Accurate Calculation of Hazardous Materials Transport Risks

Cataloged from PDF version of article.We propose two path-selection algorithms for the transport of hazardous materials. The algorithms can deal with link impedances that are path-dependent. This approach is superior to the use of a standard shortest path algorithm, common in the literature and practice, which results in inaccuracies

On the X-Ray Light Curve, Pulsed-Radio Emission, and Spin Frequency Evolution of the Transient Anomalous X-Ray Pulsar Xte J1810--197 During its X-Ray Outburst

We show that: (i) the long-term X-ray outburst light curve of the transient AXP XTE J1810-197 can be accounted for by a fallback disk that is evolving towards quiescence through a disk instability after having been heated by a soft gamma-ray burst, (ii) the spin-frequency evolution of this source in the same period can also be explained by the disk torque acting on the magnetosphere of the neutron star, (iii) most significantly, recently observed pulsed-radio emission from this source coincides with the epoch of minimum X-ray luminosity. This is natural in terms of a fallback disk model, as the accretion power becomes so low that it is not sufficient to suppress the beamed radio emission from XTE J1810-197.Comment: 13 pages, 2 Figures, accepted for publication in Ap

The cost and risk impacts of rerouting railroad shipments of hazardous materials

Cataloged from PDF version of article.Rail shipments of hazardous materials expose the population near the routes to the possibility of an accident resulting in a spill. Rail routes are determined by economic concerns such as route length and the revenue generated for the originating carrier. In this paper we consider an alternate routing strategy that takes accident risks into account. We employ a model to quantify rail transport risk and then use a weighted combination of cost and risk and generate alternate routes. In some cases the alternate routes achieve significantly lower risk values than the practical routes at a small incremental cost. While there are generally fewer rerouting alternatives for rail than for road transport, considering the possible consequences of a train derailment we argue that risk should be taken into account when selecting rail routes and that the cost–risk tradeoffs should be evaluated. © 2007 Elsevier Ltd. All rights reserved

The Network Design Problem with Relays

Cataloged from PDF version of article.The network design problem with relays (NDPR) is defined on an undirected graph G = (V,E,K), where V = {1,...,n} is a vertex set, E = {(i,j):i,j 2 V,i < j} is an edge set. The set K = {(o(k),d(k))} is a set of communication pairs (or commodities): o(k) 2 V and d(k) 2 V denote the origin and the destination of the kth commodity, respectively. With each edge (i,j) are associated a cost cij and a length dij. With vertex i is associated a fixed cost fi of locating a relay at i. The NDPR consists of selecting a subset E of edges of E and of locating relays at a subset V of vertices of V in such a way that: (1) the sum Q of edge costs and relay costs is minimized; (2) there exists a path linking the origin and the destination of each commodity in which the length between the origin and the first relay, the last relay and the destination, or any two consecutive relays does not exceed a preset upper bound k. This article develops a lower bound procedure and four heuristics for the NPDR. These are compared on several randomly generated instances with |V| 6 1002 and |E| 6 1930. 2006 Elsevier B.V. All rights reserved

Stability of the Magnetopause of Disk-Accreting Rotating Stars

We discuss three modes of oscillation of accretion disks around rotating magnetized neutron stars which may explain the separations of the kilo-Hertz quasi periodic oscillations (QPO) seen in low mass X-ray binaries. The existence of these compressible, non-barotropic magnetohydrodynamic (MHD) modes requires that there be a maximum in the angular velocity $\Omega_\phi(r)$ of the accreting material larger than the angular velocity of the star $\Omega_*$, and that the fluid is in approximately circular motion near this maximum rather than moving rapidly towards the star or out of the disk plane into funnel flows. Our MHD simulations show this type of flow and $\Omega_\phi(r)$ profile. The first mode is a Rossby wave instability (RWI) mode which is radially trapped in the vicinity of the maximum of a key function $g(r){\cal F}(r)$ at $r_{R}$. The real part of the angular frequency of the mode is $\omega_r=m\Omega_\phi(r_{R})$, where $m=1,2...$ is the azimuthal mode number. The second mode, is a mode driven by the rotating, non-axisymmetric component of the star's magnetic field. It has an angular frequency equal to the star's angular rotation rate $\Omega_*$. This mode is strongly excited near the radius of the Lindblad resonance which is slightly outside of $r_R$. The third mode arises naturally from the interaction of flow perturbation with the rotating non-axisymmetric component of the star's magnetic field. It has an angular frequency $\Omega_*/2$. We suggest that the first mode with $m=1$ is associated with the upper QPO frequency, $\nu_u$; that the nonlinear interaction of the first and second modes gives the lower QPO frequency, $\nu_\ell =\nu_u-\nu_*$; and that the nonlinear interaction of the first and third modes gives the lower QPO frequency $\nu_\ell=\nu_u-\nu_*/2$, where $\nu_*=\Omega_*/2\pi$.Comment: 10 pages, 7 figure

The role of Hall diffusion in the magnetically threaded thin accretion discs

We study role of the Hall diffusion in the magnetic star-disc interaction. In a simplified steady state configuration, the total torque is calculated in terms of the fastness parameter and a new term because of the Hall diffusion. We show the total torque reduces as the Hall term becomes more significant. Also, the critical fastness parameter (at which the total torque is zero) reduces because of the Hall diffusion.Comment: Accepted for publication in Astrophysics and Space Scienc

On the rotational dynamics of magnetically threaded disks around neutron stars

We investigate the rotational dynamics of disk accretion around a strongly magnetized neutron star with an aligned dipole field. The magnetospheric field is assumed to thread the disk plasma both inside and outside the corotation radius. As a result of disk-star interaction, the magnetic torque on the disk affects the structure of accretion flow to yield the observed spin- up or spin- down rates for a source of given fastness, magnetic field strength, and mass accretion rate. Within the model we obtain a prescription for the dynamical viscosity of such magnetically modified solutions for a Keplerian disk. We then use this prescription to find a model solution for the rotation rate profile throughout the entire disk, including the non-Keplerian inner disk. We find that the non-Keplerian angular velocity transition region is not necessarily narrow for a source of given spin state. The boundary layer approximation, as in the standard magnetically threaded disk model, holds only in the case of dynamical viscosity decreasing all the way to the innermost edge of the disk. These results are applied to several observed disk-fed X-ray pulsars that have exhibited quasi-periodic oscillations (QPOs). The QPO frequencies provide a constraint on the fastness parameter and enable one to determine uniquely the width of the angular velocity transition zone for each source within model assumptions. We discuss the implications of these results on the value of the critical fastness parameter for a magnetized star in spin equilibrium. Applications of our model are also made with relevant parameters from recent numerical simulations of quasi-stationary disk - magnetized star interactions

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy