Three-dimensional MHD Simulations of Radiatively Inefficient Accretion Flows

We present three-dimensional MHD simulations of rotating radiatively inefficient accretion flows onto black holes. In the simulations, we continuously inject magnetized matter into the computational domain near the outer boundary, and we run the calculations long enough for the resulting accretion flow to reach a quasi-steady state. We have studied two limiting cases for the geometry of the injected magnetic field: pure toroidal field and pure poloidal field. In the case of toroidal field injection, the accreting matter forms a nearly axisymmetric, geometrically-thick, turbulent accretion disk. The disk resembles in many respects the convection-dominated accretion flows found in previous numerical and analytical investigations of viscous hydrodynamic flows. Models with poloidal field injection evolve through two distinct phases. In an initial transient phase, the flow forms a relatively flattened, quasi-Keplerian disk with a hot corona and a bipolar outflow. However, when the flow later achieves steady state, it changes in character completely. The magnetized accreting gas becomes two-phase, with most of the volume being dominated by a strong dipolar magnetic field from which a thermal low-density wind flows out. Accretion occurs mainly via narrow slowly-rotating radial streams which `diffuse' through the magnetic field with the help of magnetic reconnection events.Comment: 35 pages including 3 built-in plots and 14 separate jpg-plots; version accepted by Ap

Triacylglycerol hydrolase: role in intracellular lipid metabolism

Recent scientific advances have revealed the identity of several enzymes involved in the synthesis, storage and catabolism of intracellular neutral lipid storage droplets. An enzyme that hydrolyzes stored triacylglycerol (TG), triacylglycerol hydrolase (TGH), was purified from porcine, human and murine liver microsomes. In rodents, TGH is highly expressed in liver as well as heart, kidney, small intestine and adipose tissues, while in humans TGH is mainly expressed in the liver, adipose and small intestine. TGH localizes to the endoplasmic reticulum and lipid droplets. The TGH genes are located within a cluster of carboxylesterase genes on human and mouse chromosomes 16 and 8, respectively. TGH hydrolyzes stored TG, and in the liver, the lipolytic products are made available for VLDL-TG synthesis. Inhibition of TGH activity also inhibits TG and apolipoprotein B secretion by primary hepatocytes. A role for TGH in basal TG lipolysis in adipocytes has been proposed. TGH expression and activity is both developmentally and hormonally regulated. A model for the function of TGH is presented and discussed with respect to tissue specific functions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42880/1/018_2004_Article_3426.pd

CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-γ, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions

Excitation of low-frequency QPOs in black-hole accretion

We study possible mechanisms of excitation of quasiperiodic oscillations in the accretion flow of black hole accreters in their hard spectral states, in the context of the `truncated disk' model. Quasi-spherical oscillations of the inner ion-supported accretion flow (ISAF) can be excited by the interaction of this hot flow with the cool disk extending outward from it. The fundamental mode of (p-mode) oscillation is most easily excited, and has a frequency near the Kepler frequency at the inner edge of the cool disk. The strongest excitation mechanism is a feedback loop involving cooling of the ISAF by soft photons from the cool disk and heating of the cool disk by the ISAF, while synchrotron emission can be a relatively strong damping effect. Growth times are computed by detailed Comptonization calculations of the interaction of an idealized ISAF with a cool disk. Typical growth times as short as a few dynamical times are found, while amplitudes can be as large as 10%.Comment: 11 pages, 5 figures, accepted for publication in A&

Past and current asbestos exposure and future mesothelioma risks in Britain: The Inhaled Particles Study (TIPS)

BACKGROUND: Occupational and environmental airborne asbestos concentrations are too low and variable for lifetime exposures to be estimated reliably, and building workers and occupants may suffer higher exposure when asbestos in older buildings is disturbed or removed. Mesothelioma risks from current asbestos exposures are therefore not known. METHODS: We interviewed and measured asbestos levels in lung samples from 257 patients treated for pneumothorax and 262 with resected lung cancer, recruited in England and Wales. Average lung burdens in British birth cohorts from 1940 to 1992 were estimated for asbestos-exposed workers and the general population. RESULTS: Regression analysis of British mesothelioma death rates and average lung burdens in birth cohorts born before 1965 suggests a lifetime mesothelioma risk of approximately 0.01% per fibre/mg of amphiboles in the lung. In those born since 1965, the average lung burden is ∼1 fibre/mg among those with no occupational exposure. CONCLUSIONS: The average lifetime mesothelioma risk caused by recent environmental asbestos exposure in Britain will be about 1 in 10 000. The risk is an order of magnitude higher in a subgroup of exposed workers and probably in occupants in the most contaminated buildings. Further data are needed to discover whether asbestos still present in buildings, particularly schools, is a persistent or decreasing hazard to workers who disturb it and to the general population, and whether environmental exposure occurs predominantly in childhood or after beginning work. Similar studies are needed in other countries to estimate continuing environmental and occupational mesothelioma hazards worldwide, including the contribution from chrysotile

Occupational, domestic and environmental mesothelioma risks in the British population: a case–control study

We obtained lifetime occupational and residential histories by telephone interview with 622 mesothelioma patients (512 men, 110 women) and 1420 population controls. Odds ratios (ORs) were converted to lifetime risk (LR) estimates for Britons born in the 1940s. Male ORs (95% confidence interval (CI)) relative to low-risk occupations for >10 years of exposure before the age of 30 years were 50.0 (25.8–96.8) for carpenters (LR 1 in 17), 17.1 (10.3–28.3) for plumbers, electricians and painters, 7.0 (3.2–15.2) for other construction workers, 15.3 (9.0–26.2) for other recognised high-risk occupations and 5.2 (3.1–8.5) in other industries where asbestos may be encountered. The LR was similar in apparently unexposed men and women (∼1 in 1000), and this was approximately doubled in exposed workers' relatives (OR 2.0, 95% CI 1.3–3.2). No other environmental hazards were identified. In all, 14% of male and 62% of female cases were not attributable to occupational or domestic asbestos exposure. Approximately half of the male cases were construction workers, and only four had worked for more than 5 years in asbestos product manufacture

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

The 5T4 oncofoetal antigen is a heavily glycosylated cell surface protein found on human placental trophoblast and on diverse types of human cancer but is not expressed at significant levels on adult human tissues in health. It therefore satisfies the criteria for a tumour-associated antigen and is an ideal target for the immunotherapy of cancer. We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein. This protein consists of a single chain antibody fragment capable of binding antigen directly at the cell surface and then activating the T cell by virtue of a CD3ζ-signalling domain. This is a powerful tool that bypasses a number of mechanisms that allow tumours to escape T-cell killing and can be readily scaled up for clinical use

Engineering T cells for cancer therapy

It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer. However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment. With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors. Using this strategy, it is potentially possible to generate large numbers of tumour reactive T cells rapidly. This review summarises the current gene therapy approaches in relation to the development of adoptive T-cell-based cancer treatments, as these methods now head towards testing in the clinical trial setting