Locoregional and systemic therapy for hepatocellular carcinoma

The management of hepatocellular carcinoma (HCC) remains challenging due to late presentation and the presence of accompanying liver dysfunction. As such, most patients are not eligible for curative resection and liver transplant. Management in this scenario depends on a number of factors including hepatic function, tumor burden, patency of hepatic vasculature and patients' functional status. Based on these, patients can be offered catheter based intra-arterial therapy for intermediate stage disease and in more advanced disease, sorafenib. Given recent data, regorafenib is now an option following failure of sorafenib. Catheter directed intra-arterial therapy takes advantage of tumor hypervascularity and the unique dual blood supply of the liver, as hepatic tumors receive arterial perfusion via the hepatic artery while the rest of the liver is supplied by the portal vein. This allows selective embolization and delivery of chemotherapeutic agents to the tumor. Compared to best supportive care, intra-arterial therapy offers a survival benefit in intermediate stage HCC and is the recommended approach for treatment. None of the catheter based approaches; including bland embolization, conventional trans-arterial chemoembolization (cTACE), drug eluting bead trans-arterial chemoembolization (DEB-TACE) or trans-arterial radioembolization (TARE) offers a clear advantage over the other, although DEB-TACE may be characterized by less systemic toxicity. All of these approaches are contraindicated in patients with portal vein thrombosis (PVT). On the other hand, intra-arterial, radio embolization, with Yttrium-90 (Y90) can be offered to patients with PVT. The place of this modality in management of HCC is still being investigated. The role of sorafenib in advanced HCC is not in doubt, as until recently, it was the only systemic therapy approved for the management in this setting. This is despite multiple trials evaluating other agents. The addition of sorafenib to catheter-based therapy in intermediate stage disease has also failed to show any benefit. The modest survival benefit with sorafenib and the failure of other targeted agents suggest that it is important to look beyond inhibition of angiogenesis in advanced HCC. Identification of key drivers and mediators of HCC remains paramount for successful drug development. In line with this, it is refreshing that the excitement that has followed developments in cancer immunotherapy is finding its way to HCC with early trials of anti-PD1 monoclonal antibodies showing sufficient activity that phase III trials are now ongoing for Pembrolizumab and Nivolumab in advanced HCC. Future drug development efforts will focus on defining the feasibility of combining different treatment approaches targeting multiple important modulators of HCC

Implementation of Multidimensional Databases with Document-Oriented NoSQL

International audienceNoSQL (Not Only SQL) systems are becoming popular due to known advantages such as horizontal scalability and elasticity. In this paper, we study the implementation of data warehouses with document-oriented NoSQL systems. We propose mapping rules that transform the multidimensional data model to logical document-oriented models. We consider three different logical models and we use them to instantiate data warehouses. We focus on data loading, model-to-model conversion and OLAP cuboid computation

A threshold phenomenon for embeddings of H0mH^m_0 into Orlicz spaces

We consider a sequence of positive smooth critical points of the Adams-Moser-Trudinger embedding of $H^m_0$ into Orlicz spaces. We study its concentration-compactness behavior and show that if the sequence is not precompact, then the liminf of the $H^m_0$-norms of the functions is greater than or equal to a positive geometric constant.Comment: 14 Page

Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma

BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α) is a gene that regulates tumor survival, neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma (HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC. AIM: To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179. METHODS: In the preclinical study of RO7070179 in a HCC xenograft model, the mice were separated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment, received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179. RESULTS: Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and 1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies (each biopsy was divided into 2 specimens, the tip and the root). CONCLUSION: RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity. This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either mRNA level or DCE-MRI within 1 cycle of therapy

Asymptotic stability, concentration, and oscillation in harmonic map heat-flow, Landau-Lifshitz, and Schroedinger maps on R^2

We consider the Landau-Lifshitz equations of ferromagnetism (including the harmonic map heat-flow and Schroedinger flow as special cases) for degree m equivariant maps from R^2 to S^2. If m \geq 3, we prove that near-minimal energy solutions converge to a harmonic map as t goes to infinity (asymptotic stability), extending previous work down to degree m = 3. Due to slow spatial decay of the harmonic map components, a new approach is needed for m=3, involving (among other tools) a "normal form" for the parameter dynamics, and the 2D radial double-endpoint Strichartz estimate for Schroedinger operators with sufficiently repulsive potentials (which may be of some independent interest). When m=2 this asymptotic stability may fail: in the case of heat-flow with a further symmetry restriction, we show that more exotic asymptotics are possible, including infinite-time concentration (blow-up), and even "eternal oscillation".Comment: 34 page

Complex ecologies of trust in data practices and data-driven systems

Trust in data practices and data-driven systems is widely seen as both important and elusive. A data trust deficit has been identified, to which proposed solutions are often localised or individualised, focusing either on what institutions can do to increase user trust in their data practices or on data management models that empower the individual user. Scholarship on trust often focuses on typologies of trust. This paper shifts the emphasis to those doing the trusting, by presenting findings from empirical research which explored user perspectives on the data practices of the BBC. These findings challenge the assumption that localised or individualised solutions can be effective. They also suggest that conceptualisations of trust in data practices need to account for the complex range of factors which come into play in relation to trust in data and so move beyond the production of typologies. In this paper, we propose the concept of ‘complex ecologies of trust’ as a way of addressing all of these issues

Creating and studying ion acoustic waves in ultracold neutral plasmas

We excite ion acoustic waves in ultracold neutral plasmas by imprinting density modulations during plasma creation. Laser-induced fluorescence is used to observe the density and velocity perturbations created by the waves. The effect of expansion of the plasma on the evolution of the wave amplitude is described by treating the wave action as an adiabatic invariant. After accounting for this effect, we determine that the waves are weakly damped, but the damping is significantly faster than expected for Landau damping

Academic freedom in Europe: reviewing UNESCO’s recommendation

This paper examines the compliance of universities in the European Union with the UNESCO Recommendation concerning the Status of Higher–Education Teaching Personnel, which deals primarily with protection for academic freedom. The paper briefly surveys the European genesis of the modern research university and academic freedom, before evaluating compliance with the UNESCO recommendation on institutional autonomy, academic freedom, university governance and tenure. Following from this, the paper examines the reasons for the generally low level of compliance with the UNESCO Recommendation within the EU states, and considers how such compliance could be improved

Long-time discrete particle effects versus kinetic theory in the self-consistent single-wave model

The influence of the finite number N of particles coupled to a monochromatic wave in a collisionless plasma is investigated. For growth as well as damping of the wave, discrete particle numerical simulations show an N-dependent long time behavior resulting from the dynamics of individual particles. This behavior differs from the one due to the numerical errors incurred by Vlasov approaches. Trapping oscillations are crucial to long time dynamics, as the wave oscillations are controlled by the particle distribution inhomogeneities and the pulsating separatrix crossings drive the relaxation towards thermal equilibrium.Comment: 11 pages incl. 13 figs. Phys. Rev. E, in pres

Optical application and measurement of torque on microparticles of isotropic nonabsorbing material

We show how it is possible to controllably rotate or align microscopic particles of isotropic nonabsorbing material in a TEM00 Gaussian beam trap, with simultaneous measurement of the applied torque using purely optical means. This is a simple and general method of rotation, requiring only that the particle is elongated along one direction. Thus, this method can be used to rotate or align a wide range of naturally occurring particles. The ability to measure the applied torque enables the use of this method as a quantitative tool--the rotational equivalent of optical tweezers based force measurement. As well as being of particular value for the rotation of biological specimens, this method is also suitable for the development of optically-driven micromachines.Comment: 8 pages, 6 figure