Genomic homogeneity in fibrolamellar carcinomas

Background-Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) with distinctive clinical and histological features. To date there have been few studies on the genotypic aspects of FLC and no previous attempts have been made to use the arbitrarily primed-polymerase chain reaction (AF-FCR) technique to detect genetic alterations in this disease.Aim-The aim of this study was to assess the degree of genomic heterogeneity of FEC using the AP-PCR technique. Methods-A fetal of 50 tissue samples of primary and metastatic FLCs from seven patients were microdissected. AP-PCR amplification of each genomic DNA sample was carried out using two arbitrary primers.Results-DNA fingerprints of the primary FLCs and all their metastatic lesions (both synchronous and metachronous disease) were identical in an individual patient. The fingerprints were different between tumours of different patients. No evidence of intratumour heterogeneity was observed.Conclusions-Such genomic homogeneity in FLCs may explain their indolent growth. The absence of clonal evolution, which is present in other tumours (particularly HCCs), may explain the distinct behaviour in this tumour. The tumorigenic pathway and degree of somatic genomic changes in this disease may be less complex than in HCC

Constraints on cosmic-ray efficiency in the supernova remnant RCW 86 using multi-wavelength observations

Several young supernova remnants (SNRs) have recently been detected in the high-energy and very-high-energy gamma-ray domains. As exemplified by RX J1713.7-3946, the nature of this emission has been hotly debated, and direct evidence for the efficient acceleration of cosmic-ray protons at the SNR shocks still remains elusive. We analyzed more than 40 months of data acquired by the Large Area Telescope (LAT) on-board the Fermi Gamma-Ray Space Telescope in the HE domain, and gathered all of the relevant multi-wavelength (from radio to VHE gamma-rays) information about the broadband nonthermal emission from RCW 86. For this purpose, we re-analyzed the archival X-ray data from the ASCA/Gas Imaging Spectrometer (GIS), the XMM-Newton/EPIC-MOS, and the RXTE/Proportional Counter Array (PCA). Beyond the expected Galactic diffuse background, no significant gamma-ray emission in the direction of RCW 86 is detected in any of the 0.1-1, 1-10 and 10-100 GeV Fermi-LAT maps. In the hadronic scenario, the derived HE upper limits together with the HESS measurements in the VHE domain can only be accommodated by a spectral index Gamma <= 1.8, i.e. a value in-between the standard (test-particle) index and the asymptotic limit of theoretical particle spectra in the case of strongly modified shocks. The interpretation of the gamma-ray emission by inverse Compton scattering of high energy electrons reproduces the multi-wavelength data using a reasonable value for the average magnetic field of 15-25 muG. For these two scenarios, we assessed the level of acceleration efficiency. We discuss these results in the light of existing estimates of the magnetic field strength, the effective density and the acceleration efficiency in RCW 86.Comment: Accepted for publication in A&A; 10 pages and 4 figure

Fermi Detection of the Pulsar Wind Nebula HESS J1640-465

We present observations of HESS J1640-465 with the Fermi-LAT. The source is detected with high confidence as an emitter of high-energy gamma-rays. The spectrum lacks any evidence for the characteristic cutoff associated with emission from pulsars, indicating that the emission arises primarily from the pulsar wind nebula. Broadband modeling implies an evolved nebula with a low magnetic field resulting in a high gamma-ray to X-ray flux ratio. The Fermi emission exceeds predictions of the broadband model, and has a steeper spectrum, possibly resulting from a distinct excess of low energy electrons similar to what is inferred for both the Vela X and Crab pulsar wind nebulae.Comment: 6 pages, 5 figures, accepted for publication in Ap

Sticky islands in stochastic webs and anomalous chaotic cross-field particle transport by ExB electron drift instability

The ExB electron drift instability, present in many plasma devices, is an important agent in cross-field particle transport. In presence of a resulting low frequency electrostatic wave, the motion of a charged particle becomes chaotic and generates a stochastic web in phase space. We define a scaling exponent to characterise transport in phase space and we show that the transport is anomalous, of super-diffusive type. Given the values of the model parameters, the trajectories stick to different kinds of islands in phase space, and their different sticking time power-law statistics generate successive regimes of the super-diffusive transport.Comment: This manuscript contains 13 Pages and 21 figure

Optimized Anchor-Modified Peptides Targeting Mutated RAS Are Promising Candidates for Immunotherapy

RAS mutations occur in approximately 20% of all cancers and given their clonality, key role as driver mutation, association with poor prognosis and undruggability, they represent attractive targets for immunotherapy. We have identified immunogenic peptides derived from codon 12 mutant RAS (G12A, G12C, G12D, G12R, G12S and G12V), which bind to HLA-A*02:01 and HLA-A*03:01 and elicit strong peptide-specific CD8+ T cell responses, indicating that there is an effective CD8+ T-cell repertoire against these mutant RAS-derived peptides that can be mobilized. Alterations in anchor residues of these peptides enhanced their binding affinity to HLA-A*02:01 molecules and allowed generation of CD8+ T cells that responded to target cells pulsed with the anchor-modified and also with the original peptide. Cytotoxic T cells generated against these peptides specifically lysed tumor cells expressing mutant RAS. Vaccination of transgenic humanized HLA-A2/DR1 mice with a long peptide encompassing an anchor-modified 9-mer G12V epitope generated CD8+ T cells reactive to the original 9-mer and to a HLA-A*02:01-positive human cancer cell line harboring the G12V mutation. Our data provide strong evidence that mutant RAS can be targeted by immunotherapy

Hepatitis B testing and treatment in HIV patients in The Gambia - compliance with international guidelines and clinical outcomes

Background Compliance with WHO guidelines on HBV screening and treatment in HIV-coinfected patients is often challenging in resource limited countries and has been poorly assessed in sub-Saharan Africa. Methods Between 2015 and 2016, we assessed physician’s compliance with WHO guidelines on HIV-HBV coinfection in the largest HIV clinic in The Gambia, and the hepatic outcomes in HIV-HBV coinfected patients as compared to randomly selected HIV-monoinfected controls. Results 870 HIV-infected patients regularly seen in this clinic agreed to participate in our study. Only 187 (21.5%, 95% CI 18.8–24.3) had previously been screened for HBsAg, 23 (12.3%, 95% CI 8.0–17.9) were positive of whom none had liver assessment and only 6 (26.1%) had received Tenofovir. Our HBV testing intervention was accepted by all participants and found 94/870 (10.8%, 95% CI 8.8–13.1) positive, 78 of whom underwent full liver assessment along with 40 HBsAg-negative controls. At the time of liver assessment, 61/78 (78.2%) HIV-HBV coinfected patients received ART with 7 (11.5%) on Tenofovir and 54 (88.5%) on Lamivudine alone. HIV-HBV coinfected patients had higher APRI score compared to controls (0.58 vs 0.42, p = 0.002). HBV DNA was detectable in 52/53 (98.1%) coinfected patients with 14/53 (26.4%) having HBV DNA >20,000 IU/L. 10/12 (83.3%) had at least one detectable 3TC-associated HBV resistance, which tended to be associated with increase in liver fibrosis after adjusting for age and sex (p = 0.05). Conclusions Compliance with HBV testing and treatment guidelines is poor in this Gambian HIV programme putting coinfected patients at risk of liver complications. However, the excellent uptake of HBV screening and linkage to care in our study suggests feasible improvements

An effective therapeutic regime for treatment of glioma using oncolytic vaccinia virus expressing IL-21 in combination with immune checkpoint inhibition

Glioblastoma (GBM) is the most common primary malignant tumor in the brain, accounting for 51.4% of all primary brain tumors. GBM has a highly immunosuppressive tumor microenvironment (TME) and, as such, responses to immunotherapeutic strategies are poor. Vaccinia virus (VV) is an oncolytic virus that has shown tremendous therapeutic effect in various tumor types. In addition to its directly lytic effect on tumor cells, it has an ability to enhance immune cell infiltration into the TME allowing for improved immune control over the tumor. Here, we used a new generation of VV expressing the therapeutic payload interleukin-21 to treat murine GL261 glioma models. After both intratumoral and intravenous delivery, virus treatment induced remodeling of the TME to promote a robust anti-tumor immune response that resulted in control over tumor growth and long-term survival in both subcutaneous and orthotopic mouse models. Treatment efficacy was significantly improved in combination with systemic α-PD1 therapy, which is ineffective as a standalone treatment but synergizes with oncolytic VV to enhance therapeutic outcomes. Importantly, this study also revealed the upregulation of stem cell memory T cell populations after the virus treatment that exert strong and durable anti-tumor activity

Evidence for proton acceleration and escape from the Puppis A SNR using Fermi-LAT observations

Supernova remnants (SNRs) are the best candidates for galactic cosmic ray acceleration to rela- tivistic energies via diffusive shock acceleration. The gamma-ray emission of SNRs can provide direct evidence of leptonic (inverse Compton and bremsstrahlung) and hadronic (proton-proton interaction and subsequently pion decay) processes. Puppis A is a ∼4 kyr old SNR interacting with interstellar clouds which has been observed in a broad energy band, from radio to gamma-ray. We performed a morphological and spectral analysis of 14 years of observations with Fermi-LAT telescope in order to study its gamma-ray emission. We found a clear asymmetry in high-energy brightness between the eastern and western sides of the remnant, reminiscent to that observed in the X-ray emission. The eastern side, interacting with a molecular cloud, shows a spectrum which can be reproduced by a pion decay model. Moreover, we analyzed two gamma-ray sources located close to the remnant. The hardness of their spectra suggests that the gamma-ray emission can be due to particles escaping from the shock of Puppis A

Cost-effectiveness of different monitoring strategies in a screening and treatment programme for hepatitis B in The Gambia

Background: Clinical management of chronic hepatitis B virus (HBV) infection is complex and access to antiviral treatment remains limited in sub-Saharan Africa. International guidelines recommend monitoring at least annually for disease progression among HBV-infected people not meeting treatment criteria at initial diagnosis. This study aimed to assess the impact and cost-effectiveness of alternative strategies for monitoring. Methods: We used a mathematical model of HBV transmission and natural history, calibrated to all available West African data, to project the population-level health impact, costs and cost-effectiveness of different monitoring strategies for HBV-infected individuals not initially eligible for antiviral treatment. We assumed that these patients were found in the year 2020 in a hypothetical community-based screening programme in The Gambia. Monitoring frequencies were varied between every 5 and every 1 year and targeted different age groups. Results: The currently recommended annual monitoring frequency was likely to be not cost-effective in comparison with other strategies in this setting. 5-yearly monitoring in 15-45-year olds, at US$338 per disability-adjusted life year averted, had the highest probability of being the most effective cost-effective monitoring strategy. Conclusions: Monitoring less frequently than once a year is a cost-effective strategy in a community-based HBV screening and treatment programme in The Gambia, with the optimal strategy depending on the cost-effectiveness threshold. Efficiencies may be gained by prioritising the 15-45-year age group for more intensive monitoring

Non-resonant diagrams in radiative four-fermion processes

The complete tree level cross section for $e^+e^- \to e^- \bar\nu_e u \bar{d} \gamma$ is computed and discussed in comparison with the cross sections for $e^+e^- \to e^- \bar\nu_e u \bar{d}$ and $e^+e^- \to \bar{u} d u \bar{d}$. Event generators based on the GRACE package for the non-radiative and radiative case are presented. Special interest is brought to the effect of the non-resonant diagrams overlooked so far in other studies. Their contribution to the total cross section is presented for the LEP II energy range and for future linear colliders ($\sqrt s$ =500 GeV). Effects, at the W pair threshold, of order 3\% ($e^- \bar\nu_e u \bar{d}$) and 27\% ($\bar{u} d u \bar{d}$) are reported. Similar behaviour for the radiative case is shown. At $\sqrt s$ = 500 GeV, the relative contribution of the non-resonant diagrams for the radiative channel reaches 42.5\%.Comment: 6 pages, latex, KEK-CP-015, KEK Preprint 94-46, LAPP-Exp.-94.0