Therapeutic Strategies Targeting Urokinase and Its Receptor in Cancer

Several studies have ascertained that uPA and uPAR do participate in tumor progression and metastasis and are involved in cell adhesion, migration, invasion and survival, as well as angiogenesis. Increased levels of uPA and uPAR in tumor tissues, stroma and biological fluids correlate with adverse clinic–pathologic features and poor patient outcomes. After binding to uPAR, uPA activates plasminogen to plasmin, a broad-spectrum matrix-and fibrin-degrading enzyme able to facilitate tumor cell invasion and dissemination to distant sites. Moreover, uPAR activated by uPA regulates most cancer cell activities by interacting with a broad range of cell membrane receptors. These findings make uPA and uPAR not only promising diagnostic and prognostic markers but also attractive targets for developing anticancer therapies. In this review, we debate the uPA/uPAR structure–function relationship as well as give an update on the molecules that interfere with or inhibit uPA/uPAR functions. Additionally, the possible clinical development of these compounds is discussed

Early stage sinkhole formation in the acque albule basin of central Italy from geophysical and geochemical observations

Sinkhole occurrence along the Tyrrhenian margin of the Central Apennines is of great importance for applied research, land management and civil protection. This study reports on GPS-altimetry magnetic, gravity, geoelectric, seismic, and soil gas measurements of a rapidly developing sinkhole near the Guidonia military airport. The measurements revealed an elliptical 2-m depression elongated 220 m in the NNE-SSW direction with the minor axis of 110 m. In spring of 2013, two vertical cavities formed in the eastern and northeastern flanks of the depression whose depths and shapes are rapidly evolving with the formation of widespread fracturing along the same side. The geophysical observations image the developing sinkhole to a depth of some 50 m, the presence of the Travertino lithotype around the depression (down to at least 40 m), and the lack of this lithotype below the lowered area. The sinkhole's evolution appears to be structurally controlled by local and regional faulting. These results are useful for designing further geophysical, geotechnical and geochemical studies to monitor the sinkhole's evolution and to assess the hazard it presents in densely urbanized area.Published36-477A. Geofisica di esplorazioneJCR Journalreserve

Imaging the structural style of an active normal fault through multidisciplinary geophysical investigation: a case study from the Mw 6.1, 2009 L'Aquila earthquake region (central Italy)

The normal fault-system responsible of the 2009 Mw 6.1 L'Aquila earthquake (Paganica-San Demetrio fault-system) comprises several narrow, fault-parallel valleys of controversial origin. We investigated a key section of the southeastern portion of this fault network along the small Verupola Valley. In order to characterize its nature and possible tectonic activity, we applied multiple-geosciences techniques able to image at depth the structure associated to this peculiar landform. We integrated magnetometry, 2-D P wave and resistivity tomography, surface waves and seismic noise analysis coupled with field mapping, shallow boreholes and trenching. According to our results, the Verupola Valley is a ∼30–40-m-deep graben controlled by a SW-dipping master fault and synthetic splays paired with an antithetic NE-dipping fault. The SW-dipping splays are active and cut very shallow (<2 m deep) Late Pleistocene sediments. The small amount of cumulated vertical offset (∼15 m) across the conjugated system may indicate a young fault inception or very low Quaternary slip-rates. Due to its structural continuity with the adjacent mapped strands of the Paganica–San Demetrio fault network, we relate the Verupola Valley to the recent activity of the southeastern segment of this fault system. We also suggest that other fault-parallel valleys can have the same tectonic origin and setting of the Verupola Valley. This latter represents a scale-independent analogue from metric scale (exposed in the palaeoseismological trenches) to the Middle Aterno Basin scale (seen from seismic profiles and fault mapping). Overall, the imaged structural style is coherent with the regional tectonic setting due to Quaternary crustal extension

Geological reconstruction in the area of maximum co-seismic subsidence during the 2009 Mw=6.1 L’Aquila earthquake using geophysical analyses and borehole stratigraphy.

InSAR images showed that the 2009 Mw=6.1 normal faulting L'Aquila earthquake (Abruzzi region, central Italy) produced a maximum co-seismic subsidence of ca. 24 cm in the epicentral area. We report new results about the stratigraphic architecture of this area by means of the integration of geophysical and stratigraphic data from a new 151 m deep borehole. According to the indication of preliminary geophysical (electrical resistivity tomography and seismic noise) surveys, the borehole was drilled where maximum thicknesses of fine-grained sediments were expected. The geophysical results were also useful to estimate the basin substrate depth and to define the geometry of the continental deposits, successively constrained by the core stratigraphy. The core is characterized by two sequences separated by an erosional discontinuity. The upper sequence is composed by silty, sandy and gravelly deposits, mainly characterized by high values of electrical resistivity. The lower sequence is characterized by prevalence of grey clayey silt and sandy sediments, with low values of resistivity. Based on correlations among the stratigraphic core and outcrop data of the Aterno Valley, we interpret the upper sequence as related to fluvial-alluvial depositional environment during Middle Pleistocene-Holocene, whereas the lower sequence is related to deposition in a prevalent marshy floodplain environment during Early Pleistocene.Published350-3621A. Geomagnetismo e PaleomagnetismoJCR Journalrestricte

S100B protein as a therapeutic target in multiple sclerosis: The S100B inhibitor arundic acid protects from chronic experimental autoimmune encephalomyelitis

S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pattern molecule. A direct correlation between the increased amount of S100B and inflammatory processes has been demonstrated, and in particular, the inhibitor of S100B activity pentamidine has been shown to ameliorate clinical scores and neuropathologic-biomolecular parameters in the relapsing-remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This study investigates the effect of arundic acid (AA), a known inhibitor of astrocytic S100B synthesis, in the chronic experimental autoimmune encephalomyelitis, which is another mouse model of multiple sclerosis usually studied. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the spinal cord, we observed that the AA-treated group showed lower severity compared to the vehicle-treated mice, particularly in the early phase of disease onset. We also observed a significant reduction of astrocytosis, demyelination, immune infiltrates, proinflammatory cytokines expression and enzymatic oxidative reactivity in the AA-treated group. Overall, our results reinforce the involvement of S100B in the development of animal models of multiple sclerosis and propose AA targeting the S100B protein as a focused potential drug to be considered for multiple sclerosis treatment

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study

Purpose: To evaluate the clinical features, the prognostic factors, and the efficacy of treatments in patients (pts) with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) with leukemic presentation. Methods: A retrospective multicenter study was carried out during the period 2005-2011 in 28 Italian hematology divisions among GIMEMA centres. Results: A total of 43 cases were collected (M/F 31/12; median age 68 yo).At diagnosis the median bone-marrow infiltration was 73%; 33 pts (77%) had peculiar skin lesions; lymph nodes and/or spleen involvements were documented in 24 (56%), and extramedullary disease in 9 (21%). In 28 pts (65%) cytogenetic study was performed, revealing an unfavourable karyotype in 12. Forty-one pts received an induction therapy (2 died early), consisting of AML-type regimen in 26 (60%), and ALL/lymphoma-type in 15 (35%); 6 pts (14%) underwent allo-HSCT. Complete remission (CR) was achieved in 17 pts (41%), registering 7 CR after AML-type and 10 after ALL/lymphoma-type regimen, with a significant advantage for ALL/lymphoma-type chemotherapy (p=0.02). The median OS was 8.7 months (range 0.2-32.9):7.1 months (range 0.2-19.5) and 12.3 months (range 1-32.9) in pts received AML-type and ALL/lymphoma-type regimen, respectively (p=0.02). In HSCT-pts the median OS was 22.7 months (range 12-32.9), with a significant advantage with respect to the non-transplanted (median 7.1 months, range 0.2-21.3, p=0.03). Conclusions: BPDCN with bone-marrow involvement is an aggressive subtype of high-risk acute leukemia.With intensive therapy according to ALL/lymphoma-type induction the rate of CR increases. Allo-HSCT performed in first remission may lead to long-term survival in selected cases, but more data are needed

Commodity risk assessment of Malus sylvestris plants from United Kingdom

The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as 'High risk plants, plant products and other objects'. This Scientific Opinion covers plant health risks posed by rooted plants and bundles of bare root plants or rooted cell grown young plants of Malus sylvestris imported from the UK, taking into account the available scientific information, including the technical information provided by the UK. All pests associated with the commodities were evaluated against specific criteria for their relevance for this opinion. Two quarantine pests (tobacco ringspot virus and tomato ringspot virus), one protected zone quarantine pest (Erwinia amylovora) and four non-regulated pests (Colletotrichum aenigma, Meloidogyne mali, Eulecanium excrescens and Takahashia japonica) that fulfilled all relevant criteria were selected for further evaluation. For Erwinia amylovora, special requirements are specified in Commission Implementing Regulation (EU) 2019/2072. Based on the information provided in the dossier, these specific requirements for E. amylovora are met. For the remaining six pests, the risk mitigation measures proposed in the technical Dossier from the UK were evaluated, taking into account the possible limiting factors. For these pests, expert judgement is given on the likelihood of pest freedom, taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. The degree of pest freedom varies among the pests evaluated, with scales (Eulecanium excrescens and Takahashia japonica) being the pests most frequently expected on the imported bundles of bare root plants or rooted cell grown young plants. The expert knowledge elicitation indicated with 95% certainty that between 9,976 and 10,000 bundles (one bundle consisting of 5-15 plants for bare root plants or 25-50 plants for cell grown young plants) per 10,000 would be free from the above-mentioned scales