Investigation of refractive index dynamics during in vitro embryo development using off-axis digital holographic microscopy

Funding: Engineering and Physical Sciences Research Council - EP/P030017/1, EP/R004854/1; Australian Research Council - FL210100099; National Health and Medical Research Council - APP2003786; Future Making Fellowship (University of Adelaide); Hospital Research Foundation (Mid-career fellowship C-MCF58-2019).Embryo quality is a crucial factor affecting live birth outcomes. However, an accurate diagnostic for embryo quality remains elusive in the in vitro fertilization clinic. Determining physical parameters of the embryo may offer key information for this purpose. Here, we demonstrate that digital holographic microscopy (DHM) can rapidly and non-invasively assess the refractive index of mouse embryos. Murine embryos were cultured in either low- or high-lipid containing media and digital holograms recorded at various stages of development. The phase of the recorded hologram was numerically retrieved, from which the refractive index of the embryo was calculated. We showed that DHM can detect spatio-temporal changes in refractive index during embryo development that are reflective of its lipid content. As accumulation of intracellular lipid is known to compromise embryo health, DHM may prove beneficial in developing an accurate, non-invasive, multimodal diagnostic.Publisher PDFPeer reviewe

First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas

Antibodies; Combination; NeoplasmAnticossos; Combinació; NeoplàsiaAnticuerpos; Combinación; NeoplasiaBackground GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed. Methods Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10–1500 mg) or GWN323+spartalizumab (GWN323 10–750 mg+spartalizumab 100–300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1. Results Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures. Conclusions GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.This study was supported by Novartis Oncology

Economic and Environmental Impacts of Harmful Non-Indigenous Species in Southeast Asia

Harmful non-indigenous species (NIS) impose great economic and environmental impacts globally, but little is known about their impacts in Southeast Asia. Lack of knowledge of the magnitude of the problem hinders the allocation of appropriate resources for NIS prevention and management. We used benefit-cost analysis embedded in a Monte-Carlo simulation model and analysed economic and environmental impacts of NIS in the region to estimate the total burden of NIS in Southeast Asia. The total annual loss caused by NIS to agriculture, human health and the environment in Southeast Asia is estimated to be US$33.5 billion (5th and 95th percentile US$25.8–39.8 billion). Losses and costs to the agricultural sector are estimated to be nearly 90% of the total (US$23.4–33.9 billion), while the annual costs associated with human health and the environment are US$1.85 billion (US$1.4–2.5 billion) and US$2.1 billion (US$0.9–3.3 billion), respectively, although these estimates are based on conservative assumptions. We demonstrate that the economic and environmental impacts of NIS in low and middle-income regions can be considerable and that further measures, such as the adoption of regional risk assessment protocols to inform decisions on prevention and control of NIS in Southeast Asia, could be beneficial

Electronic structure of Li2 RuO3 studied by LDA and LDA+DMFT calculations and soft x-ray spectroscopy

The electronic structure of Li2RuO3 was investigated using x-ray emission and absorption spectroscopy and by theoretical calculations employing two approaches: the local density approximation (LDA) and a combination of LDA with the cluster extension of dynamical mean-field theory (LDA+DMFT). The evolution of the spectral properties with the strength of electronic correlations is analyzed. We show that for moderate values of on-site Coulomb repulsion U and intra-atomic Hund's rule exchange JH,Li2RuO3 is in an orbital-selective strongly correlated state in the sense that a part of the t2g manifold (i.e., xz/yz) behaves as local atomic orbitals susceptible to Hubbard correlations, while the remaining (xy) orbitals must be described as bond-centered molecular orbitals. Both theoretical approaches succeed in explaining the x-ray data, and a comparison of the theoretical and experimental spectra provides a reasonable estimate of the possible correlation strength (U) and Hund's coupling (JH) in Li2RuO3. © 2015 American Physical Society1771sciescopu