Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci

The promise of cancer immunotherapy is that it will not only eradicate primary tumors but will generate systemic antitumor immunity capable of destroying distant metastases. A major problem that must first be surmounted relates to the immune resistance of large tumors. Here we reveal that immune resistance can be overcome by combining immunotherapy with a concerted attack on the tumor vasculature. The functionally related antitumor drugs 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone acetic acid (FAA), which cause tumor vasculature collapse and tumor necrosis, were used to attack the tumor vasculature, whereas the T-cell costimulator B7.1 (CD80), which costimulates T-cell proliferation via the CD28 pathway, was used to stimulate antitumor immunity. The injection of cDNA (60–180 µg) encoding B7.1 into large EL-4 tumors (0.8 cm in diameter) established in C57BL/6 mice, followed 24 h later by i.p. administration of either DMXAA (25 mg/kg) or FAA (300 mg/kg), resulted in complete tumor eradication within 2–6 weeks. In contrast, monotherapies were ineffective. Both vascular attack and B7.1 immunotherapy led to up-regulation of heat shock protein 70 on stressed and dying tumor cells, potentially augmenting immunotherapy. Remarkably, large tumors took on the appearance of a wound that rapidly ameliorated, leaving perfectly healed skin. Combined therapy was mediated by CD8+ T cells and natural killer cells, accompanied by heightened and prolonged antitumor cytolytic activity (P < 0.001), and by a marked increase in tumor cell apoptosis. Cured animals completely rejected a challenge of 1 x 107 parental EL-4 tumor cells but not a challenge of 1 x 104 Lewis lung carcinoma cells, demonstrating that antitumor immunity was tumor specific. Adoptive transfer of 2 x 108 splenocytes from treated mice into recipients bearing established (0.8 cm in diameter) tumors resulted in rapid and complete tumor rejection within 3 weeks. Although DMXAA and B7.1 monotherapies are complicated by a narrow range of effective doses, combined therapy was less dosage dependent. Thus, a broad range of amounts of B7.1 cDNA were effective in combination with 25 mg/kg DMXAA. In contrast, DMXAA, which has a very narrow range of high active doses, was effective at a low dose (18 mg/kg) when administered with a large amount (180 µg) of B7.1 cDNA. Importantly, combinational therapy generated heightened antitumor immunity, such that gene transfer of B7.1 into one tumor, followed by systemic DMXAA treatment, led to the complete rejection of multiple untreated tumor nodules established in the opposing flank. These findings have important implications for the future direction and utility of cancer immunotherapies aimed at harnessing patients’ immune responses to their own tumors.

A practical guide to the application of the IUCN Red List of Ecosystems criteria

The newly developed IUCN Red List of Ecosystems is part of a growing toolbox for assessing risks to biodiversity, which addresses ecosystems and their functioning. The Red List of Ecosystems standard allows systematic assessment of all freshwater, marine, terrestrial and subterranean ecosystem types in terms of their global risk of collapse. In addition, the Red List of Ecosystems categories and criteria provide a technical base for assessments of ecosystem status at the regional, national, or subnational level. While the Red List of Ecosystems criteria were designed to be widely applicable by scientists and practitioners, guidelines are needed to ensure they are implemented in a standardized manner to reduce epistemic uncertainties and allow robust comparisons among ecosystems and over time. We review the intended application of the Red List of Ecosystems assessment process, summarize 'best-practice' methods for ecosystem assessments and outline approaches to ensure operational rigour of assessments. The Red List of Ecosystems will inform priority setting for ecosystem types worldwide, and strengthen capacity to report on progress towards the Aichi Targets of the Convention on Biological Diversity. When integrated with other IUCN knowledge products, such as the World Database of Protected Areas/Protected Planet, Key Biodiversity Areas and the IUCN Red List of Threatened Species, the Red List of Ecosystems will contribute to providing the most complete global measure of the status of biodiversity yet achieved.

Higher adherence to the Australian dietary guidelines is associated with better mental health status among Australian adult first-time mothers

Background: Mental health disorders are a leading cause of disability worldwide, including in first-time mothers. Understanding the associations between diet and depressive symptoms could assist in improving mental health status in this group. Objective: Our aim was to determine the association between diet quality, fruit, vegetable, and fish consumption and depressive symptoms in first-time mothers aged 19 to 45 years.

Design: We analyzed cross-sectional, baseline data (3 months postpartum) from the Melbourne InFANT (Infant Feeding, Activity, and Nutrition Trial) Extend Program.

Participants/setting: Participants were first-time Australian mothers aged 19 to 45 years from the Geelong and Melbourne regions of Victoria, Australia (n=457).

Main outcome measures: A self-administered, 137-item food frequency questionnaire assessed dietary intake over the past year. Adherence to the 2013 Australian Dietary Guidelines was assessed using the Dietary Guideline Index as a measure of diet quality. Depressive symptoms were determined using the Center for Epidemiologic Studies Depression Scale.

Statistical analysis performed: Relationships between diet quality, fruit, vegetable, and fish intake and depressive symptoms were investigated using linear regression adjusted for relevant covariates (age, smoking status, sleep quality, education, physical activity status, and body mass index).

Results: Better diet quality, as indicated by a higher score on the Dietary Guideline Index, was associated with lower depressive symptoms after adjusting for relevant covariates (β=-.034; 95% CI -.056 to -0.012). There were no other associations between dietary intake and depressive symptoms.

Conclusions: Adherence to the Australian Dietary Guidelines was associated with better mental health status among first-time mothers. Further research, including longitudinal and intervention studies, are required to determine causality between dietary intake and depressive symptoms, which might help inform future public health nutrition programs for this target group.

Molecular dynamics approach to the structural characterization and transport properties of poly(acrylonitrile)/N,N-dimethylformamide solutions

Poly(acrylonitrile) (PAN) in N,N-dimethylformamide (DMF) is a popular solution for producing large variety of polymer products. To precisely describe the behaviours of PAN and DMF in the synthesis processes, it is significant to call for more details about the structure, some thermodynamic and dynamical properties of PAN-DMF solutions. A PAN-DMF solution was simulated via molecular dynamics with an all-atom OPLS type potential in both the NPT and NVT ensembles. The simulation results were evaluated with quantum mechanical calculations (MP2/6-311 ++G(d,p) and counterpoise procedure) and were compared with available experimental results. The liquid structure was illustrated with pair correlation functions and transport and dynamics properties were calculated with the mean-square displacements MSD and the velocity autocorrelation functions. The strong H-bonds of C≡N « H-C=O, CH » O=C-H and CH2 O=C-H, with distances of 2.55 Å, 2.55 Å and 2.65 Å, respectively, were found. The largest interaction energy of - 7.157 kcal/mol between DMF molecules and PAN molecules was found at 4.9 Å center-of-mass distance. A potential profile of intermolecular interaction of DMF with PAN along the interaction distance was presented, clearly showing an increase of DMF vaporisation heat when it getting close to PAN molecules. This provided very useful information to analyse the vaporisation behaviours of DMF at the microscopic level, which is essential to comprehensively understand molecular rearrangements towards the design of synthetic processes. The impact of the presence of the PAN on the DMF solution properties were also benchmarked with pure DMF solution.

Collapse of the world’s largest herbivores

Large wild herbivores are crucial to ecosystems and human societies. We highlight the 74 largest terrestrial herbivore species on Earth (body mass≥100 kg), the threats they face, their important and often overlooked ecosystem effects, and the conservation efforts needed to save them and their predators from extinction. Large herbivores aregenerally facing dramatic population declines and range contractions, such that ~60% are threatened with extinction. Nearly all threatened species are in developing countries, where major threats include hunting, land-use change, and resource depression by livestock. Loss of large herbivores can have cascading effects on other species including large carnivores, scavengers, mesoherbivores, small mammals, and ecological processes involving vegetation, hydrology, nutrient cycling, and fire regimes. The rate of large herbivore decline suggests that ever-largerswaths of the world will soon lack many of the vital ecological services these animals provide, resulting in enormous ecological and social costs.