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Supplementary Figures S1-S6. Supplementary Figure S1. Liquid chromatography electrospray ionization tandem mass spectrometry analysis; Supplementary Figure S2. TM4SF1 expression in human breast and colon cancers; Supplementary Figure S3A. Clearance of anti-TM4SF1 antibody from HUVEC surface; Supplementary Figure S3B. Uptake of anti-TM4SF1 antibody in HUVEC; Supplementary Figure S4A. NSCLC killing by anti-TM4SF1 ADC; Supplementary Figure S4B. Tumor cell killing by anti-TM4SF1 ADC; Supplementary Figure S5. Expression level of TM4SF1 and other endothelial cell markers in tumor xenografts; Supplementary Figure S6. Clearance of anti-TM4SF1 ADCs; tolerance in mice.

Introduction: Thermocouples located inside conventional ablation catheters do not measure tissue temperature nor determine thermal lesion size during cardiac catheter ablation. Hypothesis: Progressive, thermally mediated changes in tissue composition can be detected by the return loss spectrum of a microwave antenna coupling to tissue in the microwave band. Results: Return loss (RL) exhibited characteristic changes in the 1.6 to 1.7 GHz band during heating (Panel A). Heating to a temperature lethal to the myocardium (50°C) reduced the RL amplitude of the sample from baseline by 346.7% (-10.80 ± 4.430 dB, p = 0.0055). Further temperature rise restituted RL amplitude back to approximately baseline values at 64°C to 70°C (Panel B). Conclusion: The pattern of RL amplitude change in the 1.6 - 1.7 GHz microwave band may be useful for detecting lethal thermal myocardial injury and prevent overheating. This observation may have applications for monitoring cardiac catheter ablation.

Purpose Impaired digital reactive hyperaemia and flicker-stimulated retinal vascular response are commonly reported risk markers of cardiovascular disease. This is the first study to determine the correlation of these risk markers with diabetes mellitus by comparing our novel flicker-modulated ECG-gated fundoscope with the EndoPAT2000 system. Methods In total, 119 controls and 120 participants with diabetes mellitus partook in this cross-sectional study. The EndoPAT2000 system assessed digital reactive hyperaemia under fasting conditions. A mydriatic ECG-gated fundoscope with a novel flicker module acquired digital retinal images of the left eye before, during and after flicker stimulation. An inhouse semi-automated software measured retinal vessel diameters using a validated protocol with two observers repeating measurements in a subset of 10 controls and 10 participants with diabetes mellitus. Intra- and inter-observer reliability analyses occurred by the interclass correlation coefficient. A receiver operating characteristic curve established associations of variables with diabetes mellitus. Results Diabetes mellitus was more strongly associated with flicker-stimulated retinal arteriolar calibre change from baseline (AUC 0.81, 95% CI 0.75–0.87, p p p = 0.003) were lower in diabetes mellitus than controls. Intra- and inter-observer reliability coefficients were high from 0.87 to 0.93. Conclusions Impaired flicker-stimulated retinal arteriolar calibre change from baseline is more highly correlated with diabetes mellitus in this study than a reduced reactive hyperaemia index.

Set pieces in soccer (i.e., free kicks and corners) have been examined in detail and are a common focus for coaches during training and performance preparation. However, limited evidence is available on the impact of throw-ins on soccer performance and if coaches should dedicate time in training towards this specific set piece. Therefore, this research aimed to firstly examine if throw-in performance is linked with soccer performance, and secondly the effect throw-in direction and length has on first contact success rate, possession retention, mean time in possession and shot creation. 16,154 throw-ins from 380 English Premier League matches during the 2018–2019 season were analysed. Higher final league position was correlated to increased throw-in first contact success and possession retention. 83% of throw-in’s resulted in a successful first contact, 54% resulted in possession being retained and 8.8% of throw-ins led to a shot at goal from the possession achieved after a successful first contact. Throw-in’s which went backwards or laterally in direction resulted in increased first contact success, retaining of possession, and shot creation. The least efficient throw-in was forwards and long, which resulted in both reduced first contact success and possession retention. Findings highlight, that throwing the ball laterally or backwards should be a focus for coaches and players during attacking training. In contrast, a team’s defensive strategy should reduce the opportunities to throw backwards or laterally with a higher press and look to force a long forward throw-in, therefore, increasing the likelihood of winning possession and counter attacking.

IL-13 contributes to airway hyperresponsiveness, mucus secretion, inflammation, and fibrosis, suggesting that it plays a central role in asthma pathogenesis. Neutralization of IL-13 with sIL-13Ralpha2-Fc (sIL-13R) reduces allergen-induced airway responses in rodent models of respiratory disease, but its efficacy in a large animal model has not been previously reported. In this study, we determined whether two different strategies for IL-13 neutralization modified experimental asthma in sheep. Sheep with natural airway hypersensitivity to Ascaris suum antigen were treated intravenously either with sIL-13R, a strong antagonist of sheep IL-13 bioactivity in vitro, or with IMA-638 (IgG1, kappa), a humanized antibody to human IL-13. Higher doses of IMA-638 were used because, although it is a potent antagonist of human IL-13, this antibody has 20 to 30 times lower binding and neutralization activity against sheep IL-13. Control animals received human IgG of irrelevant specificity. Sheep were treated 24 h before inhalation challenge with nebulized A. suum. The effects on antigen-induced early and late bronchial responses, and antigen-induced hyperresponsiveness, were assessed. Both sIL-13R and IMA-638 provided dose-dependent inhibition of the antigen-induced late responses and airway hyperresponsiveness. The highest dose of IMA-638 also reduced the early phase response. These findings suggest that IL-13 contributes to allergen-induced airway responses in this sheep model of asthma, and that neutralization of IL-13 is an effective strategy for blocking these A. suum-induced effects.

Antibody–drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report a novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on the plasma membranes of many human cancer cells and also on the endothelial cells lining tumor blood vessels. TM4SF1 is internalized upon interaction with antibodies. We hypothesized that an ADC against TM4SF1 would inhibit cancer growth directly by killing cancer cells and indirectly by attacking the tumor vasculature. We generated a humanized anti-human TM4SF1 monoclonal antibody, v1.10, and armed it with an auristatin cytotoxic agent LP2 (chemical name mc-3377). v1.10-LP2 selectively killed cultured human tumor cell lines and human endothelial cells that express TM4SF1. Acting as a single agent, v1.10-LP2 induced complete regression of several TM4SF1-expressing tumor xenografts in nude mice, including non–small cell lung cancer and pancreas, prostate, and colon cancers. As v1.10 did not react with mouse TM4SF1, it could not target the mouse tumor vasculature. Therefore, we generated a surrogate anti-mouse TM4SF1 antibody, 2A7A, and conjugated it to LP2. At 3 mpk, 2A7A-LP2 regressed several tumor xenografts without noticeable toxicity. Combination therapy with v1.10-LP2 and 2A7A-LP2 together was more effective than either ADC alone. These data provide proof-of-concept that TM4SF1-targeting ADCs have potential as anticancer agents with dual action against tumor cells and the tumor vasculature. Such agents could offer exceptional therapeutic value and warrant further investigation. Mol Cancer Ther; 14(8); 1868–76. ©2015 AACR . This article is featured in Highlights of This Issue, [p. 1765][1] [1]: /lookup/volpage/14/1765?iss=8

Pulmonary vein isolation is an effective treatment for atrial fibrillation. Current endocardial ablation techniques require catheter contact for lesion formation. Inadequate or inconsistent catheter contact results in difficulty with achieving acute and long-term isolation and consequent atrial arrhythmia recurrence. Microwave energy produces radiant heating and therefore can be used for noncontact catheter ablation. We hypothesized that it is possible to design a microwave catheter to produce a circumferential transmural thermal lesion in an in vitro model of a pulmonary vein antrum.A monopole microwave catheter with a sideways firing axially symmetrical heating pattern was designed. Noncontact ablations were performed in a perfused pulmonary vein model constructed from microwave myocardial phantom embedded with a sheet of thermochromic liquid crystal to permit visualization and measurement of thermal lesions from color changes. 1200 J ablations were performed at 150 W for 80 seconds and 120 W for 100 seconds at high (0.8 L/min) and low (0.06 L/min) flow through the modeled pulmonary vein. Myocardial tissue was substituted for the phantom material and ablations repeated at 150 W for 180 seconds and stained with nitro-blue tetrazolium. The catheter was able to induce deep circumferential antral lesions in myocardial phantom and myocardial tissue. Higher power and shorter ablations delivering the same amount of microwave energy resulted in larger lesions with less surface sparing.A microwave catheter can be designed to produce a circumferential thermal lesion on noncontact ablation and may have possible applications for pulmonary vein isolation.

Root lesion nematode (Pratylenchus thornei) is a relatively new problem in the wheat growing areas of central and northern New South Wales. Despite this, the nematode has become endemic on heavy clay soils which have a long history of wheat production. The objectives of the research reported in this thesis were to investigate the influence of environmental factors on the population dynamics and distribution of P. thornei, and the tolerance and resistance of commercial cultivars and advanced breeding lines to the nematode. The population dynamics of the nematode were investigated in 1989, 1990 and 1991 by sampling a wheat field at monthly intervals. P. thornei populations remained static for a three month period following sowing, then increased in October. The increase in nematode populations was correlated with increases in soil temperature in 1989 and 1990. The influence of soil temperature on the multiplication and development of P. thornei was investigated in a growth chamber study at three temperatures; 10, 20 and 30 °C. Nematode populations developed slowly at 10 °C, increased rapidly and then declined at 30 °C and increased in an exponential pattern at 20 °C. In the 20 °C treatment wheat shoot growth was correlated to nematode populations, with increasing populations increasing shoot weight until nematodes exceeded 3000 per g of root. Root weights at 20 °C declined with increasing nematode populations. The distribution of P. thornei in a wheat field was investigated over two consecutive years in 1989 and 1990 by taking regular monthly samples 4 m apart on a 0.23 ha grid. The aggregation of the nematodes was close to random at the time of sowing, however, as the nematodes multiplied the distribution patterns became aggregated, with areas of very high populations. The areas of dense nematode populations could not be correlated to any plant or edaphic factor. However, the consistent seasonal nematode aggregation was shown to part of the nematode biology and allowed a sampling protocol to be developed which could be linked to sampling errors, depending on the precision of the field mean required. Twenty seven fields in northern NSW were sampled prior to sowing winter crops and again at harvest. Soil physical factors were not found to be correlated with initial nematode populations or multiplication of nematodes. However, the cropping history and the previous crop prior to sampling were found to be major factors influencing the initial population of nematodes at sowing. Continual cultivation of susceptible crops, such as wheat and legumes was found to increase the nematode population at the time of sowing. A study of thirty six cereal cultivars at two sites near Narrabri in northern NSW identified problems with the use of nematicides as a control when studying tolerance reactions of cereals. Differences in soil characteristics between the two sites and in genotype reactions to the nematicide were identified as the main causes of variation in cereal tolerance reactions to P. th o rn ei. Resistance to P. thornei was measured as the multiplication of nematodes from sowing to harvest. The initial population of nematodes at the time of sowing was identified as an important covariate influencing multiplication rates of the nematodes. Resistant cereals with good tolerance to P. thornei were identified as barley and durum wheat, as well as three breeding lines; SUN 289 A, SUN 290 B and SUN 277 A. From the studies of this thesis sustainable wheat production in northern NSW where P. thornei was identified as a potential problem was possible using an integrated management system. This involves crop rotation to non-host crops and quantifying nematode populations before sowing wheat crops to assess the risks of yield losses. As part of a management system wheat crops should be sown early to allow for maximum root development before nematodes multiply in warmer soils and where possible, tolerant and resistant wheat varieties grown.