I-fibrinogen as an oncophilic radiodiagnostic agent: distribution kinetics in tumour-bearing mice.

Fibrinogen radioiodinated by the iodine monochloride method was tested as a tumour radiodiagnostic agent in mice. The I-fibrinogen cleared from the blood of tumour-bearing mice more rapidly than from that of normal mice, but it cleared from the whole body more slowly, suggesting it accumulated in a substantial tumour-related compartment in the abnormal mice. The tumour concentration steadily increased for 4 h after injection, at which time it reached a peak concentration of 11-4% of the injected dose/g. This concentration was higher than the peak concentration for Ga-citrate (not reached until 24 h) or any other oncophilic radiopharmaceutical tested in this tumour model. The early accumulation is consistent with the use of 123I as a tracer label for fibrinogen. A combination of the large tumour concentration of I-fibrinogen, an increased catabolic rate induced by chemical modification, and the exceptional nuclear properties of 123I for scintigraphic imaging, could lead to a very useful radiodiagnostic procedure for cancer

Rethinking immune checkpoint blockade: Beyond the T cell

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies

Hepatic heparan sulfate is a master regulator of hepcidin expression and iron homeostasis in human hepatocytes and mice.

Hepcidin is a liver-derived peptide hormone that controls systemic iron homeostasis. Its expression is regulated by the bone morphogenetic protein 6 (BMP6)/SMAD1/5/8 pathway and by the proinflammatory cytokine interleukin 6 (IL6). Proteoglycans that function as receptors of these signaling proteins in the liver are commonly decorated by heparan sulfate, but the potential role of hepatic heparan sulfate in hepcidin expression and iron homeostasis is unclear. Here, we show that modulation of hepatic heparan sulfate significantly alters hepcidin expression and iron metabolism both in vitro and in vivo Specifically, enzymatic removal of heparan sulfate from primary human hepatocytes, CRISPR/Cas9 manipulation of heparan sulfate biosynthesis in human hepatoma cells, or pharmacological manipulation of heparan sulfate-protein interactions using sodium chlorate or surfen dramatically reduced baseline and BMP6/SMAD1/5/8-dependent hepcidin expression. Moreover inactivation of the heparan sulfate biosynthetic gene N-deacetylase and N-sulfotransferase 1 (Ndst1) in murine hepatocytes (Ndst1 f/f AlbCre +) reduced hepatic hepcidin expression and caused a redistribution of systemic iron, leading to iron accumulation in the liver and serum of mice. Manipulation of heparan sulfate had a similar effect on IL6-dependent hepcidin expression in vitro and suppressed IL6-mediated iron redistribution induced by lipopolysaccharide in vivo These results provide compelling evidence that hepatocyte heparan sulfate plays a key role in regulating hepcidin expression and iron homeostasis in mice and in human hepatocytes

Black Hole Evaporation in an Expanding Universe

We calculate the quantum radiation power of black holes which are asymptotic to the Einstein-de Sitter universe at spatial and null infinities. We consider two limiting mass accretion scenarios, no accretion and significant accretion. We find that the radiation power strongly depends on not only the asymptotic condition but also the mass accretion scenario. For the no accretion case, we consider the Einstein-Straus solution, where a black hole of constant mass resides in the dust Friedmann universe. We find negative cosmological correction besides the expected redshift factor. This is given in terms of the cubic root of ratio in size of the black hole to the cosmological horizon, so that it is currently of order $10^{-5} (M/10^{6}M_{\odot})^{1/3} (t/14 {Gyr})^{-1/3}$ but could have been significant at the formation epoch of primordial black holes. Due to the cosmological effects, this black hole has not settled down to an equilibrium state. This cosmological correction may be interpreted in an analogy with the radiation from a moving mirror in a flat spacetime. For the significant accretion case, we consider the Sultana-Dyer solution, where a black hole tends to increase its mass in proportion to the cosmological scale factor. In this model, we find that the radiation power is apparently the same as the Hawking radiation from the Schwarzschild black hole of which mass is that of the growing mass at each moment. Hence, the energy loss rate decreases and tends to vanish as time proceeds. Consequently, the energy loss due to evaporation is insignificant compared to huge mass accretion onto the black hole. Based on this model, we propose a definition of quasi-equilibrium temperature for general conformal stationary black holes.Comment: Accepted for publication in Class.Quant.Grav., 18 pages and 3 figure

Gravity from Spinors

We investigate a possible unified theory of all interactions which is based only on fundamental spinor fields. The vielbein and metric arise as composite objects. The effective quantum gravitational theory can lead to a modification of Einstein's equations due to the lack of local Lorentz-symmetry. We explore the generalized gravity with global instead of local Lorentz symmetry in first order of a systematic derivative expansion. At this level diffeomorphisms and global Lorentz symmetry allow for two new invariants in the gravitational effective action. The one which arises in the one loop approximation to spinor gravity is consistent with all present tests of general relativity and cosmology. This shows that local Lorentz symmetry is tested only very partially by present observations. In contrast, the second possible new coupling is severely restricted by present solar system observations.Comment: New material on absence of observational tests of local Lorentz invariance, 21 pages, to appear in Phys.Rev.

Kinks Dynamics in One-Dimensional Coupled Map Lattices

We examine the problem of the dynamics of interfaces in a one-dimensional space-time discrete dynamical system. Two different regimes are studied : the non-propagating and the propagating one. In the first case, after proving the existence of such solutions, we show how they can be described using Taylor expansions. The second situation deals with the assumption of a travelling wave to follow the kink propagation. Then a comparison with the corresponding continuous model is proposed. We find that these methods are useful in simple dynamical situations but their application to complex dynamical behaviour is not yet understood.Comment: 17pages, LaTex,3 fig available on cpt.univ-mrs.fr directory pub/preprints/94/dynamical-systems/94-P.307

GenomeVIP: A cloud platform for genomic variant discovery and interpretation

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional “download and analyze” paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.</jats:p

Intraoperative angiography via the popliteal artery: a useful technique for patients in the prone position

OBJECTIVE Intraoperative angiography can be a valuable tool in the surgical management of vascular disorders in the CNS. This is typically accomplished via femoral artery puncture; however, this can be technically difficult in patients in the prone position. The authors describe the feasibility of intraoperative angiography via the popliteal artery in the prone patient. METHODS Three patients underwent intraoperative spinal angiography in the prone position via vascular access through the popliteal artery. Standard angiography techniques were used, along with ultrasound and a micropuncture needle for initial vascular access. Two patients underwent intraoperative angiography to confirm the obliteration of dural arteriovenous fistulas. The third patient required unexpected intraoperative angiography when a tumor was concerning for a vascular malformation in the cervical spine. RESULTS All 3 patients tolerated the procedure without complication. The popliteal artery was easily accessed without any adaptation to typical patient positioning for these prone-position cases. This proved particularly beneficial when angiography was not part of the preoperative plan. CONCLUSIONS Intraoperative angiography via the popliteal artery is feasible and well tolerated. It presents significant benefit when obtaining imaging studies in patients in a prone position, with the added benefit of easy access, familiar anatomy, and low concern for catheter thrombosis or kinking

The Fulling-Unruh effect in general stationary accelerated frames

We study the generalized Unruh effect for accelerated reference frames that include rotation in addition to acceleration. We focus particularly on the case where the motion is planar, with presence of a static limit in addition to the event horizon. Possible definitions of an accelerated vacuum state are examined and the interpretation of the Minkowski vacuum state as a thermodynamic state is discussed. Such athermodynamic state is shown to depend on two parameters, the acceleration temperature and a drift velocity, which are determined by the acceleration and angular velocity of the accelerated frame. We relate the properties of Minkowski vacuum in the accelerated frame to the excitation spectrum of a detector that is stationary in this frame. The detector can be excited both by absorbing positive energy quanta in the "hot" vacuum state and by emitting negative energy quanta into the "ergosphere" between the horizon and the static limit. The effects are related to similar effects in the gravitational field of a rotating black hole.Comment: Latex, 39 pages, 5 figure

Existence and Stability of Steady Fronts in Bistable CML

We prove the existence and we study the stability of the kink-like fixed points in a simple Coupled Map Lattice for which the local dynamics has two stable fixed points. The condition for the existence allows us to define a critical value of the coupling parameter where a (multi) generalized saddle-node bifurcation occurs and destroys these solutions. An extension of the results to other CML's in the same class is also displayed. Finally, we emphasize the property of spatial chaos for small coupling.Comment: 18 pages, uuencoded PostScript file, J. Stat. Phys. (In press