Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Previously we demonstrated that addition of Tumour Necrosis Factor-α to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan

Seismic site characterization of the Kastelli (Kissamos) Basin in northwest Crete (Greece): Assessments using ambient noise recordings

Crete is actively seismic and site response studies are needed for estimating local site conditions subjected to seismic activity. In order to collect basic data, we performed ambient noise recordings to estimate the site response of the surface and near subsurface structure of the small-scale Kastelli Basin in northwest Crete. The spatial horizontal to vertical spectral ratios (HVSR) resonance pattern of the investigated sites in the centre of the Basin consists of either one or two peaks divided into low to high frequency range in different sites as follows: (a) in some sites only one amplified peak at low frequencies (0.6–1.2 Hz), (b) in other sites only one amplified peak at medium frequencies (2.9–8.5 Hz) and (c) in yet other sites two amplified peaks in the low to high frequency range (0.6–15.5 Hz). The investigated sites are amplified in the frequency range 0.6–15.5 Hz, while the amplitude reaches to a factor of 4 in the spectral ratios. The one HVSR amplified peak at low frequencies is related to locally soft or thick Quaternary deposits. Microtremors were measured in the coastal northwest part of the Basin in a well—lithified Cretaceous limestone site characterized by fractures and faults striking predominantly in a sector NNE to NNW. Sites of one amplified peak at medium frequencies are extended from coastal northwest to southwest delineating a structure striking to NNW. The two amplified peaks are attributed to shallow subsurface heterogeneities/irregularities, locally induced by fault zones and to the overlying Quaternary deposits. Spatial HVSR variations in the frequency and HVSR shape delineate four structures striking NNE, NNW and in a sector NW to WNW, crosscutting the dense populated Basin suggesting that microtremors could be a valuable tool for providing a first approximation of fault zone delineation at least for the Kastelli-Kissamos Basin. The Basin is classified into the X soil category of the Greek Seismic Code 2000.This work was implemented through the project entitled “Interdisciplinary Multi-Scale Research of Earth-quake Physics and Seismotectonics at the Front of the Hellenic Arc (IMPACT-ARC)” in the framework of action “ARCHIMEDES III—Support of Research Teams at TEI of Crete” (MIS380353) of the Operational Program “Education and Lifelong Learning” and is co-financed by the European Union (European Social Fund) and Greek national fund

Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-α) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-α in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-α contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastas

Reconciling the stratigraphy and depositional history of the Lycian orogen-top basins, SW Anatolia

Terrestrial fossil records from the SW Anatolian basins are crucial both for regional correlations and palaeoenvironmental reconstructions. By reassessing biostratigraphic constraints and incorporating new fossil data, we calibrated and reconstructed the late Neogene and Quaternary palaeoenvironments within a regional palaeogeographical framework. The culmination of the Taurides in SW Anatolia was followed by a regional crustal extension from the late Tortonian onwards that created a broad array of NE-trending orogen-top basins with synchronic associations of alluvial fan, fluvial and lacustrine deposits. The terrestrial basins are superimposed on the upper Burdigalian marine units with a c. 7 myr of hiatus that corresponds to a shift from regional shortening to extension. The initial infill of these basins is documented by a transition from marginal alluvial fans and axial fluvial systems into central shallow-perennial lakes coinciding with a climatic shift from warm/humid to arid conditions. The basal alluvial fan deposits abound in fossil macro-mammals of an early Turolian (MN11–12; late Tortonian) age. The Pliocene epoch in the region was punctuated by subhumid/humid conditions resulting in a rise of local base levels and expansion of lakes as evidenced by marsh-swamp deposits containing diverse fossil mammal assemblages indicating late Ruscinian (late MN15; late Zanclean) age. A second pulse of extension, accompanied by regional climatic changes, prompted subsequent deepening of the lakes as manifested by thick and laterally extensive carbonate successions. These lakes, which prevailed c. 1 myr, later shrank due to renewed progradation of alluvial fans and eventually filled up and dried out, reflected by marsh-swamp deposits at the top of a complete lacustrine succession that contains diverse micro-mammal assemblages indicating a latest Villanyian (MN17; Gelasian) age. A third pulse of tectonic reorganisation and associated extension dissected the basins into their present-day configuration from the early Pleistocene onwards under warm/humid climatic conditions. The new age data provide means to correlate deposits across various basins in the region that help to place the basin development into a regional tectonic framework, which can be attributed to the consequence of the well-articulated regional phenomena of slab-tear/detachment-induced uplift followed by crustal extension and basin formation (late Tortonian), the outward extension of the Aegean arc (early Pliocene) and eventually accompanied by westward extrusion of the Anatolian Plate (early Pleistocene)

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Reconciling the stratigraphy and depositional history of the Lycian orogen-top basins, SW Anatolia

Terrestrial fossil records from the SWAnatolian basins are crucial both for regional correlations and palaeoenvironmental reconstructions. By reassessing biostratigraphic constraints and incorporating new fossil data, we calibrated and reconstructed the late Neogene andQuaternary palaeoenvironments within a regional palaeogeographical framework. The culmination of the Taurides inSWAnatolia was followed by a regional crustal extension from the late Tortonian onwards that created a broad array of NE-trending orogen-top basins with synchronic associations of alluvial fan, fluvial and lacustrine deposits. The terrestrial basins are superimposed on the upper Burdigalian marine units with a c. 7 myr of hiatus that corresponds to a shift from regional shortening to extension. The initial infill of these basins is documented by a transition from marginal alluvial fans and axial fluvial systems into central shallow-perennial lakes coinciding with a climatic shift from warm/humid to arid conditions. The basal alluvial fan deposits abound in fossil macro-mammals of an early Turolian (MN11–12; late Tortonian) age. The Pliocene epoch in the region was punctuated by subhumid/humid conditions resulting in a rise of local base levels and expansion of lakes as evidenced by marsh-swamp deposits containing diverse fossilmammal assemblages indicating late Ruscinian (lateMN15; late Zanclean) ageWe are grateful for the support of the international bilateral project between The Scientific and Technological Research Council of Turkey (TUBITAK) and The Russian Scientific Foundation (RFBR) with grant a number of 111Y192. M.C.A. is grateful to the Turkish Academy of Sciences (TUBA) for a GEBIP (Young Scientist Award) grant. T.K. and S.M. are grateful to the Ege University Scientific Research Center for the TTM/002/2016 and TTM/001/2016 projects. M.C.A., H.A., S.M. and M.B. have obtained Martin and Temmick Fellowships at Naturalis Biodiversity Center (Leiden). F.A.D. is supported by a Mehmet Akif Ersoy University Scientific Research Grant. T.A.N. is supported by an Alexander-von-Humboldt Scholarship. L.H.O. received support from TUBITAK under the 2221 program for visiting scientists

Search for heavy neutral Higgs bosons produced in association with b-quarks and decaying into b-quarks at root s=13 TeV with the ATLAS detector

A search for heavy neutral Higgs bosons produced in association with one or two b -quarks and decaying to b -quark pairs is presented using 27.8  fb − 1 of √ s = 13  TeV proton-proton collision data recorded by the ATLAS detector at the Large Hadron Collider during 2015 and 2016. No evidence of a signal is found. Upper limits on the heavy neutral Higgs boson production cross section times its branching ratio to b ¯ b are set, ranging from 4.0 to 0.6 pb at 95% confidence level over a Higgs boson mass range of 450 to 1400 GeV. Results are interpreted within the two-Higgs-doublet model and the minimal supersymmetric Standard Model