Garlic compounds selectively kill childhood pre-B acute lymphoblastic leukemia cells in vitro without reducing T-cell function: Potential therapeutic use in the treatment of ALL

Drugs used for remission induction therapy for childhood precursor-B acute lymphoblastic leukemia (ALL) are nonselective for malignant cells. Several garlic compounds have been shown to induce apoptosis of cancer cells and to alter lymphocyte function. To investigate the effect of garlic on the apoptosis of ALL cells and lymphocyte immune function, cells from newly diagnosed childhood ALL patients were cultured with several commonly used chemotherapeutic agents and several garlic compounds. Apoptosis, lymphocyte proliferation and T-cell cytokine production were determined using multiparameter flow cytometry. At concentrations of garlic compounds that did not result in significant increases in Annexin V and 7-AAD staining of normal lymphocytes, there was a significant increase in apoptosis of ALL cells with no alteration of T-cell proliferation as determined by CD25/CD69 upregulation or interferonγ, interleukin-2 or tumor necrosis factor-α intracellular cytokine production. In contrast, the presence of chemotherapeutic agents resulted in nonselective increases in both lymphocyte and ALL apoptosis and a decrease in T-cell proliferation and cytokine production. In conclusion, we show selective apoptosis of malignant cells by garlic compounds that do not alter T-cell immune function and indicate the potential therapeutic benefit of garlic compounds in the treatment of childhood ALL

Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome

BackgroundMannose binding lectin (MBL) is a key mediator of both innate immunity and efferocytosis (phagocytosis of apoptotic cells) in the airway. Defective efferocytosis results in a net increase in apoptotic material that can undergo secondary necrosis, leading to tissue damage and chronic inflammation. We have shown reduced MBL and efferocytosis in other chronic inflammatory lung diseases; we therefore hypothesized that reduced MBL and efferocytosis in the airways may be a determinant of bronchiolitis obliterans syndrome (BOS) after lung transplantation.MethodsWe investigated MBL (enzyme-linked immunosorbent assay [ELISA]), MBL-mediated complement deposition (UC4, ELISA), and efferocytosis of apoptotic bronchial epithelial cells (flow cytometry) in bronchoalveolar lavage (BAL) and peripheral blood from 75 lung transplant recipients, comprising 16 with stable graft function, 34 stable with proven infection, 25 with BOS, and 14 healthy controls.ResultsIn plasma, MBL levels were highly variable (0-17.538 μg/ml), but increased in infected patients vs control (p = 0.09) or stable groups (p = 0.003). There was a similar increase in UC4 in infected patients and a significant correlation between MBL and UC4. There was no correlation between MBL and time after transplant. In BAL, MBL levels were less variable (0-73.3 ng/ml) and significantly reduced in patients with BOS vs controls and stable groups. Efferocytosis was significantly reduced in the BOS group vs control and stable groups (mean [SEM] control, 20% [1.3%]; stable, 20.5% [2.5%]; infected, 17.3% [2.8%]; BOS, 11.3% [1.5%], p = 0.04).ConclusionsLow levels of MBL in the airway may play a role in reduced efferocytosis, subsequent tissue damage, and BOS after lung transplantation.Sandra Hodge, Melinda Dean, Greg Hodge, M Holmes, Paul N Reynold

Integrated Energy Planning with a High Share of Variable Renewable Energy Sources for a Caribbean Island

Although it can be complex to integrate variable renewable energy sources such as wind power and photovoltaics into an energy system, the potential benefits are large, as it can help reduce fuel imports, balance the trade, and mitigate the negative impacts in terms of climate change. In order to try to integrate a very large share of variable renewable energy sources into the energy system, an integrated energy planning approach was used, including ice storage in the cooling sector, a smart charging option in the transport sector, and an excess capacity of reverse osmosis technology that was utilised in order to provide flexibility to the energy system. A unit commitment and economic dispatch tool (PLEXOS) was used, and the model was run with both 5 min and 1 h time resolutions. The case study was carried out for a typical Caribbean island nation, based on data derived from measured data from Aruba. The results showed that 78.1% of the final electricity demand in 2020 was met by variable renewable energy sources, having 1.0% of curtailed energy in the energy system. The total economic cost of the modelled energy system was similar to the current energy system, dominated by the fossil fuel imports. The results are relevant for many populated islands and island nations

Defective lung macrophage function in lung cancer +/- chronic obstructive pulmonary disease (COPD/emphysema)-mediated by cancer cell production of PGE2?

In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective ‘efferocytosis’), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells. We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis. Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown. Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.Francis C. Dehle, Violet R. Mukaro, Craig Jurisevic, David Moffat, Jessica Ahern, Greg Hodge, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodg

Lectins offer new perspectives in the development of macrophage-targeted therapies for COPD/emphysema

We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells (‘efferocytosis’) in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.Violet R. Mukaro, Johan Bylund, Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodg

Deep Synoptic Array Science: Polarimetry of 25 New Fast Radio Bursts Provides Insights into their Origins

We report on a full-polarization analysis of the first 25 as yet non-repeating FRBs detected at 1.4 GHz by the 110-antenna Deep Synoptic Array (DSA-110) during commissioning observations. We present details of the data reduction, calibration, and analysis procedures developed for this novel instrument. The data have 32 $\mu$s time resolution and sensitivity to Faraday rotation measures (RMs) between $\pm10^{6}$rad m$^{-2}$. RMs are detected for 20 FRBs with magnitudes ranging from $4-4670$ rad m$^{-2}$. $9/25$ FRBs are found to have high ($\ge 70\%$) linear-polarization fractions. The remaining FRBs exhibit significant circular polarization ($3/25$), or are either partially depolarized ($8/25$) or unpolarized ($5/25$). We investigate the mechanism of depolarization, disfavoring stochastic RM variations within a scattering screen as a dominant cause. Polarization-state and possible RM variations are observed in the four FRBs with multiple sub-components, but only one other FRB shows a change in polarization state. We combine the DSA-110 sample with polarimetry of previously published FRBs, and compare the polarization properties of FRB sub-populations and FRBs with Galactic pulsars. Although FRBs are typically far more polarized than the average profiles of Galactic pulsars, and exhibit greater spread in polarization fractions than pulsar single pulses, we find a remarkable similarity between FRB polarization fractions and the youngest (characteristic ages $<10^{5}$ yr) pulsars. Our results support a scenario wherein FRB emission is intrinsically highly linearly polarized, and where propagation effects within progenitor magnetospheres can result in conversion to circular polarization and depolarization. Young pulsar emission and magnetospheric-propagation geometries may form a useful analogy for the origin of FRB polarization.Comment: 43 pages, 17 figure

Deep Synoptic Array Science: Implications of Faraday Rotation Measures of Localized Fast Radio Bursts

Faraday rotation measures (RMs) of fast radio bursts (FRBs) offer the prospect of directly measuring extragalactic magnetic fields. We present an analysis of the RMs of ten as yet non-repeating FRBs detected and localized to host galaxies by the 110-antenna Deep Synoptic Array (DSA-110). We combine this sample with published RMs of 15 localized FRBs, nine of which are repeating sources. For each FRB in the combined sample, we estimate the host-galaxy dispersion measure (DM) contributions and extragalactic RM. We find compelling evidence that the extragalactic components of FRB RMs are often dominated by contributions from the host-galaxy interstellar medium (ISM). Specifically, we find that both repeating and as yet non-repeating FRBs show a correlation between the host-DM and host-RM in the rest frame, and we find an anti-correlation between extragalactic RM (in the observer frame) and redshift for non-repeaters, as expected if the magnetized plasma is in the host galaxy. Important exceptions to the ISM origin include a dense, magnetized circum-burst medium in some repeating FRBs, and the intra-cluster medium (ICM) of host or intervening galaxy clusters. We find that the estimated ISM magnetic-field strengths, $B_{||}$, are characteristically larger than those inferred from Galactic radio pulsars. This suggests either increased ISM magnetization in FRB hosts in comparison with the Milky Way, or that FRBs preferentially reside in regions of increased magnetic-field strength within their hosts

Deep Synoptic Array science I: discovery of the host galaxy of FRB 20220912A

We report the detection and interferometric localization of the repeating fast radio burst (FRB) source FRB 20220912A during commissioning observations with the Deep Synoptic Array (DSA-110). Two bursts were detected from FRB 20220912A, one each on 2022 October 18 and 2022 October 25. The best-fit position is (R.A. J2000, decl. J2000) = (23:09:04.9, +48:42:25.4), with a 90% confidence error ellipse of $\pm2$ arcsec and $\pm1$ arcsec in right ascension and declination respectively. The two bursts have disparate polarization properties and temporal profiles. We find a Faraday rotation measure that is consistent with the low value of $+0.6$ rad m$^{-2}$ reported by CHIME/FRB. The DSA-110 localization overlaps with the galaxy PSO J347.2702+48.7066 at a redshift $z=0.0771$, which we identify as the likely host. PSO J347.2702$+$48.7066 has a stellar mass of approximately $10^{10}M_{\odot}$, modest internal dust extinction, and a star-formation rate likely in excess of $0.1\,M_{\odot}$ yr$^{-1}$. The host-galaxy contribution to the dispersion measure is likely $\lesssim50$ pc cm$^{-3}$. The FRB 20220912A source is therefore likely viewed along a tenuous plasma column through the host galaxy.Comment: 10 pages, 7 figures, 2 tables, submitted to AAS Journal