Effect of dietary omega-3 fatty acids on castrate-resistant prostate cancer and tumor-associated macrophages.

BackgroundM2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages.MethodsMycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm2. To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay.ResultsThe ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm3) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3).ConclusionsDietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC

Risk-informed analysis of the large break loss of coolant accident and PCT margin evaluation with the RISMC methodology

For general design basis accidents, such as SBLOCA and LBLOCA, the traditional deterministic safety analysis methodologies are always applied to analyze events based on a so called surrogate or licensing sequence, without considering how low this sequence occurrence probability is. In the to-be-issued 10 CFR 50.46a, the LBLOCA will be categorized as accidents beyond design basis and the PCT margin shall be evaluated in a risk-informed manner. According to the risk-informed safety margin characterization (RISMC) methodology, a process has been suggested to evaluate the risk-informed PCT margin. Following the RISMC methodology, a load spectrum of PCT for LBLOCA has been generated for the Taiwan’s Maanshan Nuclear Power plant and 14 probabilistic significant sequences have been identified. It was observed in the load spectrum that the conditional PCT generally ascends with the descending sequence occurrence probability. With the load spectrum covering both aleatory and epistemic uncertainties, the risk-informed PCT margin can be evaluated by either expecting value estimation method or sequence probability coverage method. It was found that by comparing with the traditional deterministic methodology, the PCT margin evaluated by the RISMC methodology can be greater by 44–62 K. Besides, to have a cumulated occurrence probability over 99% in the load spectrum, the occurrence probability of the sequence referred is about 5.07 * 10−3, whereas for the traditional surrogate or licensing sequence generally applied in the deterministic methodology, the occurrence probability is only about 5.46 * 10−5

Strong tuning of Rashba spin orbit interaction in single InAs nanowires

A key concept in the emerging field of spintronics is the gate voltage or electric field control of spin precession via the effective magnetic field generated by the Rashba spin orbit interaction. Here, we demonstrate the generation and tuning of electric field induced Rashba spin orbit interaction in InAs nanowires where a strong electric field is created either by a double gate or a solid electrolyte surrounding gate. In particular, the electrolyte gating enables six-fold tuning of Rashba coefficient and nearly three orders of magnitude tuning of spin relaxation time within only 1 V of gate bias. Such a dramatic tuning of spin orbit interaction in nanowires may have implications in nanowire based spintronic devices.Comment: Nano Letters, in pres

The Halo Beaming Model for Gamma-Ray Bursts

We consider a model for gamma-ray bursts (GRBs) from high-velocity neutron stars in the galactic halo. In this model, bursters are born in the galactic disk with large recoil velocities V_r, and GRBs are beamed to within emission cones of half-angle \phi centered on V_r. We describe scenarios for magnetically -channeled GRBs that have such beaming characteristics. We then make detailed comparisons of this halo beaming model (HBM) to BATSE and PVO data for GRB intensity & angular position distributions. Acceptable fits to observations of over 1000 bursts are obtained for \phi = 15 - 30 degrees and for a BATSE sampling depth ~ 180 kpc. Present data favor a truly isotropic (cosmological) model over the HBM, but not by a statistically compelling margin. Bursters born in nearby external galaxies, such as M31, are almost entirely undetectable in the HBM because of misdirected beaming. We analyze several refinements of the basic HBM: gamma-ray intensities that vary with angle from the beam axis; non-standard-candle GRB luminosity functions; and models including a subset of bursters that do not escape from the galaxy. We also discuss the energy budgets for the bursters, the origins of their recoils, and the physics of burst beaming and alignment. One possible physical model is based on the magnetar model of soft gamma repeaters (SGRs). Empirical bounds on the rate of formation and peculiar velocities of SGRs imply that there exist ~ 10^4 to ~ 10^7 aged SGRs in the galactic halo within a distance of 100 kpc. The HBM gives an acceptable fit to observations only if it satisfies certain conditions (e.g. \phi ~ 20 deg) which are possible, but for which there exist no clear & compelling theoretical justifications. The cosmological burster hypothesis is more generic and thus more attractive in this sense. (Abbreviated Abstract).Comment: ApJ accepted, 9 figures, AASTE

Role of mTOR through Autophagy in Esophageal Cancer Stemness

SIMPLE SUMMARY: Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis, which seems related to esophageal cancer stem-like cells (CSCs), which reside in a hypoxic niche. We demonstrated, using EC cell lines and patient-derived organoids, that the hypoxia-responding mammalian target of rapamycin (mTOR) can suppress autophagy and stemness of esophageal CSCs. In addition, mTOR inhibitor Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Collectively, our data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. The mTOR pathway could be a novel therapeutic target for putative esophageal CSCs. ABSTRACT: Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis. Therapy resistance and early recurrences are major obstacles in reaching a better outcome. Esophageal cancer stem-like cells (CSCs) seem tightly related with chemoradiation resistance, initiating new tumors and metastases. Several oncogenic pathways seem to be involved in the regulation of esophageal CSCs and might harbor novel therapeutic targets to eliminate CSCs. Previously, we identified a subpopulation of EC cells that express high levels of CD44 and low levels of CD24 (CD44(+)/CD24(−)), show CSC characteristics and reside in hypoxic niches. Here, we aim to clarify the role of the hypoxia-responding mammalian target of the rapamycin (mTOR) pathway in esophageal CSCs. We showed that under a low-oxygen culture condition and nutrient deprivation, the CD44(+)/CD24(−) population is enriched. Since both low oxygen and nutrient deprivation may inhibit the mTOR pathway, we next chemically inhibited the mTOR pathway using Torin-1. Torin-1 upregulated SOX2 resulted in an enrichment of the CD44(+)/CD24(−) population and increased sphere formation potential. In contrast, stimulation of the mTOR pathway using MHY1485 induced the opposite effects. In addition, Torin-1 increased autophagic activity, while MHY1485 suppressed autophagy. Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Finally, a clearly defined CD44(+)/CD24(−) CSC population was detected in EC patients-derived organoids (ec-PDOs) and here, MHY1485 also reduced this population. These data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. Stimulation of the mTOR pathway might aid in the elimination of putative esophageal CSCs

Increasing Therapy Related Myeloid Neoplasms in Multiple Myeloma

© 2018 Stichting European Society for Clinical Investigation Journal Foundation. This document is made available under the CC-BY-NC 4.0 license http://creativecommons.org/licenses/by-nc /4.0/ This document is the submitted version of a published work that appeared in final form in European Journal of Clinical Investigation.Background: Despite the longer survival achieved in multiple myeloma (MM) patients due to new therapy strategies, a concern is emerging regarding an increased risk of secondary primary malignancies (SPMs) and how to characterize those patients at risk. We performed a retrospective study covering a 28‐year follow‐ up period (1991‐2018) in a tertiary single institution. Material and Methods: Data of 403 MM patients were recorded and compared with the epidemiologic register of the population area covered by our centre, calculating the standardize incidence ratio (SIR) for the different types of SPMs diagnosed in the MM cohort. Fine and Gray regression models were used to identify risk factors for SPMs. Results: Out of the 403 MM patients, 23 (5.7%) developed SPMs: 13 therapyrelated myeloid (TRM) malignancies (10 of them (77%) myelodysplastic syndrome (MDS), 1 acute lymphoid leukaemia and 9 solid neoplasms. In the MM cohort, the relative risk of MDS was significantly higher than in the general population. Survival of patients with TRM malignancies was poor with a median of 4 months from the diagnosis, and most of them showed complex karyotype. Within the MM subset, multivariable analysis showed a higher risk of TRM malignancies in patients that previously received prolonged treatment with lenalidomide (>18 months). Conclusions: Though the improvement in MM outcome during the last decades is an unprecedented achievement, it has been accompanied by the rise in TRM malignancies with complex cytogenetic profile and poor prognosis that are in the need of an improved biologic and therapeutic approach

Cyclic-di-AMP synthesis by the diadenylate cyclase CdaA is modulated by the peptidoglycan biosynthesis enzyme GlmM in lactococcus lactis

© 2016 John Wiley & Sons Ltd. The second messenger cyclic-di-adenosine monophosphate (c-di-AMP) plays important roles in growth, virulence, cell wall homeostasis, potassium transport and affects resistance to antibiotics, heat and osmotic stress. Most Firmicutes contain only one c-di-AMP synthesizing diadenylate cyclase (CdaA); however, little is known about signals and effectors controlling CdaA activity and c-di-AMP levels. In this study, a genetic screen was employed to identify components which affect the c-di-AMP level in Lactococcus. We characterized suppressor mutations that restored osmoresistance to spontaneous c-di-AMP phosphodiesterase gdpP mutants, which contain high c-di-AMP levels. Loss-of-function and gain-of-function mutations were identified in the cdaA and gdpP genes, respectively, which led to lower c-di-AMP levels. A mutation was also identified in the phosphoglucosamine mutase gene glmM, which is commonly located within the cdaA operon in bacteria. The glmM I154F mutation resulted in a lowering of the c-di-AMP level and a reduction in the key peptidoglycan precursor UDP-N-acetylglucosamine in L. lactis. C-di-AMP synthesis by CdaA was shown to be inhibited by GlmMI154F more than GlmM and GlmMI154F was found to bind more strongly to CdaA than GlmM. These findings identify GlmM as a c-di-AMP level modulating protein and provide a direct connection between c-di-AMP synthesis and peptidoglycan biosynthesis. c-di-AMP is an essential signalling molecule which affects peptidoglycan homeostasis and resistance against various stressors, however little is known regarding how the c-di-AMP level is regulated in the cell. Here we identify the peptidoglycan biosynthesis enzyme GlmM as a modulator of c-di-AMP synthesis through its regulation of diadenylate cyclase enzyme CdaA activity in Lactococcus lactis

Electric Field Control of Spin Transport

Spintronics is an approach to electronics in which the spin of the electrons is exploited to control the electric resistance R of devices. One basic building block is the spin-valve, which is formed if two ferromagnetic electrodes are separated by a thin tunneling barrier. In such devices, R depends on the orientation of the magnetisation of the electrodes. It is usually larger in the antiparallel than in the parallel configuration. The relative difference of R, the so-called magneto-resistance (MR), is then positive. Common devices, such as the giant magneto-resistance sensor used in reading heads of hard disks, are based on this phenomenon. The MR may become anomalous (negative), if the transmission probability of electrons through the device is spin or energy dependent. This offers a route to the realisation of gate-tunable MR devices, because transmission probabilities can readily be tuned in many devices with an electrical gate signal. Such devices have, however, been elusive so far. We report here on a pronounced gate-field controlled MR in devices made from carbon nanotubes with ferromagnetic contacts. Both the amplitude and the sign of the MR are tunable with the gate voltage in a predictable manner. We emphasise that this spin-field effect is not restricted to carbon nanotubes but constitutes a generic effect which can in principle be exploited in all resonant tunneling devices.Comment: 22 pages, 5 figure