Search

Recurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but pre-clinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin-dependent SREBP2 expression.

Context Acacia longifolia is a native legume of south-eastern Australia and Tasmania and is invasive in many parts of the world. A key feature to its success is the production of a high quantity of flowers every season, resulting in a massive seedbank that remains dormant in the soil for decades. Many studies have been performed on this species’ reproductive biology, but none has focused on flowering in detail. Aims Our main objective was to understand this species’ resource allocation strategy that ensures its successful reproduction in the invasive range. Methods We developed an integrative approach, assessing flowering at different levels, namely, canopy and branch flowering (macro scale), downscaling to individual flower functional stages and their duration, pollen longevity and stigma receptivity (micro scale). We performed this study in three different locations in sand dunes along the Portuguese coast with different environmental conditions. Key results Canopy flowering shows no difference among sites. Pollen and stigma assessment showed that this species is protogynous, with the stigma being highly receptive long before pollen is released. Once released, pollen lasts roughly 72 h. Individual flowers are relatively short-lived, with a rapid progression from closed flower buds to fully open flowers. Implications Our results indicated that A. longifolia has a resource trade-off strategy of investing in flowers and pollen that are relatively short-lived, which are counterbalanced by their massive quantities.

Acacia longifolia (Sydney golden wattle) is considered one of the most problematic plant invaders in Mediterranean-type ecosystems. In this study, we investigate the species’ invasion history by comparing the genetic diversity and structure of native (Australia) and several invasive range (Brazil, Portugal, South Africa, Spain, and Uruguay) populations and by modelling different introduction scenarios using these data. We sampled 272 A. longifolia individuals – 126 from different invasive ranges and 146 from the native range – from 41 populations. We genotyped all individuals at four chloroplast and 12 nuclear microsatellite markers. From these data we calculated diversity metrics, identified chloroplast haplotypes, and estimated population genetic structure based on Bayesian assignment tests. We used Approximate Bayesian Computation (ABC) models to infer the likely introduction history into each invaded country. In Australia, population genetic structure of A. longifolia appears to be strongly shaped by the Bass Strait and we identified two genetic clusters largely corresponding to mainland Australian and Tasmanian populations. We found invasive populations to represent a mixture of these clusters. Similar levels of genetic diversity were present in native and invasive ranges, indicating that invasive populations did not go through a genetic bottleneck. Bayesian assignment tests and chloroplast haplotype frequencies further suggested a secondary introduction event between South Africa and Portugal. However, ABC analyses could not confidently identify the native source(s) of invasive populations in these two countries, probably due to the known high propagule pressure that accompanied these introductions. ABC analyses identified Tasmania as the likely source of invasive populations in Brazil and Uruguay. A definitive native source for Spanish populations could also not be identified. This study shows that tracing the introduction history of A. longifolia is difficult, most likely because of the complexity associated with the extensive movement of the species around the world. Our findings should be considered when planning management and control efforts, such as biological control, in some invaded regions.

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. We demonstrate that the ribose subunit of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors, and that cancer cells display diverse capacities to utilize inosine as a carbon source. Moreover, the supplementation with inosine enhances the anti-tumour efficacy of immune checkpoint blockade and adoptive T-cell transfer in solid tumours that are defective in metabolizing inosine, reflecting the capability of inosine to relieve tumour-imposed metabolic restrictions on T cells.

This paper proposes using a sparse-structured multivariate Gaussian to provide a closed-form approximator for the output of probabilistic ensemble models used for dense image prediction tasks. This is achieved through a convolutional neural network that predicts the mean and covariance of the distribution, where the inverse covariance is parameterised by a sparsely structured Cholesky matrix. Similarly to distillation approaches, our single network is trained to maximise the probability of samples from pre-trained probabilistic models, in this work we use a fixed ensemble of networks. Once trained, our compact representation can be used to efficiently draw spatially correlated samples from the approximated output distribution. Importantly, this approach captures the uncertainty and structured correlations in the predictions explicitly in a formal distribution, rather than implicitly through sampling alone. This allows direct introspection of the model, enabling visualisation of the learned structure. Moreover, this formulation provides two further benefits: estimation of a sample probability, and the introduction of arbitrary spatial conditioning at test time. We demonstrate the merits of our approach on monocular depth estimation and show that the advantages of our approach are obtained with comparable quantitative performance., Comment: Accepted at CVPR 2022

Endometriosis (EM) is a hormone-dependent gynecological disease associated with chronic pelvic pain and altered immuno-inflammatory processes. It shares some cancer-like characteristics such as increased proline biosynthesis and activated glutaminolysis. Both proline and glutamine are interconvertible metabolically, and studies have shown their roles in cancer cell metabolic reprogramming, redox homeostasis, occurrence/development of endometrial carcinoma, and its further progression toward the malignant state. So based on this, we hypothesized that the circulatory proline to glutamine ratio (PQR) would be altered in EM and may serve as an indicative biomarker to improve the clinical diagnosis of EM. In present study, the circulatory-PQR levels were estimated for 39 EM patients and 48 age matched healthy female subjects using 800 MHz NMR spectroscopy. Among 39 EM patients, 15 were in the clinical stages I to II and referred to here as moderate EM (MEM) patients and 24 were in the clinical stages III to IV and referred here as severe EM (SEM) patients. The circulatory-PQR levels were significantly increased in EM patients (0.99 ± 0.13 μM in MEM; 1.39 ± 0.22 μM in SEM) compared to normal control (NC) subjects (0.52 ± 0.05 μM in NC). Further, the circulatory PQR levels exhibit the highest diagnostic potential with area under receiver operating characteristic (AUROC) curve values equal to 0.87 ± 0.04 [95%CI = 0.79-0.96] for MEM and 0.89 ± 0.04 [95% CI = 0.82-0.96] for SEM. These results suggested that circulatory-PQR has significant potential to serve as a noninvasive biomarker for diagnostic/prognostic screening of EM and further underscored the importance of these two nonessential amino acids (proline and glutamine) in cancer metabolism.

In the current context, strongly marked by globalization, organizations have undergone a period of changes induced by economic, social, and political changes, which have led to changes in the relationships between individuals and society. In this way, organizations, through the implementation of new values and strategies, have established themselves as socially responsible organizations, characterized by their ethical essence. This chapter intends to evaluate the organizational virtuousness, affective well-being at work, and organizational citizenship behaviors, following the studies developed by Cameron et al. and by Rego et al., which relate organizational virtuosity, well-being at work, and behaviors of organizational citizenship. The study was applied in the municipalities of the Intermunicipal Community (CIM) – Trás-os-Montes, and 760 employees were surveyed. Findings indicate that perceptions of organizational virtuousness and well-being at work are related to organizational citizenship behaviors.

The taxonomic identity of Mentha species is difficult as it displays variations at morphochemical characters. The aim of this investigation was to study Mentha spp. diversity in 60 Tunisian accessi...

A substantial fraction of common metabolites contains carboxyl functional groups. Their 13C isotopomer analysis by nuclear magnetic resonance (NMR) is hampered by the low sensitivity of the 13C nucleus, the slow longitudinal relaxation for the lack of an attached proton, and the relatively low chemical shift dispersion of carboxylates. Chemoselective (CS) derivatization is a means of tagging compounds in a complex mixture via a specific functional group. 15N1-cholamine has been shown to be a useful CS agent for carboxylates, producing a peptide bond that can be detected via 15N-attached H with high sensitivity in heteronuclear single quantum coherence experiments. Here, we report an improved method of derivatization and show how 13C-enrichment at the carboxylate and/or the adjacent carbon can be determined via one- and two-bond coupling of the carbons adjacent to the cholamine 15N atom in the derivatives. We have applied this method for the determination of 13C isotopomer distribution in the extracts of A549 cell culture and liver tissue from a patient-derived xenograft mouse.

Background and Aims Invasive species may undergo rapid evolution despite very limited standing genetic diversity. This so-called genetic paradox of biological invasions assumes that an invasive species has experienced (and survived) a genetic bottleneck and then underwent local adaptation in the new range. In this study, we test how often Australian acacias (genus Acacia), one of the world’s most problematic invasive tree groups, have experienced genetic bottlenecks and inbreeding. Methods We collated genetic data from 51 different genetic studies on Acacia species to compare genetic diversity between native and invasive populations. These studies analysed 37 different Acacia species, with genetic data from the invasive ranges of 11 species, and data from the native range for 36 species (14 of these 36 species are known to be invasive somewhere in the world, and the other 22 are not known to be invasive). Key Results Levels of genetic diversity are similar in native and invasive populations, and there is little evidence of invasive populations being extensively inbred. Levels of genetic diversity in native range populations also did not differ significantly between species that have and that do not have invasive populations. Conclusion We attribute our findings to the impressive movement, introduction effort and human usage of Australian acacias around the world.

Introduction: Glycogen is a readily deployed intracellular energy storage macromolecule composed of branched chains of glucose. Although glycogen primarily occurs in the liver and muscle, it can be found in most tissues throughout the body, and its metabolism has been shown to be important in cancers and immune cells. Robust analysis of glycogen turnover requires stable isotope tracing plus a reliable means of quantifying total and labeled glycogen derived from precursors such as 13C6-glucose. Current methods for analyzing glycogen are time- and sample-consuming, at best semi-quantitative, and unable to measure stable isotope enrichment. Methods: We have developed a microscale method for quantifying both intact and acid-hydrolyzed glycogen by ultra-high-resolution Fourier transform mass spectrometric (UHR-FTMS) and/or NMR analysis in stable isotope resolved metabolomics (SIRM) studies. Polar metabolites, including intact glycogen and their 13C positional isotopomer distributions were first measured in crude biological extracts by high resolution NMR, followed by rapid and efficient acid hydrolysis to glucose in 1 N HCl for 10 minutes at 110 °C under a N2 atmosphere in a microwave-assisted synthesis reactor. The resulting glucose and its 13C isotopologues were then analyzed by UHR-FTMS and/or NMR. Results: We optimized the microwave digestion time, temperature, and oxygen purging in terms of recovery versus degradation and found 10 minutes at 110-115 °C to give > 90% recovery. The method was applied to track the fate of 13C6-glucose in primary human lung BEAS-2B cells, human macrophages, murine liver and patient-derived tumor xenograft (PDTX) in vivo, and the fate of 2H7-glucose in ex vivo lung organotypic tissue cultures of a lung cancer patient. We showed the incorporation of 13C6-glucose into glycogen and its metabolic intermediates, UDP-Glucose and glucose-1-phosphate, both in terms of the 13C levels and fractional enrichment, thereby demonstrating the utility of the method in tracing glycogen turnover in cells and tissues. Conclusions: The method offers a quantitative, sensitive, and convenient means to analyze glycogen turnover in mg amounts of complex biological materials. Keywords: glycogen turnover; 13C6-glucose, stable isotope resolved metabolomics (SIRM); microwave-assisted hydrolysis. Citation Format: Andrew N. Lane, Timothy L. Scott, Juan Zhu, Teresa A. Cassel, Sara Vicente-Munoz, Penghui Lin, Richard M. Higashi, Teresa W-M Fan. Small-scale microwave-assisted acid hydrolysis method for glycogen determination and turnover in tumors using Stable Isotope Resolved Metabolomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2324.

Contemporary climate change, in particular higher temperatures, may greatly enhance the expansion of invasive species. Acacia longifolia (Fabaceae, subgenus Phyllodineae) is a native species of Southeast Australia and Tasmania, invasive in South Africa, Mediterranean Europe and South America. According to several records, this species has been introduced in Southern Brazil and Uruguay for fixation of dunes and for ornamental purposes in the mid-20th century and has since then caused several environmental and socio-economic problems. However, its current distribution in these south American countries is undocumented, as well as the types of habitats it has invaded since its introduction. In this context, during May 2019 we performed a study through a latitudinal and climatic gradient along the coast, from southern Brazil (Santa Catarina and Rio Grande do Sul states) to Uruguay, to evaluate the presence of A. longifolia taking into consideration previous records of this species. Our observations showed an increase in tree density along the coast, from Brazil to Uruguay, with a clear distribution southward. It was not possible to confirm earlier observations of this species in southern Brazil (with the exception of Florianópolis), which may be associated with changes in temperature and precipitation in this region.

Deep neural networks have recently been used to edit images with great success, in particular for faces. However, they are often limited to only being able to work at a restricted range of resolutions. Many methods are so flexible that face edits can often result in an unwanted loss of identity. This work proposes to learn how to perform semantic image edits through the application of smooth warp fields. Previous approaches that attempted to use warping for semantic edits required paired data, i.e. example images of the same subject with different semantic attributes. In contrast, we employ recent advances in Generative Adversarial Networks that allow our model to be trained with unpaired data. We demonstrate face editing at very high resolutions (4k images) with a single forward pass of a deep network at a lower resolution. We also show that our edits are substantially better at preserving the subject's identity. The robustness of our approach is demonstrated by showing plausible image editing results on the Cub200 birds dataset. To our knowledge this has not been previously accomplished, due the challenging nature of the dataset., CVPR 2020