To determine the effect of exposure to cigarette smoke on the elastolytic activity of guinea pigs' alveolar macrophages (AMs), and to compare elastolytic activity of AMs obtained by BAL with that of ...lung macrophages (LMs) obtained from minced lung tissue.
AMs were obtained by BAL from seven adult guinea pigs exposed to cigarette smoke for 5 d/wk during 6 weeks, as well as from age-matched control guinea pigs. From each animal, one lung was used to obtain LMs by mincing and teasing the lung, followed by enzymatic digestion and isolation of mononuclear cells by Hypaque-Ficoll separation. The other lung was inflated and fixed to quantitate emphysema by the destructive index (DI). Elastolytic activity (microgram of elastin degraded by 106 macrophages) was determined at 24, 48, and 72 h, by culturing AMs and LMs (1×106 cells in 1 mL of medium) in 3H-elastin-coated wells.
In animals exposed to cigarette smoke, the total number of BAL cells (8.6±2.1 ×106) and DI (21.8±8.1) were significantly higher than in nonexposed animals (6.4±1.8×106, p<0.05 for cells, and 12.1 ±4.1, p<0.01 for DI). Elastolytic activity of AMs from smoke-exposed guinea pigs was significantly higher at 24, 48, and 72 h than elastolytic activity of AMs from control animals (19.0±9.4 vs 10.0±5.3, p<0.05 at 72 h). Likewise, elastolytic activity of LMs was significantly higher in exposed than nonexposed guinea pigs (11.8±7.7 vs 7.4±5.0 at 72 h, p<0.05). Elastolytic activity of LMs was not significantly different from elastolytic activity of AMs, both in exposed guinea pigs (11.8±7.7 vs 19.0±9.4 at 72 h) and nonexposed animals (7.4±5.0 vs 10.0±5.3 at 72 h).
These results indicate that elastolytic activity of both AMs and LMs of guinea pigs increases significantly after exposure to cigarette smoke and that AMs and LMs have similar elastolytic activities.
Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to ...reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8
T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8
T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year overall survival of only 11%. Treatment failure is ubiquitous, driven by genetic and ...phenotypic heterogeneity combined with a highly desmoplastic and immunosuppressive microenvironment. Identifying novel therapeutic targets in the tumor microenvironment (TME) is critical to improving patient outcomes and can be advanced through understanding the cell intrinsic states and cell-cell interactions driving clinically-relevant properties. Recent applications of single-cell and spatial proteo-transcriptomic technologies to PDAC have enhanced our understanding of intratumoral heterogeneity, cell state plasticity, and neighborhood composition. However, prior studies were unable to provide high-plex molecular information while preserving in situ spatial relationships at single-cell resolution, limiting detailed analyses of cell-cell interactions and potential therapeutic avenues. Advances in spatial technology have enabled subcellular resolution while profiling up to several thousand transcripts. We performed spatial molecular profiling (SMI; NanoString CosMx) on 13 patient-derived PDAC tumors using a 990-plex mRNA panel, which yielded 753,133 high confidence single-cell profiles. We then developed a novel method for inferring multicellular interactions—Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand–receptor (LR) gene expression. We used SCOTIA to dissect the remodeled TME in response to neoadjuvant FOLFIRINOX and chemoradiotherapy. Our results uncovered a marked change in LR interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by results from experiments using a murine tumoroid co-culture system. We observed in treated specimens a lower abundance of myofibroblastic CAFs (myCAFs) and higher prevalence of inflammatory CAFs (iCAFs), which express high levels of IL6 family cytokines and spatially co-localize with cancer cell subtypes previously associated with therapeutic resistance (i.e., neural-like, basal/mesenchymal). Two of the most consistent treatment-enriched LR interactions between CAFs and cancer cells were CLCF1-CNTFR and LIF-IL6ST, members of the IL6 cytokine family. While CAF-derived IL6 family ligands and downstream JAK/STAT3 and MAPK activation have been linked to induction of a mesenchymal cancer cell phenotype in several malignancies as well as neuroendocrine differentiation in prostate cancer, an association with the neural-like malignant cell state in pancreatic cancer has not been previously established. Overall, this study demonstrates that characterization of the TME using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.
Citation Format: Alexander T.F. Bell, Jacob T. Mitchell, Ashley L. Kiemen, Melissa Lyman, Kohei Fujikura, Jae W. Lee, Erin Coyne, Sarah M. Shin, Pei-Hsun Wu, Jacquelyn W. Zimmerman, Denis Wirtz, Won J. Ho, Neeha Zaidi, Elizabeth Thompson, Elizabeth M. Jaffee, Laura D. Wood, Elana J. Fertig, Luciane T. Kagohara. Spatially-constrained optimal transport interaction analysis reveals therapy-associated remodeling in the pancreatic cancer microenvironment abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B106.
In the Northwest coast of Portugal, the shoreline evolution is leading to several problems, such as loss of territory and infrastructural damages, mainly caused by the sea wave's action. This study ...aims to predict the impacts of climate change on the shoreline evolution in this coastal area. Coastal stretches studied were Esmoriz-Furadouro and Vagueira- Mira, due to their vulnerability related with the low lying sandy coast, the deficit of sediments, the presence of urban waterfronts and the narrow width of the sand spit that separates the ocean from the Aveiro lagoon. This article describes the application of two shoreline evolution models (LTC and GENESIS) to the projection of shoreline evolution between 2010 and 2100. Considering the numerical models' results, maps of the shoreline position were represented every 30 years. The results allowed the analysis of the shoreline retreat, the areas of lost territory and the alongshore sediment transport volumes in several cross sections.
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Abstract
Objective
To validate the translation and adaptation to Brazilian Portuguese of 36 items from the World Health Organizaton Disability Assessment Schedule 2.0 (WHODAS 2.0), regarding their ...content and structure (construct), in a female population after pregnancy.
Methods
This is a validation of an instrument for the evaluation of disability and functioning and an assessment of its psychometric properties, performed in a tertiary maternity and a referral center specialized in high-risk pregnancies in Brazil. A sample of 638 women in different postpartum periods who had either a normal or a complicated pregnancy was included. The structure was evaluated by exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), while the content and relationships among the domains were assessed through Pearson's correlation coefficient. The sociodemographic characteristics were identified, and the mean scores with their standard deviations for the 36 questions of the WHODAS 2.0 were calculated. The internal consistency was evaluated byCronbach's α.
Results
Cronbach's α was higher than 0.79 for both sets of questons of the questionnaire. The EFA and CFA for the main 32 questions exhibited a total variance of 54.7% (Kaiser-Meyer-Olkin KMO measure of sampling adequacy = 0.934;
p
< 0.001) and 53.47% (KMO = 0.934;
p
< 0.001) respectively. There was a significant correlation among the 6 domains (r = 0.571–0.876), and a moderate correlation among all domains (r = 0.476–0.694).
Conclusion
The version of the WHODAS 2.0 instrument adapted to Brazilian Portuguese showed good psychometric properties in this sample, and therefore could be applied to populations of women regarding their reproductive history.
Pereira, C., Coelho, C., Ribeiro, A., Fortunato, A., Lopes, C.L. and Dias, J.M., 2013. Numerical modelling of shoreline evolution in the Aveiro coast, Portugal – climate change scenarios In the ...Northwest coast of Portugal, the shoreline evolution is leading to several problems, such as loss of territory and infrastructural damages, mainly caused by the sea wave's action. This study aims to predict the impacts of climate change on the shoreline evolution in this coastal area. Coastal stretches studied were Esmoriz-Furadouro and Vagueira-Mira, due to their vulnerability related with the low lying sandy coast, the deficit of sediments, the presence of urban waterfronts and the narrow width of the sand spit that separates the ocean from the Aveiro lagoon. The paper describes the application of two shoreline evolution models (LTC and GENESIS) to the projection of shoreline evolution between 2010 and 2100. A reference scenario considering the present typical wave climate and the mean sea water level was compared with 3 other future scenarios that may result from climate change effects, combining different wave climates and mean sea levels (0.42 and 0.64 m above present level). Considering the numerical models' results, maps of the shoreline position were represented every 30 years. The results allowed the analysis of the shoreline retreat, the areas of lost territory and the alongshore sediment transport volumes in several cross sections. A strong trend of shoreline retreat was found for all the scenarios, although the retreat rates tend to decrease along time. Comparing the reference scenario with the climate change scenarios, a slight clockwise rotation of the shoreline was predicted, also increasing the average shoreline retreat from 6% to 11%, depending on the considered scenario.
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Correspondence: 1 Corresponding Author: Lilia Cavaglieri, Departamento de Microbiología e Inmunología, Universidad Nacional de Río Cuarto, Ruta 36 Km.601, (5800) Río Cuarto, Córdoba, Argentina. ...lcavaglieri{at}arnet.com.ar
Chinchillas ( Chinehilla lanigera ) are known to be very sensitive to aflatoxins, and often a large number of animals die if toxicosis occurs. An outbreak of acute aflatoxicosis on a chinchilla farm in Argentina is described in the present study. A commercial feed suspected of causing the death of 200 animals was sampled. Livers from 9 dead chinchillas were analyzed for their macroscopic and microscopic characteristics via necropsy and histopathology. Aflatoxins B 1 , B 2 , G 1 , and G 2 were determined, by thin layer chromatography, to be in the feed. Macroscopic inspection of livers revealed general enlargement, pale-yellowish coloration, hypertrophy, rounded borders, and increased friability. Size and color were remarkably different from a healthy organ. Histopathologic analyses of hepatic parenchyma showed severe, diffuse cytoplasmic vacuolation of hepatocytes. Sudan III staining confirmed the presence of lipid within the vacuoles. The feed was positive for aflatoxin B 1 in quantities that exceeded the recommended levels. Histologic lesions were typical of aflatoxin intake. Monitoring feed for mycotoxins is crucial to prevent outbreaks of toxicosis, to improve management practices, and to diminish exposure risk of animals and humans to these harmful toxins.
Key Words: Aflatoxicosis aflatoxin B 1 chinchillas feed histopathology
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Dias, J.M., Lopes, C.L., Coelho, C., Pereira, C., Alves, F.L., Sousa, L.P., Antunes, I.C., Fernandes, M. da L., Phillips, M.R., 2014. Influence of mean sea level rise on Ria de Aveiro littoral: ...adaptation strategies for flooding events and shoreline retreat. In: Green, A.N. and Cooper, J.A.G. (eds.), Proceedings 13th International Coastal Symposium (Durban, South Africa), Journal of Coastal Research, Special Issue No. 70, pp. 320–325, ISSN 0749-0208. Floods and shoreline retreat in coastal areas threaten many millions of people across Europe. Moreover, it is agreed that climate change can amplify the magnitude and frequency of flooding events and accelerate the shoreline retreat. The main goal of this work is to assess flood and shoreline retreat risk, and define adaptation strategies under present conditions and future climate change scenarios on the Ria de Aveiro and its littoral. The hydrodynamic model ELCIRC was implemented for the Ria de Aveiro lagoon and GENESIS (U.S. Army Corps of Engineers) and LTC (Long-Term Configuration) shoreline evolution models for the littoral stretch between Esmoriz and Mira. Numerical results in present and future scenarios were used to map the flooded lagoon extension and the shoreline evolution of this coastal stretch. Analysis showed an increase of the lagoon's flooded area, relative to the present, with regions more exposed to sea level rise being lowland areas located at the margins of the lagoon's deeper channels. Examination of the littoral stretch showed a slight increasing trend of shoreline retreat under predicted future climate change scenarios, thereby increasing the probability of sand spit rupture. Data from numerical predictions were integrated into Geographical Information Systems covering the coastal and lagoon study areas, and produced hazard and risk maps including the identification of regional use and activities. Structural and non-structural measures were subsequently developed in order to mitigate flood and shoreline retreat effects.
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