Background: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1–4) catalyze collagen cross-linking, ...thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. Methods: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. Results: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. Conclusions: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.
OBJECTIVEThe aim of this study was to assess whether physical performance correlates with metabolic and inflammatory measures in research subjects with chronic liver disease.
DESIGNThis is a ...prospective, descriptive cohort study correlating performance on a 6-min walk test with cardiorespiratory variables, metabolic measures (glucose GLU, C-peptide insulin, and lipids), liver enzymes (aspartate aminotransferase and alanine aminotransferase), and the proinflammatory cytokine interleukin-8 (IL-8).
RESULTSThis study enrolled 51 subjects (18 women) with chronic liver disease41% (n = 21) with nonalcoholic fatty liver disease and 59% (n = 30) with hepatitis C virus. Age, resting heart rate, and fasting GLU correlated significantly with distance walked (P’s < 0.05). First quartile “poor performers” (n = 14) and fourth quartile “high performers” (n = 14) showed differences in age, sex, fasting GLU, and IL-8 level (P’s < 0.05). Combining the number of abnormal serum values (IL-8, C-peptide insulin, GLU, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein, triglyceride, and total cholesterol) did not correlate with distance walked (P > 0.90). However, in multiple regression analysis, a model that included sex, age, resting heart rate, IL-8 level, and fasting GLU level explained approximately 39% of the variance in the distance walked during the test.
CONCLUSIONSOlder age, female sex, abnormal levels of the proinflammatory cytokine IL-8, abnormalities of GLU metabolism, and high resting heart rate are associated with poor physical performance in subjects with chronic liver disease. Poor physical performance is associated with physiologic, metabolic, and inflammatory abnormalities in subjects with nonalcoholic fatty liver disease and hepatitis C virus.
...in June 2013 the NHLBI initiated collaboration with the ACC and AHA to work with other organizations to complete and publish the guidelines noted above and make them available to the widest ...possible constituency. ...the format of the recommendations differs from other ACC/AHA guidelines. Each recommendation has been mapped from the NHLBI grading format to the ACC/ AHA Classification of Recommendation/Level of Evidence (COR/ LOE) construct (Table 1) and is expressed in both formats. Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats is in some cases imperfect. According to the 1998 "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults- The Evidence Report" (5), overweight is defined as a body mass index (BMI) of 25 kg/m2 to 29.9 kg/m2 and obesity as a BMI of >30 kg/m2.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This study investigates the impact that different magnitudes and combinations of thermal and axial mechanical loads have on the mechanical behaviour of energy piles in saturated sand. The work is ...based on the results of a series of thermo-hydro-mechanical finite element analyses, which are compared with centrifuge data, and parametric numerical runs. The analyses prove that an increase in heating loads induces a significant amount of stress and displacement in energy piles, with a remarkable mobilisation of their shaft and end-bearing capacity. Temperature variations up to ΔT= 50 °C induce axial stress up to σth=716kPa and pile heave up to dyth=−14.09mm. These temperature variations mobilise an average side shear resistance and an end-bearing load normalised with respect to those mobilised at failure up to qs,ave/qs,ULT,ave=−14.11% and Qb/Qb,ULT=27.35%, respectively. The magnitude of these phenomena depends on the significance of the applied temperature variation, the significance of the applied mechanical load to the foundation head prior to thermal loading with respect to the pile axial capacity and the soil response to additional loading/unloading processes. These aspects serve a major role in the evolution of the foundation constraint, which governs the mechanical performance of energy piles when subjected to thermo-mechanical loads.
•Null point movement appears to be a critical characteristics of energy piles.•Null point movement is controlled by distribution of forces at pile–soil interface.•Plastic strain at pile–soil interface markedly influences null point shifts.•Capturing null point shifts is crucial for the mechanical analysis of energy piles.•A suitable plasticity model for pile–soil interface and soil behaviour is essential.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of terpene isonitriles, isolated from marine sponges, have previously been shown to exhibit antimalarial activities. Molecular modeling studies employing 3D-QSAR with receptor modeling ...methodologies performed with these isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biological activities. It was also shown that one of the modeled compounds, diisocyanoadociane (4), as well as axisonitrile-3 (2), both of which have potent antimalarial activity, interacts with heme (FP) by forming a coordination complex with the FP iron. Furthermore, these compounds were shown to inhibit sequestration of FP into β-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mimic the environment within the malaria parasite. By contrast, two of the modeled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed little antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile compounds, like the quinoline antimalarials, exert their antiplasmodial activity by preventing FP detoxification. Molecular dynamics simulations performed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their different binding to FP to be distinguished.
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