Automated analysis of retinal imaging using machine learning techniques for computer vision

There are almost two million people in the United Kingdom living with sight loss, including around 360,000 people who are registered as blind or partially sighted. Sight threatening diseases, such as diabetic retinopathy and age related macular degeneration have contributed to the 40% increase in outpatient attendances in the last decade but are amenable to early detection and monitoring. With early and appropriate intervention, blindness may be prevented in many cases. Ophthalmic imaging provides a way to diagnose and objectively assess the progression of a number of pathologies including neovascular (“wet”) age-related macular degeneration (wet AMD) and diabetic retinopathy. Two methods of imaging are commonly used: digital photographs of the fundus (the ‘back’ of the eye) and Optical Coherence Tomography (OCT, a modality that uses light waves in a similar way to how ultrasound uses sound waves). Changes in population demographics and expectations and the changing pattern of chronic diseases creates a rising demand for such imaging. Meanwhile, interrogation of such images is time consuming, costly, and prone to human error. The application of novel analysis methods may provide a solution to these challenges. This research will focus on applying novel machine learning algorithms to automatic analysis of both digital fundus photographs and OCT in Moorfields Eye Hospital NHS Foundation Trust patients. Through analysis of the images used in ophthalmology, along with relevant clinical and demographic information, Google DeepMind Health will investigate the feasibility of automated grading of digital fundus photographs and OCT and provide novel quantitative measures for specific disease features and for monitoring the therapeutic success

Alternative somatic cell count traits exploitable in genetic selection for mastitis resistance in Italian Holsteins

The aim of the present study was to characterize alternative somatic cell count (SCC) traits that could be exploited in genetic selection for mastitis resistance. Data were from 66,407 first-parity Holsteins in 404 herds. Novel SCC traits included average somatic cell score (SCS, log-transformation of SCC) in early lactation (SCS_150), standard deviation of SCS of the entire lactation (SCS_SD), the presence of at least one test-day (TD) SCC >400,000 cells/mL in the lactation, and the ratio of number of TD SCC >400,000 cells/mL to total number of TD in the lactation. Novel traits and lactation-mean SCS (SCS_LM) were analyzed using linear mixed or logistic regression models, including month of calving, year of calving, number of TD, and milk yield as fixed effects, and herd and residual as random terms. A multitrait linear animal model was applied to a random subset of 152 herds (n = 22,695 cows) to assess heritability of and genetic correlations between SCC traits. Alternative SCC traits were affected by the environmental factors included in the model; in particular, results suggested a seasonal effect and a tendency toward an improvement of the udder health status in the last years. Association was also found between novel SCC traits and milk production. Alternative SCC traits exhibited coefficients of additive genetic variation that were similar to or larger than that of traditional SCS_LM. Heritability of novel SCC traits was smaller than heritability of SCS_LM (0.126 \ub1 0.014), ranging from 0.044 \ub1 0.008 (SCS_SD) to 0.087 \ub1 0.010 (SCS_150). Genetic correlations between SCC traits ranged from 0.217 \ub1 0.096 (SCS_150 and SCS_SD) to 0.969 \ub1 0.010 (SCS_LM and SCS_150). Alternative SCC traits exhibited additive genetic variation that is potentially exploitable in breeding programs of Italian Holstein population to improve resistance to mastitis

A critical review of palladium organometallic anticancer agents

With the aim of overcoming the well-known limitations of platinum-based antineoplastic drugs, recent efforts have focused on the development of new anticancer agents containing metals other than platinum. Among these agents, organopalladium compounds have received significant recent attention due to their generally high stability under physiological conditions. A significant number of these compounds have shown promising in vitro and in vivo antiproliferative activity toward several cisplatin-sensitive and cisplatin-resistant tumors and have sometimes exhibited a different mechanism of action compared to platinum-based drugs. In this review, recent advances in the field of organopalladium compounds as potential anticancer agents are discussed

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

Trissolcus kozlovi in North Italy: host specificity and augmentative releases against Halyomorpha halys in hazelnut orchards

Trissolcus kozlovi (Hymenoptera: Scelionidae) emerged from field-laid eggs of Halyomorpha halys (Hemiptera: Pentatomidae) in North Italy, and it emerged in significantly higher numbers from fresh H. halys eggs compared to other native scelionids. Since few data on T. kozlovi are available, its host-specificity and some biological traits were investigated in laboratory tests, and its impact after augmentative releases was evaluated in two hazelnut orchards. Among the 12 tested bug species (Hemiptera: Pentatomidae, Scutelleridae), only Nezara viridula was an unsuitable host, while the highest offspring proportions were obtained from Arma custos, Pentatoma rufipes, and Peribalus strictus, followed by Acrosternum heegeri and Palomena prasina. Furthermore, when reared on P. strictus, T. kozlovi showed a high longevity as well as a high adaptation to H. halys eggs. In both hazelnut orchards, T. kozlovi emerged from H. halys eggs after field releases, but it was not found in the next two years. The physiological host range of T. kozlovi was quite similar to that of T. japonicus, and probably T. kozlovi has just begun to attack H. halys as a new host. This aspect needs to be further investigated, as well as its favorable environmental conditions, its distribution and also its possible interaction with T. japonicus, currently present in Italy

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

Palladium(II)-η3-Allyl Complexes Bearing N-Trifluoromethyl N-Heterocyclic Carbenes: A New Generation of Anticancer Agents that Restrain the Growth of High-Grade Serous Ovarian Cancer Tumoroids

The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η3-allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02–0.5 μm). By choosing 1,3,5-triaza-7-phosphaadamantane (PTA) as co-ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2-methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3-allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids

Synthesis and anticancer activity of Pt(0)-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane and N-heterocyclic carbene ligands

A series of Pt(0)-η2-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane (PTA) or N-heterocyclic carbenes are prepared following different synthetic strategies depending on the nature of coordinated alkene and spectator ligands. These new platinum(0) derivatives have been tested in vitro as anticancer agents toward three different tumor (human ovarian cancer A2780 and A2780cis and K562 myelogenous leukemia) and one non-tumor (Hacat keratinocytes) cell lines, proving to be in several cases highly and selectively cytotoxic against ovarian cancer cells. Furthermore, this antiproliferative effect is associated with the activation of an apoptosis process. In particular, complexes equipped with PTA as spectator ligand give comparable IC50 values on A2780 (cisplatin sensitive) and A2780cis (cisplatin resistant) cell lines, indirectly proving that these new Pt(0) substrates act with a mechanism of action conceivably different from cisplatin. This hypothesis is also confirmed by the fact that our compounds, in contrast to cisplatin, are not able to promote erythroid-differentiation activity on the K562 myelogenous leukemia cell line