Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis

This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection model

An overview of population-based algorithms for multi-objective optimisation

In this work we present an overview of the most prominent population-based algorithms and the methodologies used to extend them to multiple objective problems. Although not exact in the mathematical sense, it has long been recognised that population-based multi-objective optimisation techniques for real-world applications are immensely valuable and versatile. These techniques are usually employed when exact optimisation methods are not easily applicable or simply when, due to sheer complexity, such techniques could potentially be very costly. Another advantage is that since a population of decision vectors is considered in each generation these algorithms are implicitly parallelisable and can generate an approximation of the entire Pareto front at each iteration. A critique of their capabilities is also provided

HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC) function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α), a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver), and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO) approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPCs) are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPCs and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

GALILEO Knowledge Repository (GKR) Metadata

Presented at the Cooperative Curation Symposium and Workshop, Thursday, August 9, 2012 in the Clough Commons classroom 102, Georgia Tech Library.Cooperative Curation Workshop: Georgia’s Approach to Statewide Repository Services - Technology Track: Metadata - Breakout Session 2.Catherine Jannik Downey, Head of Access Services at Georgia Gwinnett College, moderated this presentation.Andy Carter is the Digital Projects Archivist at Digital Library of Georgia. Robin Fay is Head, Database Maintenance for the University of Georgia Libraries. Marlee Givens is the GALILEO Knowledge Repository (GKR) Manager, Georgia Tech Library. Susan Wells Parham is Head of Scholarly Communication and Digital Curation, Georgia Tech Library.GKR metadata origins and guidelines, creating metadata in DSpace, training GKR partners and a list of disciplines

Proposal that the strains of the Mycoplasma ovine/caprine serogroup 11 be reclassified as Mycoplasma bovigenitalium

This proposal is our response to the recommendation of the International Committee on Systematics of Prokaryotes (Subcommittee on the taxonomy of Mollicutes) that we 'write a proposal to classify Mycoplasma bovigenitalium and ovine/caprine serogroup 11 as a single species'. Physiological and phylogenetic comparisons between 27 strains of M. bovigenitalium and Mycoplasma serogroup 11 showed that (i) growth and patterns of organic acid substrate use completely overlapped among strains; (ii) all had lipase and phosphatase activities; (iii) the strains were indistinguishable in their SIDS-PAGE whole-cell protein profiles, which differed from five other species; (iv) strains were indistinguishable in immunoblotting of cell proteins and cross- reactivity in ELISA, but differed from other Mycoplasma species; (v) DNA-DNA hybridization did not distinguish between the two groups, and (vi) comparison of 16S and 23S rRNA gene sequences of ten strains of Mycoplasma serogroup 11 and six strains of M. bovigenitalium showed that they shared 98-100 % similarity across all strains tested, but only 86-95 % to other Mycoplasma species. Strains of the Mycoplasma ovine/caprine serogroup 11 must therefore be reassigned as Mycoplasma bovigenitalium