93 research outputs found
Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug conjugates (ADcs)
Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation. For antibody selection, we evaluated internalization by target cells using streptavidin-linked antibodies conjugated to biotinylated saporin, a toxin unable to cross cell membranes. For payload selection, we biotinylated toxins and conjugated them to antibodies linked to streptavidin to evaluate antitumour activity and pre-clinical safety. As proof of principle, we compared trastuzumab conjugated to emtansine via streptavidin-biotin (Trastuzumab-SB-DM1) to the clinically approved trastuzumab emtansine (T-DM1). We showed comparable potency in reduction of breast cancer cell survival in vitro and in growth restriction of orthotopic breast cancer xenografts in vivo. Our findings indicate efficient generation of functionally active ADCs. This approach can facilitate the study of antibody and payload combinations for selection of promising candidates for future ADC development
Targeting Potential Drivers of COVID-19: Neutrophil Extracellular Traps
Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19
Schottky barrier heights at polar metal/semiconductor interfaces
Using a first-principle pseudopotential approach, we have investigated the
Schottky barrier heights of abrupt Al/Ge, Al/GaAs, Al/AlAs, and Al/ZnSe (100)
junctions, and their dependence on the semiconductor chemical composition and
surface termination. A model based on linear-response theory is developed,
which provides a simple, yet accurate description of the barrier-height
variations with the chemical composition of the semiconductor. The larger
barrier values found for the anion- than for the cation-terminated surfaces are
explained in terms of the screened charge of the polar semiconductor surface
and its image charge at the metal surface. Atomic scale computations show how
the classical image charge concept, valid for charges placed at large distances
from the metal, extends to distances shorter than the decay length of the
metal-induced-gap states.Comment: REVTeX 4, 11 pages, 6 EPS figure
HAS-1 genetic polymorphism in sporadic abdominal aortic aneurysm
The hyaluronan synthase 1 (HAS-1) gene encodes a plasma membrane protein that synthesizes hyaluronan (HA), an extracellular matrix molecule. Accumulating evidence emphasizes the relevance of HA metabolism in an increasing number of processes of clinical interest, including abdominal aortic aneurysm (AAA). The existence of aberrant splicing variants of the HAS-1 gene could partly explain the altered extracellular matrix architecture and influence various biological functions, resulting in progressive arterial wall failure in the development of AAA. In the present study, we assessed the hypothesis that HAS-1 genetic 833A/G polymorphism could be associated with the risk of AAA by performing a case-control association study, involving AAA patients and healthy matched donors
Physics of Solar Prominences: I - Spectral Diagnostics and Non-LTE Modelling
This review paper outlines background information and covers recent advances
made via the analysis of spectra and images of prominence plasma and the
increased sophistication of non-LTE (ie when there is a departure from Local
Thermodynamic Equilibrium) radiative transfer models. We first describe the
spectral inversion techniques that have been used to infer the plasma
parameters important for the general properties of the prominence plasma in
both its cool core and the hotter prominence-corona transition region. We also
review studies devoted to the observation of bulk motions of the prominence
plasma and to the determination of prominence mass. However, a simple inversion
of spectroscopic data usually fails when the lines become optically thick at
certain wavelengths. Therefore, complex non-LTE models become necessary. We
thus present the basics of non-LTE radiative transfer theory and the associated
multi-level radiative transfer problems. The main results of one- and
two-dimensional models of the prominences and their fine-structures are
presented. We then discuss the energy balance in various prominence models.
Finally, we outline the outstanding observational and theoretical questions,
and the directions for future progress in our understanding of solar
prominences.Comment: 96 pages, 37 figures, Space Science Reviews. Some figures may have a
better resolution in the published version. New version reflects minor
changes brought after proof editin
Recent Advances in Understanding Particle Acceleration Processes in Solar Flares
We review basic theoretical concepts in particle acceleration, with
particular emphasis on processes likely to occur in regions of magnetic
reconnection. Several new developments are discussed, including detailed
studies of reconnection in three-dimensional magnetic field configurations
(e.g., current sheets, collapsing traps, separatrix regions) and stochastic
acceleration in a turbulent environment. Fluid, test-particle, and
particle-in-cell approaches are used and results compared. While these studies
show considerable promise in accounting for the various observational
manifestations of solar flares, they are limited by a number of factors, mostly
relating to available computational power. Not the least of these issues is the
need to explicitly incorporate the electrodynamic feedback of the accelerated
particles themselves on the environment in which they are accelerated. A brief
prognosis for future advancement is offered.Comment: This is a chapter in a monograph on the physics of solar flares,
inspired by RHESSI observations. The individual articles are to appear in
Space Science Reviews (2011
Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume
The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes
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