Levels of the cancer biomarker CA 19-9 are associated with thrombin generation in plasma from treatment-na?ve pancreatic cancer patients

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a hypercoagulable state and high mortality. Increases in the plasma levels of tumor marker carbohydrate antigen (CA) 19-9 are used in diagnosis and follow-up but have also been reported to precede venous thromboembolism (VTE). Aims: We examined the association between CA 19-9 and thrombin generation (TG) in plasma from PDAC patients, as well as their association with coagulation biomarkers prior to pancreatic surgery. In addition, we determined the effect of commercial sources of CA 19-9 on TG. Methods: We collected plasma from 58 treatment-naive PDAC patients without any signs of VTE. We measured levels of CA 19-9, FVIII, fibrinogen, D-dimer, antithrombin and extracellular vesicle (EV) tissue factor (TF) activity and TG using a Calibrated Automated Thrombogram (CAT). The effect of different commercial sources of CA 19-9 on TG in Standard Human Plasma (SHP) was also studied. Results: Patient plasma samples were divided into 4 preoperative groups based on the level of CA 19-9: none 1000 U/mL. CA 19-9 levels were associated with several of the TG parameters, including endogenous thrombin potential, peak, and time to peak. CA 19-9 did not associate with any of the coagulation biomarkers. Spiking of SHP with CA 19-9 increased TG but this was decreased by an antiTF antibody. Conclusions: CA 19-9 was associated with TG in patients prior to any pancreatic cancer treatments or signs of VTE. Some commercial sources of CA 19-9 enhanced TG in SHP seemingly due to contaminating TF.Peer reviewe

Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome

Towards automated characterisation of fatigue damage in composites using thermoelastic stress analysis

Composite materials demonstrate complicated fatigue behaviour due to their microstructure and the varied types of defects that can occur during loading. This necessitates experimentation to determine their performance under loading. In this study an algorithm is introduced for identifying and categorising different defects forming during fatigue tests. Thermoelastic stress analysis was used to obtain high spatial and temporal resolution stress information from the surface of notched composite specimens. Specimens with three different geometries were loaded in tension–tension fatigue to failure. An algorithm was used to identify when and where matrix cracking and delaminations formed within the specimens as well as quantify how this changed over time. By improving how damage events are identified and characterised, the algorithm reduces the amount of time needed to process experimental fatigue data and helps to provide greater understanding of fatigue processes in new materials from early small-scale cracking all the way to final failure

Exclusive neuronal expression of SUCLA2 in the human brain

SUCLA2 encodes the ATP-forming subunit (A-SUCL-) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL- immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming subunit (G-SUCL-) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL- immunoreactivity that was however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex

THE OAK ORCHARD SOIL WATER ASSESSMENT TOOL A decision support system for watershed management Part 1: Calibration and Validation

A hydrologic model (SWAT) was developed and calibrated for the Oak Orchard watershed to evaluate sources and sinks of sediment and nutrients. The model included the most important anthropogenic features that impacted water flow and nonpoint source pollution in the watershed. These features included reservoirs at the Iroquois National Wildlife Refuge, Waterport and Medina; point sources such as the Erie Canal, US Gypsum, Allen Canning, wastewater treatment plants at Medina, Oakfield and Elba, and tiledrains at the mucklands, an intensely farmed area that was drained to combat malaria in the 19th century. The model included point sources for every subbasin so that the effects of future point sources can be evaluated. The model was calibrated for waterflow and sediment using observed loading data collected by Makarewicz and Lewis (2000, 2009). To achieve the proper water balance observed at the watershed, seasonal inputs of water had to be added from the Erie Canal and the Onondaga escarpment. This water came from outside of the watershed. The resulting calibration had a Nash-Sutcliffe (NS) prediction efficiency of 0.81 for the calibration period (1997-1999). The total cumulative sediment loading was within 2%, of observed and the monthly sediment loads fell within the uncertainty of the observed data (NS=0.31). Cumulative total phosphorous loads were within 2% of observed and the NS prediction efficiency was 0.91. The model validated very poorly in the 2008 time period primarily because of inaccurate precipitation data and incorrect groundwater fluxes from the escarpment. Further research needs to evaluate the timing and amount of groundwater flow from the escarpment because it has a significant impact on monthly flows in this watershed. It is likely that other watersheds that are nestled against the Onondaga escarpment are impacted by spring flows from this geologic feature

Measuring Cosmic Rays with the RadMap Telescope on the International Space Station

The RadMap Telescope is a new radiation-monitoring instrument operating in the U.S. Orbital Segment (USOS) of the International Space Station (ISS). The instrument was commissioned in May 2023 and will rotate through four locations inside American, European, and Japanese modules over a period of about six months. In some locations, it will take data alongside operational, validated detectors for a cross-check of measurements. RadMap’s central detector is a finely segmented tracking calorimeter that records detailed depth-dose data relevant to studies of the radiation exposure of the ISS crew. It is also able to record particle-dependent energy spectra of cosmic-ray nuclei with energies up to several hundred MeV per nucleon. A unique feature of the detector is its ability to track nuclei with omnidirectional sensitivity at an angular resolution of two degrees. In this contribution, we present the design and capabilities of the RadMap Telescope and give an overview of the instrument’s commissioning on the ISS