be successfully treated by surgical resection. While two cases of trauma-associated epibulbar nodular fasciitis have been present in the literature, our case did not have such a history. The etiology of nodular fasciitis remains unclear.

BACKGROUND eHealth is a broad term referring to the application of information and communication technologies in the health sector, ranging from health records to telemedicine and multiple forms of health education and digital tools. By providing increased and anytime access to information, opportunities to exchange experiences with others, and self-management support, eHealth has been heralded as transformational. It has created a group of informed, engaged, and empowered patients as partners, equipped to take part in shared decision making and effectively self-manage chronic illness. Less attention has been given to health care professionals’ (HCPs) experiences of the role of eHealth in patient encounters. OBJECTIVE The objective of this study was to examine HCPs’ perspectives on how eHealth affects their relationships with patients living with multiple chronic conditions, as well as its ethical and practical ramifications. METHODS We interviewed HCPs about their experiences with eHealth and its impact on the office visit. Eligible participants needed to report a caseload of ≥25% of patients with multimorbidity to address issues of managing complex chronic conditions and coordination of care. We used a semistructured discussion guide for in-depth interviews, and follow-up interviews served to clarify and expand upon initial discussions. Constant comparisons and a narrative approach guided the analyses, and a relational ethics conceptual lens was applied to the data to identify emergent themes. RESULTS A total of 12 physicians and nurses (6 male, 6 female; median years of practice=13) participated. eHealth tools most frequently described were Web-based educational resources for patients and Web-based resources for HCPs such as curated scientific summaries on diagnostic criteria, clinical therapies, and dosage calculators. Analysis centered on a grand theme of the two-way conversation between HCPs and patients, which addresses a general recentering of the ethical relationship between HCPs and patients around engagement. Subthemes explain the evolution of the two-way conversation, and having, using, and supporting the two-way conversation with patients, primarily as this relates to achieving adherence and health outcomes. CONCLUSIONS Emerging ethical concerns were related to the ambiguity of the ideal of empowered patients and the ways in which health professionals described enacting those ideals in practice, showing how the cultural shift toward truly mutually respectful and collaborative practice is in transition. HCPs aim to act in the best interests of their patients; the challenge is to benefit from emergent technologies that may enhance patient-HCP interactions and effective care, while abiding by regulations, dealing with the strictures of the technology itself, and managing changing demands on their time.

Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycin-induced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399–409. ©2013 AACR.

Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy resistant recurrence in the majority of patients. To effectively treat SCLC we have developed a unique T cell engaging bi-specific antibody that can potently re-direct T cells to specifically lyse SCLC cells expressing Delta-like Ligand 3 (DLL3). DLL3 is frequently expressed on the cell surface of neuroendocrine tumors, with no to very little expression in normal tissues, thus making DLL3 an ideal targeting antigen with which to safely re-direct cytolytic T cells to tumor cells. The bi-specific monovalent DLL3/CD3 IgG-like T cell Engager (ITE) is designed to have sustained serum exposure and simultaneously bind to CD3 on T cells and DLL3 on SCLC cells, resulting in formation of the cytolytic synapse. In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several DLL3 expressing SCLC cell lines and increasing concentrations of the DLL3/CD3 ITE. The DLL3/CD3 ITE induced potent dose-dependent lysis of SCLC cell lines with EC90 values ranging from 15 to 150 ng/mL, whereas viability of DLL3-negative cells was unaffected, demonstrating the specificity of the DLL3/CD3 ITE for the DLL3 antigen. In addition, the DLL3/CD3 ITE induced DLL3-dependent activation and proliferation of T cells, and granzyme B and cytokine secretion. In vivo anti-tumor activity of the DLL3/CD3 ITE was assessed in NOG mice bearing subcutaneous xenografts of the SHP77 SCLC cell line and reconstituted with human T cells. Complete tumor regressions were observed with a dose of 0.25 mg/kg administered once weekly by i.v. administration, with the onset of activity being observed after the first dose. Consistent with the mode-of-action the DLL3/CD3 ITE led to a profound infiltration of both CD8 and CD4 T cell subsets in the tumors, which correlated with cleaved caspase 3 expression on tumor cells and tumor shrinkage. The inflammatory tumor microenvironment that was created by treatment with the DLL3/CD3 ITE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells. The DLL3/CD3 ITE shows cross-reactivity to both DLL3 and CD3 of human and cynomolgus monkey origin respectively, thus allowing the assessment of pharmacodynamics, pharmacokinetics, and safety in cynomolgus monkeys. In a single dose study in cynomolgus monkeys, the DLL3/CD3 ITE demonstrated antibody-like pharmacokinetic properties. These pre-clinical data demonstrate that the DLL3/CD3 ITE is a highly potent, efficacious, and DLL3-selective T cell redirecting agent, and supports future clinical development. Citation Format: Susanne Hipp, Vladimir Voynov, Barbara Drobits-Handl, Francesca Trapani, Craig Giragossian, Justin M. Scheer, Paul J. Adam. A novel T cell engaging bispecific antibody induces specific and efficacious lysis of small cell lung cancer cells in vitro and potent T cell re-directed anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 549.

We tested for correlations in the degree of spatial similarity between algal and terrestrial plants communities along 5500 km of temperate Australian coastline and whether the strength of correlation weakens with increasing distance from the coast. We identified strong correlations between macroalgal and terrestrial plant communities within the first 100 km from shore, where the strength of these marine–terrestrial correlations indeed weakens with increasing distance inland. As such, our results suggest that marine-driven community homogenization processes decompose with increasing distance from the shore toward inland. We speculate that the proximity to the marine environment produces lower levels of community turnover on land, and this effect decreases progressively farther inland. Our analysis suggests underlying ecological and evolutionary processes that give rise to continental-scale biogeographic influence from sea to land.

Student interest in botany and enrolment in plant sciences courses tends to be low compared to that in other biological disciplines. One potential way of increasing student interest in botany is to focus on course material designed to raise student enthusiasm and satisfaction. Here, we introduce and evaluate virtual microscopy in botany teaching. Virtual microscopy uses high-resolution digital ‘virtual slides’ that allow students to explore microscope sections without the advanced skills required to prepare glass slides. Questionnaire feedback from students indicated that students found the virtual slides an effective learning tool. Further, we found that student performance in assessments was significantly higher when using virtual slides than when using traditional glass slides. We suggest that virtual slides are an effective tool for increasing student satisfaction in introductory botany courses, and have the potential for increasing student enrolment in higher-level courses (honours) and research degrees.

Intertidal wetlands are recognised for the provision of a range of valued ecosystem services. The two major categories of intertidal wetlands discussed in this contribution are saltmarshes and mangrove forests. Intertidal wetlands are under threat from a range of anthropogenic causes, some site-specific, others acting globally. Globally acting factors include climate change and its driving cause-the increasing atmospheric concentrations of greenhouse gases. One direct consequence of climate change will be global sea level rise due to thermal expansion of the oceans, and, in the longer term, the melting of ice caps and glaciers. The relative sea level rise experienced at any one locality will be affected by a range of factors, as will the response of intertidal wetlands to the change in sea level. If relative sea level is rising and sedimentation within intertidal wetlands does not keep pace, then there will be loss of intertidal wetlands from the seaward edge, with survival of the ecosystems only possible if they can retreat inland. When retreat is not possible, the wetland area will decline in response to the "squeeze" experienced. Any changes to intertidal wetland vegetation, as a consequence of climate change, will have flow on effects to biota, while changes to biota will affect intertidal vegetation. Wetland biota may respond to climate change by shifting in distribution and abundance landward, evolving or becoming extinct. In addition, impacts from ocean acidification and warming are predicted to affect the fertilisation, larval development, growth and survival of intertidal wetland biota including macroinvertebrates, such as molluscs and crabs, and vertebrates such as fish and potentially birds. The capacity of organisms to move and adapt will depend on their life history characteristics, phenotypic plasticity, genetic variability, inheritability of adaptive characteristics, and the predicted rates of environmental change.

This review brings together observations on the stress-induced regulation of resilience mechanisms in body tissues. It is argued that the stresses that induce tissue resilience in mammals arise from everyday sources: sunlight, food, lack of food, hypoxia and physical stresses. At low levels, these stresses induce an organised protective response in probably all tissues; and, at some higher level, cause tissue destruction. This pattern of response to stress is well known to toxicologists, who have termed it hormesis. The phenotypes of resilience are diverse and reports of stress-induced resilience are to be found in journals of neuroscience, sports medicine, cancer, healthy ageing, dementia, parkinsonism, ophthalmology and more. This diversity makes the proposing of a general concept of induced resilience a significant task, which this review attempts. We suggest that a system of stress-induced tissue resilience has evolved to enhance the survival of animals. By analogy with acquired immunity, we term this system ‘acquired resilience’. Evidence is reviewed that acquired resilience, like acquired immunity, fades with age. This fading is, we suggest, a major component of ageing. Understanding of acquired resilience may, we argue, open pathways for the maintenance of good health in the later decades of human life.

Summary The potential impacts of climate change on threatened species, populations and communities are considered. It is suggested that minor changes to legislation will be required to address the consequences of movement of threatened species but that threatened species legislation will remain relevant as an important tool for prioritizing conservation actions. The importance of taking proactive steps now to permit future movement of species and communities across fragmented landscapes is emphasized.

Onychomycosis in children is often accompanied by tinea pedis and a family history of onychomycosis. The prevalence of onychomycosis in children is substantially lower than that of adults; therefore it is important to confirm the clinical diagnosis. The most common presentation of onychomycosis is the distal and lateral subungual type. The organism most commonly isolated in North America is Trichophyton rubrum. Oral antifungal therapy is required, especially when the onychomycosis is of moderate to severe intensity, with nail matrix involvement. The new oral antifungal agents itraconazole, terbinafine, and fluconazole are being increasingly used for the treatment of onychomycosis. Review of the literature suggests that these agents are effective and safe in managing onychomycosis in children. The short duration of therapy required with these drugs should help improve compliance. The data suggest that the new oral antifungal agents have a role in the treatment of onychomycosis in children. Further experience will help us better position these drugs when evaluating the management of onychomycosis in children.

Multiple questionnaires completed over the semester by 514 students enrolled in a first year psychology course reveal that no single pattern of reliance on print, online, or in-person resources guarantees a high mark. Analyses of the reported and measured frequency of use of various resources correlated against students’, performance on both individual assessments and their final marks suggests that students employ a range of strategies in their use of class resources. They tend to rely on their textbooks, Web-based lecture notes, and online quizzes, but their final marks are more strongly determined by their university entrance scores than by their resource use strategy, their sex, or whether or not English is their first language. The data suggest that students adapt their learning strategies to the resources available, with an apparent emphasis on learning what will be assessed rather than exploring for understanding. Importantly, the results argue that investment in development of educational technologies – and students’, use of educational technologies – must be informed by empirical data concerning its impact on the efficiency and quality of learning.

The basis for a classification of the vegetation occurring on British saltmarshes is discussed and a dichotomous key, using floristic information, to the majority of plant communities on British marshes is presented. Brief descriptions of the communities are given, including information on their position in the saltmarsh zonation and their geographical distribution.

We compared the floristic composition and structure of restoration areas of eucalypt woodland with untreated pasture (control) and remnant vegetation (reference) in western Sydney. The restored areas comprised over 1,000 ha of abandoned pasture, which had been treated to reduce weeds and planted with seedlings of 26 native plant species raised from seed obtained locally from remnant vegetation. Plantings were carried out 0–9 years ago. Floristic composition was measured in quadrats using frequency scores and cover abundance. As far as possible treatments and restoration ages were replicated across sites. Ordination and analyses of similarity failed to distinguish the composition of restored vegetation from that of untreated pasture, which were both significantly different from that of remnant vegetation. There was a weak compositional trend with age of restored vegetation, but this was not in the direction of increasing resemblance to remnant vegetation. There was some evidence for convergence in structural features of restored with remnant vegetation, but this was at least partly attributed to plant growth. Subject to constraints imposed by the sampling design, environmental factors, and spatial variation were discounted as explanations for the results. The results therefore suggest either failure of restoration treatments or a restoration trajectory that is too slow to detect within 10 years of establishment. Our conclusions agree with those of similar studies in other ecosystems and support: (1) the need to monitor restoration projects against ecological criteria with rigorous sampling designs and analytical methods, (2) further development of restoration methods, and (3) regulatory approaches that seek to prevent damage to ecosystems rather than those predicated on replacing losses with reconstructed ecosystems.

The proportion of the root system comprising hair roots and their ericoid mycorrhizal colonization have been estimated in Woollsia pungens (Cav.) F. Muell. (Epacridaceae) at a site in New South Wales, Australia over a 12 month period. The technique used was a modification of the grid-line intercept method. Hair roots persisted and comprised at least about 50% of the root system all year round. The percentage of root length that was hair root varied with the season, being lowest in April/May (50%) and highest in October (70%). Hair root colonization differed significantly over the 12 month period, being highest over the winter to spring period (June–Oct) but there were infected hair roots present at all times of the year. There was a significant negative relationship between the percentage hair root length infected and log10 transformations of both mean daily maximum and minimum temperatures, but no correlation with rainfall or soil moisture content. These findings contrast with those for south-west Australia where hair roots (and mycorrhizal colonization) are reported to disappear in summer.

Saltmarshes are a major, widely distributed, intertidal habitat. They are dynamic systems, responding to changing environmental conditions. For centuries, saltmarshes have been subject to modification or destruction because of human activity. In this review, the range of factors influencing the survival of saltmarshes is discussed. Of critical importance are changes in relative sea level and in tidal range. Relative sea level is affected by changes in absolute sea level, changes in land level and the capacity of saltmarshes to accumulate and retain sediment. Many saltmarshes are starved of sediment because of catchment modification and coastal engineering, or exposed to erosive forces, which may be of natural origin or reflect human interference. The geographical distribution of individual saltmarsh species reflects climate, so that global climatic change will be reflected by changes in distribution and abundance of species, although the rate of change in communities dominated by perennial plants is difficult to predict. Humans have the ability to create impacts on saltmarshes at a range of scales from individual sites to globally. Pressures on the environment created by the continued increase in the human population, particularly in developing tropical countries, and the likely consequences of the enhanced greenhouse effect on both temperature and sea level give rise to particular concerns. Given the concentration of population growth and development in the coastal zone, and the potential sensitivity of saltmarsh to change in sea level, it is timely to review the present state of saltmarshes and to assess the likelihood of changes in the near (25 years) future. By 2025, global sea level rise and warming will have impacts on saltmarshes. However, the most extensive changes are likely to be the direct result of human actions at local or regional scales. Despite increasing recognition of the ecological value of saltmarsh, major projects involving loss of saltmarshes but deemed to be in the public interest will be approved. Pressures are likely to be particularly severe in the tropics, where very little is known about saltmarshes. At the local scale the cumulative impacts of activities, which individually have minor effects, may be considerable. Managers of saltmarshes will be faced with difficult choices including questions as to whether traditional uses should be retained, whether invasive alien species or native species increasing in abundance should be controlled, whether planned retreat is an appropriate response to rising relative sea level or whether measures can be taken to reduce erosion. Decisions will need to take into account social and economic as well as ecological concerns.

Background: The proliferative and pro-survival signals driven by the insulin-like growth factor (IGF) ligands, IGF-1 and IGF-2, are transmitted through their binding to the IGF-1 receptor (IGF-1R). In addition, IGF-2 activates the insulin receptor variant A (IR-A) that is expressed during embryonic development as well as in many cancers. A large body of preclinical evidence suggests that IGF signaling plays a key role in cancer by driving therapy resistance, due to cross-talk with other signaling networks such as androgen receptor signaling. The aim of this study was to explore the potential of the IGF-1/-2 ligand blocking antibody, xentuzumab (BI 836845[1]), to enhance the anti-tumor activity of enzalutamide in prostate cancer cell lines and in a patient-derived prostate cancer xenograft model. Methods: Effects of enzalutamide, xentuzumab and combinations thereof on in vitro proliferation, survival, cell cycle and signaling were evaluated using the prostate cancer cell lines VCaP, DuCaP, MDA PCa 2b, and LNCaP. The in vivo efficacy of enzalutamide, alone and in combination with xentuzumab was investigated using LuCaP 96CR, a patient-derived xenograft model of castration-resistant prostate cancer. Tumors were implanted s.c. into castrate SCID mice. When tumors exceeded 150mm3 animals were randomized into groups: 1) Control; 2) enzalutamide (50 mg/kg QD po), 3) xentuzumab (BI 836845[1], 200 mg/kg QW ip) in combination with enzalutamide. Results: Cell viability was more effectively reduced by the combination of enzalutamide and xentuzumab than either drug alone in three of four cell lines expressing the IGF-1R and the androgen receptor (AR). In VCaP cells, prolonged inhibition of IGF pathway signaling and enhanced blockade of proliferation as well as induction of apoptosis was observed after combination treatment. In vivo, enzalutamide monotherapy did not show significant antitumor efficacy in the LuCaP 96CR model, however, combined treatment with xentuzumab significantly inhibited progression of LuCaP 96CR tumor growth (p Conclusions: These studies demonstrated that addition of the IGF-1/-2 neutralizing antibody xentuzumab to enzalutamide results in improved anti-neoplastic activity in a subset of prostate cancer cell lines in vitro, and to re-sensitization to enzalutamide in a patient-derived xenograft model of CRPC. Reference: [1] Friedbichler K et al. (2014). Mol Cancer Ther 13(2):399-409. Citation Format: Ulrike Weyer-Czernilofsky, Marco H. Hofmann, Paul J. Adam, Flavio Solca, Katrin Friedbichler, Norbert Kraut, Eva Corey, Thomas Bogenrieder. Xentuzumab, a humanized IGF-1 and IGF-2 ligand neutralizing antibody, improves the antitumor efficacy of enzalutamide in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 20. doi:10.1158/1538-7445.AM2017-20

Tinea capitis is a relatively common fungal infection of childhood. Griseofulvin has been the mainstay of management. However, newer oral antifungal agents are being used more frequently. A multicenter, prospective, randomized, single-blinded, non-industry-sponsored study was conducted in centers in Canada and South Africa to determine the relative efficacy and safety of griseofulvin, terbinafine, itraconazole, and fluconazole in the treatment of tinea capitis caused by Trichophyton species. The regimens for treating tinea capitis were griseofulvin microsize 20 mg/kg/day x 6 weeks, terbinafine [> 40 kg, one 250 mg tablet; 20-40 kg, 125 mg (half of a 250 mg tablet); < 20 kg, 62.5 mg (one-quarter of a 250 mg tablet)] x 2-3 weeks, itraconazole 5 mg/kg/day x 2-3 weeks, and fluconazole 6 mg/kg/day x 2-3 weeks. Patients were asked to return at weeks 4, 8, and 12 from the start of the study. Griseofulvin was administered for 6 weeks and the final evaluation was at week 12. Terbinafine, itraconazole, and fluconazole were administered for 2 weeks and the patient evaluated 4 weeks from the start of therapy. At this time, if clinically indicated, one extra week of therapy was given. There were 200 patients randomized to four treatment groups (50 in each group). At the final evaluation at week 12, the number of evaluable patients were griseofulvin, 46; terbinafine, 48; itraconazole, 46; and fluconazole, 46. Patients who discontinued therapy or were lost to follow-up were griseofulvin, 1/3; itraconazole, 0/4; terbinafine, 0/4; and fluconazole, 0/4. The causative organisms were Trichophyton tonsurans and T. violaceum species. Patients were regarded as effectively treated at week 12 if there was mycologic cure and either clinical cure or only a few residual symptoms. Effective treatment was recorded in, intention to treat, griseofulvin (46 of 50, 92.0%), terbinafine (47 of 50, 94.0%), itraconazole (43 of 50, 86.0%), and fluconazole (42 of 50, 84.0%) (p=0.33). Adverse effects were reported only in the griseofulvin group (gastrointestinal effects in six patients). Discontinuation from therapy due to adverse effects occurred only in the griseofulvin group (nausea in one patient). For the treatment of tinea capitis caused by the Trichophyton species, in this study, griseofulvin given for 6 weeks is similar in efficacy to terbinafine, itraconazole, and fluconazole given for 2-3 weeks. Each of the agents has a favorable adverse-effects profile.

Approximately 23 species of thrips were recorded from flowers of 26 species of Australian subtropical rainforest trees, shrubs and vines (in 17 families) in the Manning Valley, coastal northern New South Wales. Pollination by thrips (thripophily) appears more widespread in rainforest communities than has been previously recognized. The pollination ecology of Wilkiea huegeliana (Monimiaceae) was studied in detail. Wilkiea huegeliana is a small, unisexual, annually flowering tree or shrub of rainforest and associated ecotones in eastern Australia, and is a larval food plant for the Regent Skipper butterfly Euschemon rafflesia rafflesia (Hesperiidae). At this latitude W. huegeliana is pollinated solely by a species of thrips, Thrips setipennis, but T. setipennis is not restricted to W. huegeliana and was recorded from flowers of 13 rainforest plant species. It appears to be the obligate pollinator also for Rapanea howittiana and R. variabilis (Myrsinaceae). Pollinator exclusion experiments were inconclusive ...

Tinea capitis is perhaps the most common mycotic infection in children. In North America the epidemiology of tinea capitis has changed so that Trichophyton tonsurans now predominates over Micro-sporum audouinii. With this transition the utility of the Wood's light for diagnosis has been reduced since T. tonsurans infection is Wood's light negative. Griseofulvin has been the mainstay of therapy for the last 40 years. The newer antifungal agents-itraconazole, terbinafine, and fluconazole-appear to be effective and safe for the treatment of tinea capitis. When tinea capitis is due to T. tonsurans or other endothrix species the following regimens have been used: itraconazole continuous regimen (5 mg/kg/day for 4 weeks), itraconazole pulse regimen with capsules (5 mg/kg/day for 1 week plus 1-3 pulses 3 weeks apart), and itraconazole pulse regimen with oral solution (3 mg/kg/day for 1 week plus 1-3 pulses 3 weeks apart). With terbinafine tablets the continuous regimen (>40 kg body weight, 250 mg/day; 20-40 kg, 125 mg/day; and