The Influence of Parasite Infections on Host Immunity to Co-Infection with Other Pathogens

Parasites have evolved a wide range of mechanisms that they use to evade or manipulate the host's immune response and establish infection. The majority of the in vivo studies that have investigated these host-parasite interactions have been undertaken in experimental animals, especially rodents, which were housed and maintained to a high microbiological status. However, in the field situation it is increasingly apparent that pathogen co-infections within the same host are a common occurrence. For example, chronic infection with pathogens including malarial parasites, soil-transmitted helminths, Mycobacterium tuberculosis and viruses such as HIV may affect a third of the human population of some developing countries. Increasing evidence shows that co-infection with these pathogens may alter susceptibility to other important pathogens, and/or influence vaccine efficacy through their effects on host immune responsiveness. Co-infection with certain pathogens may also hinder accurate disease diagnosis. This review summarizes our current understanding of how the host's immune response to infection with different types of parasites can influence susceptibility to infection with other pathogenic microorganisms. A greater understanding of how infectious disease susceptibility and pathogenesis can be influenced by parasite co-infections will enhance disease diagnosis and the design of novel vaccines or therapeutics to more effectively control the spread of infectious diseases

Letters to the Editor

The Rangelands archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform March 202

Whitehorse Butte Allotment—Poor Public Range Policy?

This material was digitized as part of a cooperative project between the Society for Range Management, the National Agricultural Library, and the University of Arizona Libraries.The Rangelands archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform March 202

Wall Creek Game Range—A Dissenting View

This material was digitized as part of a cooperative project between the Society for Range Management, the National Agricultural Library, and the University of Arizona Libraries.The Rangelands archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform March 202

Hydrogen-bonded assemblies of dyes and extended π-conjugated systems

Recent developments in the area of hydrogen-bonded supramolecular assemblies of functional dyes and extended π-conjugated systems are described. Emphasis is given to the hydrogen-bonded assemblies of dyes such as porphyrins, perylene bisimides, cyanines and azo compounds. In addition, a state-of-the-art summary of the recent developments in the design and properties of hydrogen-bonded supramolecular architectures of extended π-conjugated systems, that is oligomers and polymers, is presented. Finally, the current status of the design and studies of hydrogen-bonded π-conjugated gel systems and their application is described

Holistic Management: Misinformation on the Science of Grazed Ecosystems

Over 3 billion hectares of lands worldwide are grazed by livestock, with a majority suffering degradation in ecological condition. Losses in plant productivity, biodiversity of plant and animal communities, and carbon storage are occurring as a result of livestock grazing. Holistic management (HM) has been proposed as a means of restoring degraded deserts and grasslands and reversing climate change. The fundamental approach of this system is based on frequently rotating livestock herds to mimic native ungulates reacting to predators in order to break up biological soil crusts and trample plants and soils to promote restoration. This review could find no peer-reviewed studies that show that this management approach is superior to conventional grazing systems in outcomes. Any claims of success due to HM are likely due to the management aspects of goal setting, monitoring, and adapting to meet goals, not the ecological principles embodied in HM. Ecologically, the application of HM principles of trampling and intensive foraging are as detrimental to plants, soils, water storage, and plant productivity as are conventional grazing systems. Contrary to claims made that HM will reverse climate change, the scientific evidence is that global greenhouse gas emissions are vastly larger than the capacity of worldwide grasslands and deserts to store the carbon emitted each year

Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies

Background: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). Methods: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics. Results: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined. Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors. Translational relevance: Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity

First-in-Human, Phase I Dose-Escalation Study of CGM097, a HDM2 Inhibitor in Adult Patients With p53 Wild-type Advanced Solid Malignancies

Background: CGM097 inhibits p53-HDM2 interaction, thus activates p53 downstream effector pathways inducing cell cycle arrest and/or apoptosis. This phase I study aimed at assessing the safety, MTD, PK/PD, and preliminary antitumor activity of CGM097 in advanced solid tumors patients (NCT01760525). Methods: Fifty-one patients received oral treatment with CGM097 10-400mg 3qw (n=31) and on an alternative regimen of 3qw 2 weeks on/1 week off (300-700mg; n=20). Choice of dose regimen was guided by PD biomarkers, PK/PD relationship, and modeling of drug-induced changes in platelet kinetics. Results: No dose-limiting toxicities were reported in any regimens. Grade 3/4 AEs suspected to be drug-related were reported in 21 patients. Main reason for discontinuation was disease progression (n=41). CGM097 plasma concentrations increased in a dose proportional manner. Disease control rate was 39%, including one partial response (300mg, 3qw) and 19 patients in stable disease (10-700mg 3qw). Forty patients had a cumulative treatment duration of >16 weeks, with 8 patients on treatment for >32 weeks. The MTD was not determined. Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. Although CGM097 is not being further developed, this study led to important modeling-derived learnings to optimize dose scheduling of next generation HDM2 inhibitors

Short and long-term phytoremediation capacity of aquatic plants in Cu-polluted environments

Freshwater ecosystems face numerous threats from human populations, including heavy metal contamination. Phytoremediation, the use of plants to remediate contaminated soils and sediments, is an effective and low-cost means of removing chemical contaminants, including heavy metals, from polluted environments. However, key questions remain unanswered in the application of this technology in aquatic environments, such as the long-term fate of pollutants following plant uptake. In this study, using two common wetland plant species (duckweed and tape grass), we first examined the capacity of plants to remove copper (Cu) from polluted water. Next, we evaluated the leaching potential of plant tissues following decomposition and how it is affected by a simulated freeze-thaw cycle. Using phytoremediated water and leachates from senesced plants we assessed phytoremediation success and Cu leaching potential by conducting standard toxicity assays using pond snails (Physa acuta), a species with known Cu sensitivity. We found that duckweed outperformed tape grass as a phytoremediator at low Cu concentrations. In addition, for plants grown in low concentrations of Cu, leaching from decaying plant material did not negatively impact snail survival, while at high concentrations of Cu, leaching did result in toxicity. Lastly, we found that a simulated freeze-thaw cycle increased the release of Cu from plant tissue in the presence of high Cu concentrations only, resulting in reduced snail survival. Our results indicate that in moderately Cu-polluted environments, some aquatic plants can remove contaminants without a long-term risk of leaching. In contrast, phytoremediation in highly polluted environments will likely require removal of plant tissue to prevent leaching of previously accumulated metals. Land managers must not only consider plant species and degree of contamination, but also geographic location, as freeze-thaw cycles may enhance plant decomposition and increase the likelihood of contaminant leaching following phytoremediation efforts in aquatic ecosystems