Metabolomic Analyses of Plasma Reveals New Insights into Asphyxia and Resuscitation in Pigs

Currently, a limited range of biochemical tests for hypoxia are in clinical use. Early diagnostic and functional biomarkers that mirror cellular metabolism and recovery during resuscitation are lacking. We hypothesized that the quantification of metabolites after hypoxia and resuscitation would enable the detection of markers of hypoxia as well as markers enabling the monitoring and evaluation of resuscitation strategies.Hypoxemia of different durations was induced in newborn piglets before randomization for resuscitation with 21% or 100% oxygen for 15 min or prolonged hyperoxia. Metabolites were measured in plasma taken before and after hypoxia as well as after resuscitation. Lactate, pH and base deficit did not correlate with the duration of hypoxia. In contrast to these, we detected the ratios of alanine to branched chained amino acids (Ala/BCAA; R(2).adj = 0.58, q-value<0.001) and of glycine to BCAA (Gly/BCAA; R(2).adj = 0.45, q-value<0.005), which were highly correlated with the duration of hypoxia. Combinations of metabolites and ratios increased the correlation to R(2)adjust = 0.92. Reoxygenation with 100% oxygen delayed cellular metabolic recovery. Reoxygenation with different concentrations of oxygen reduced lactate levels to a similar extent. In contrast, metabolites of the Krebs cycle (which is directly linked to mitochondrial function) including alpha keto-glutarate, succinate and fumarate were significantly reduced at different rates depending on the resuscitation, showing a delay in recovery in the 100% reoxygenation groups. Additional metabolites showing different responses to reoxygenation include oxysterols and acylcarnitines (n = 8-11, q<0.001).This study provides a novel strategy and set of biomarkers. It provides biochemical in vivo data that resuscitation with 100% oxygen delays cellular recovery. In addition, the oxysterol increase raises concerns about the safety of 100% O(2) resuscitation. Our biomarkers can be used in a broad clinical setting for evaluation or the prediction of damage in conditions associated with low tissue oxygenation in both infancy and adulthood. These findings have to be validated in human trials

Cyclooxygenase (COX) and 15-Lipoxygenase (15-LOX) Inhibitory Activity and HPTLC Profile of Asplenium Nidus, Diplazium Esculentum, and Drynaria Quercifolia in Bukidnon, Philippines

Diplazium esculentum, Drynaria quercifolia, and Asplenium nidus are among the fern species found in Bukidnon, Philippines which are used as traditional herbal medicines.&nbsp; The HPTLC profile and the anti-inflammatory properties against cyclooxygenase (COX) and 15-lipoxygenase (15-LOX) of the frond ethanolic extracts of D. esculentum, D. quercifolia, and A. nidus were determined.&nbsp; The High-Performance Thin Layer Chromatography (HPTLC) profile was obtained using ethyl acetate: formic acid: water (16:2:2) as mobile phase and Natural Products (NP) as derivatizing reagent.&nbsp; The HPTLC profile of the D. esculentum, D. quercifolia, and A. nidus extracts showed 10 (Rf = 0.02-0.97), 13 (Rf = 0.03-0.90), and 14 (Rf = 0.02-0.99) bands, respectively. The profiles for each fern species may be used as marker for quality evaluation and standardization of herbal formulations containing these plants.&nbsp; For the anti-inflammatory properties, D. esculentum and D. quercifolia extracts which inhibited more than 50% of the COX enzymes showed significantly higher activity than A. nidus and were considered active against COX-2 and COX-1. D. esculentum, however, gave a selectivity ratio (COX-2/COX-1) of 1.03 making its inhibitory activity selective against COX-2.&nbsp; The percent 15-LOX inhibitory activity of D. quercifolia (58.62%) is significantly higher than that of A. nidus (38.70%) but statistically comparable to D. esculentum (51.19%).&nbsp; Among the extracts, D. quercifolia and D. esculentum which inhibited more than 50% of the 15-LOX were considered active. D. esculentum and D. quercifolia can therefore be potential sources of anti-inflammatory lead compounds for future drug development.&nbsp;&nbsp;&nbsp

Spring-neap tide-induced beach water table fluctuations in a sloping coastal aquifer

Predictions of water table fluctuations in coastal aquifers are needed for numerous coastal and water resources engineering problems. Most previous investigations have been based on the Boussinesq equation for the case of a vertical beach. In this note an analytical solution based on shallow water expansion for the spring- neap tide- induced water table fluctuations in a coastal aquifer is presented. Unlike most previous investigations, multitidal signals are considered with a sloping coastal aquifer. The new solution is verified by comparing with field observations from Ardeer, Scotland. On the basis of the analytical approximation the influences of higher- order components on water table elevation are examined first. Then, a parametric study has been performed to investigate the effects of the amplitude ratio (lambda), frequency ratio (omega), and phases (delta(1) and delta(2)) on the tide- induced water table fluctuations in a sloping sandy beach

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC

Spring-neap tide-induced beach water table fluctuations in a sloping coastal aquifer

Predictions of water table fluctuations in coastal aquifers are needed for numerous coastal and water resources engineering problems. Most previous investigations have been based on the Boussinesq equation for the case of a vertical beach. In this note an analytical solution based on shallow water expansion for the spring-neap tide- induced water table fluctuations in a coastal aquifer is presented. Unlike most previous investigations, multitidal signals are considered with a sloping coastal aquifer. The new solution is verified by comparing with field observations from Ardeer, Scotland. On the basis of the analytical approximation the influences of higher-order components on water table elevation are examined first. Then, a parametric study has been performed to investigate the effects of the amplitude ratio (λ), frequency ratio (ω), and phases (δ1 and δ2) on the tide-induced water table fluctuations in a sloping sandy beach.ECO

Spring-neap tide-induced beach water table fluctuations and its influence on the behaviour of a coastal aquifer adjacent to a low-relief estuary

In this study, we investigated the effect of beach slope for a coastal aquifer adjacent to a low-relief estuary. The waste was suspected to discharge leachate towards the estuary. Field observations at various locations showed that tidally induced groundwater head fluctuations were skewed temporally. Frequency analysis suggested that the fluctuation amplitudes decreased exponentially and the phase-lags increased linearly for the primary tidal signals as they propagated inland. Flow and transport processes in a cross-section perpendicular to the estuary were simulated using SEAWAT-2000, which is capable of depicting density-dependent flow and multi-species transport. The simulations showed that the modelled water table fluctuations were in good agreement with the monitored data. The simulations showed that density difference and tidal forcing drive a more complex hydrodynamic pattern for the mildly sloping beach than the vertical beach, as well as a profound asymmetry in tidally induced water table fluctuations and enhanced salt-water intrusion. The simulation results also indicated that contaminant transport from the aquifer to the estuary was affected by the tide