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The Sadisdorf Sn-Li-(W-Cu) prospect in the eastern Erzgebirge (Germany) comprises two distinct styles of magmatic-hydrothermal mineralization, namely greisen-type mineralization at the Kupfergrube site, and stockwork-type mineralization at both the Kupfergrube and the Zinnklüfte sites. Previously, these two sites were regarded as expressions of two temporally distinct mineralization events. In this study, this temporal relation was tested by LA-ICP-MS U-Pb data obtained for 16 cassiterite samples, including samples from both sites and styles of mineralization. All 16 samples define a narrow range of ages between 315.1 ± 1.7 / 3.3 Ma and 311.0 ± 3.1 / 4.0 Ma. All ages overlap within uncertainty, suggesting that mineralization across the Sadisdorf prospect is likely related to the same magmatic-hydrothermal event. On the regional scale, the cassiterite ages suggest that Sn-Li mineralization is associated with late-stage felsic magmatism directly following the collapse (∼314–313 Ma) of the Altenberg-Teplice Caldera. The cassiterite ages also overlap with garnet U-Pb LA-ICP-MS ages of Sn-rich skarn occurrences in the western Erzgebirge (e.g., Breitenbrunn, Antonsthal and Hämmerlein). This observation provides direct evidence that greisen and skarn-hosted Sn mineralization are related to the same period of magmatism. The data indicate that the majority of Sn-mineralization in the Erzgebirge formed after 318 Ma (likely between 318 and 310 Ma), challenging previous models which invoked an older suite of granites (326–318 Ma) as causative source intrusions. [Display omitted] [ABSTRACT FROM AUTHOR]

• Understanding the quality of VX with several VM based on different XR technologies. • Exploring relations between presence, VX and attitude toward experience. • Comparing VR, AR and MR technologies to determine best solution for virtual museum. Virtual museum systems, based on different X-reality technologies, has begun to spread, as they represent decisive tools to promote exhibitions and reaching out to audiences. Although budgetary considerations have so far limited the choice of technologies a wide range of possible technological options are available today at low cost. This paper provides the results of an empirical study, with the aim to determine the most appropriate technologies to satisfy the visitors' expectation and maximise their likelihood to repeat and recommend the experience. The study focuses on the comparison of the performance of five VM systems for visualise digital reproduction of archaeological finds, based on different technologies (i.e., PC desktop, holographic display, 3D stereoscopic projection, head mounted display and mobile Augmented Reality). The results provide useful insight for the development of VM systems, in order to maximize the visitor experience in terms of presence and ability to activate an experience economy perspective. [ABSTRACT FROM AUTHOR]

Progression of contralateral carotid artery stenosis after carotid endarterectomy (CEA) has been described by several authors. The aim of this study is to determine such disease progression and its related transient ischemic attacks (TIAs) or strokes by reviewing the existing literature. We performed a systematic literature review to select randomized controlled trials and observational studies reporting outcomes of patients treated by CEA and with concomitant contralateral carotid stenosis, regardless its degree of stenosis. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42019127595). The primary study end point was the progression of contralateral carotid artery stenosis after CEA, and the secondary end point was incidence of TIAs and strokes owing to contralateral carotid stenosis. Seventeen studies were retrieved, reporting data on a total of 7679 patients who had undergone CEA, in particular they were one post hoc analysis of a randomized controlled trial, nine prospective, and seven retrospective observational studies. Among these patients, follow-up information on the contralateral carotid artery was available for 5454 cases. Disease progression was observed in 18% of patients: single class progression from mild (<50%) and from moderate (50%-70%) stenosis was observed in 15% and 23% of cases, respectively. We found 105 TIAs (4%) and 88 strokes (3%) among 2781 patients with stenosis progression, based on result from 11 studies. We found a progression of contralateral carotid stenosis in a significant number of patients treated with CEA and with baseline carotid stenosis. This systematic literature review suggests that patients with moderate contralateral carotid stenosis demonstrate more rapid progression to significant or symptomatic stenosis than patients with mild contralateral stenosis. [ABSTRACT FROM AUTHOR]

Coronaviruses (CoVs) have been documented in almost every species of bat sampled. Bat CoVs exhibit both extensive genetic diversity and a broad geographic range, indicative of a long-standing host association. Despite this, the respective roles of long-term virus-host co-divergence and cross-species transmission (host-jumping) in the evolution of bat coronaviruses are unclear. Using a phylogenetic approach we provide evidence that CoV diversity in bats is shaped by both species richness and their geographical distribution, and that CoVs exhibit clustering at the level of bat genera, with these genus-specific clusters largely associated with distinct CoV species. Co-phylogenetic analyses revealed that cross-species transmission has been more common than co-divergence across coronavirus evolution as a whole, and that cross-species transmission events were more likely between sympatric bat hosts. Notably, however, an analysis of the CoV RNA polymerase phylogeny suggested that many such host-jumps likely resulted in short-term spill-over infections, with little evidence for sustained onward transmission in new co-roosting host species. [ABSTRACT FROM AUTHOR]

Objective Perioperative cerebrospinal fluid (CSF) drainage is a well-established technique for spinal cord protection during thoracoabdominal aortic aneurysm (TAAA) open repair and is usually performed using dripping chamber-based systems. A new automated device for controlled and continuous CSF drainage, designed to maintain CSF pressure around the desired set values, thus avoiding unnecessary drainage, is currently available. The aim of our study was to determine whether the use of the new LiquoGuard automated device (Möller Medical GmbH, Fulda, Germany) during TAAA open repair was safe and effective in maintaining the desired CSF pressure values and whether the incidence of complications was reduced compared with a standard catheter connected to a dripping chamber. Methods Data of patients who underwent surgical TAAA open repair using perioperative CSF drainage at our institution between October 2012 and October 2014 were recorded. The difference in CSF pressure values between patients who underwent CSF drainage with a conventional dripping chamber-based system (manual group) and patients who underwent CSF drainage with the LiquoGuard (automated group) was measured at the beginning of the intervention (T1), 15 minutes after aortic cross-clamping (T2), just before unclamping (T3), at the end of surgery (T4), and 4 hours after the end of surgery (T5). The choice of the draining systems was randomly alternated with one-to-one rate until the last six patients consecutively treated with LiquoGuard were enrolled. Primary outcomes were occurrence of spinal cord ischemia, intracranial hemorrhage, postdural puncture headache, and in-hospital mortality. Results The study included 152 patients who underwent open surgical TAAA repair during the study period: 73 patients underwent CSF drainage with the traditional system and 79 with LiquoGuard. The CSF pressure values at T1 and T5 were not considerably different in the two groups. By repeated-measures analysis of variance, a significant upward trend of perioperative CSF pressure was observed in the automated group at T2, T3, and T4 (group × time interaction = F 3,66 ; P < .001). No difference was reported in the occurrence of spinal cord ischemia, intracranial hemorrhage, or mortality. The LiquoGuard group reported significantly reduced postdural puncture headache (3.3% vs 16.9%; P = .01). Conclusions Perioperative use of LiquoGuard during TAAA open repair was safe and effective. Despite slightly higher intraoperative CSF pressures, the rate of spinal cord ischemia did not increase in the LiquoGuard group, and postdural puncture headache significantly decreased. [ABSTRACT FROM AUTHOR]

Trihalomethanes (TTHMs) are water disinfection by-products whose consumption via drinking water may eventually be harmful for human health, as they could have carcinogenic effects, also for the exposure to them via non-ingestion routes [1] . In the present work the possibility to reduce the vulnerability of the population exposed to TTHMs by the optimal operational interventions in water distribution systems is explored. The proposed approach is formulated as a multi-objective optimization problem with two objective functions, the number of the operations and the maximum TTHMs concentration that occurs at each node in the network during time, both to minimize. The feasible operational actions concern opening/closing valves and hydrants and turning pumping stations for a fixed time. The AMGA 2 optimizer [2] is used herein for solving the problem, coupled with a module coded in C++, where the implementation of the EPANET Programmers Toolkit functions allows to run the hydraulic and water quality simulations and to calculate the objective functions. [ABSTRACT FROM AUTHOR]

Breast cancer liver metastases have traditionally been considered incurable and any treatment given therefore palliative. Liver resections for breast cancer metastases are being performed, despite there being no robust evidence for which patients benefit. This review aims to determine the safety and effectiveness of liver resection for breast cancer metastases. A systematic literature review was performed and resulted in 33 papers being assembled for analysis. All papers were case series and data extracted was heterogeneous so a meta-analysis was not possible. Safety outcomes were mortality and morbidity (in hospital and 30-day). Effectiveness outcomes were local recurrence, re-hepatectomy, survival (months), 1-, 2-, 3-, 5- year overall survival rate (%), disease free survival (months) and 1-, 2-, 3-, 5- year disease free survival rate (%). Overall median figures were calculated using unweighted median data given in each paper. Results demonstrated that mortality was low across all studies with a median of 0% and a maximum of 5.9%. The median morbidity rate was 15%. Overall survival was a median of 35.1 months and a median 1-, 2-, 3- and 5-year survival of 84.55%, 71.4%, 52.85% and 33% respectively. Median disease free survival was 21.5 months with a 3- and 5-year median disease free survival of 36% and 18%. Whilst the results demonstrate seemingly satisfactory levels of overall survival and disease free survival, the data are of poor quality with multiple confounding variables and small study populations. Recommendations are for extensive pilot and feasibility work with the ultimate aim of conducting a large pragmatic randomised control trial to accurately determine which patients benefit from liver resection for breast cancer liver metastases. [ABSTRACT FROM AUTHOR]

The objective of present paper is to propose a criterion for performing a vulnerability analysis in a water distribution system, which involves the estimation of the consumers’ exposure to pathogenic risk and to elevated trihalomethanes concentration, deriving from the reaction of natural organic matter with sodium hypochlorite, widely used for the drinking water disinfection. The analysis is carried out by introducing some index parameters, linked to a trihalomethanes fixed threshold, which has not to be exceeded. The results of the methodology show that the considered factors identify different vulnerable nodes respect to the different kind of exposure they refer to. [ABSTRACT FROM AUTHOR]

A core problem associated with the water quality monitoring in the sewer system is the optimal placement of a limited number of monitoring sites. A methodology is provided for optimally design water quality monitoring stations in sewer networks. The methodology is based on information theory, formulated as a multi-objective optimization problem and solved using NSGA-II. Computer code is written to estimate two entropy quantities, namely Joint Entropy, a measure of information content, and Total Correlation, a measure of redundancy, which are maximized and minimized, respectively. The test on a real sewer network suggests the effectiveness of the proposed methodology. [ABSTRACT FROM AUTHOR]

Illicit intrusions in Sewer Systems (SSs), modifying the wastewater characteristics, may create problems to the treatment plant and/or to the final recipient water body. For this reason, the source identification (SI) problem is becoming an important issue also in SSs. For large real systems, the computational burden might make the SI methodologies impractical. In this paper a pre-screening procedure, based on the pollution matrix concept, is introduced and applied before the SI methodology. Selecting a group of possible candidate nodes and cutting consequently the scheme, a significant improvement both in terms of time and the accuracy is obtained. [ABSTRACT FROM AUTHOR]

Objectives The aim was to determine whether physician modified stent grafts (PMSGs) are safe and effective for the treatment of high risk patients with thoraco-abdominal aortic aneurysms (TAAAs). Design This was a retrospective single institution study. Material Consecutive patients with TAAA undergoing endovascular repair using a PMSG between January 2012 and June 2014 were evaluated. Methods Fenestrations to preserve branch vessels were created in TX2 thoracic (Cook Medical) stent grafts. Pre- intra- and post-operative data were recorded by means of a prospectively maintained database. Results Eleven high risk patients with TAAA (type I, n = 4; type III, n = 3; type IV, n = 3; type V, n = 1) underwent fenestrated endovascular repair using PMSGs. Indications were painful aneurysm ( n = 5), >70 mm rapidly enlarging aneurysm ( n = 4), saccular aneurysm ( n = 1), and visceral patch false aneurysm after open repair of a type IV TAAA ( n = 1). In four asymptomatic patients, an additional fenestration was created for temporary selective sac perfusion and occluded 2–4 weeks later. Median duration for stent graft modifications was 2 hours (range 1–3 hours). The median number of fenestrations was three (range 2–4). One patient died during the post-operative period from colonic ischemia, giving a 9% in hospital mortality rate. Four (36%) patients presented with moderate to severe complications. One (9%) patient presented with a paraparesis that resolved completely after spinal fluid drainage. Among surviving patients, four required early endovascular re-intervention for type III endoleak ( n = 2), type Ia endoleak ( n = 1), or target vessel cannulation failure ( n = 1). The median follow up time was 6 months (range 3–20 months). During follow up, no other complications occurred and all target vessels remained patent. One patient presented with a persistent type II endoleak. Conclusion PMSGs provided acceptable short-term results and may be a management option for the treatment of TAAA in selected high risk patients. Durability concerns need to be assessed in additional studies with long-term follow up. [ABSTRACT FROM AUTHOR]

Abstract: The present work compares the performances of first and second order kinetic models for predicting trihalomethanes (THMs) formation in a real case-study. The kinetic parameters are evaluated through an automatic calibration procedure, in which a least-squared objective function relating measured and computed residual chlorine and THMs concentrations is adopted. The effect of measurements uncertainty on the calibrated parameters and on THMs concentrations predictions are quantified in terms of confidence limits using the First Order Second Moment approach. The study reveals that the performances of the two models are quite similar, but the second order one results less influenced by uncertainty. [Copyright &y& Elsevier]

While Europe is mostly free from terrestrial rabies, five bat lyssaviruses may cause the same clinical disease in mammals. In June 2020, we diagnosed the infection with West Caucasian Bat Lyssavirus (WCBV) in a domestic cat from Arezzo city (Italy). We diagnosed the case according to OIE standards, using fluorescence antibody test, rRT-PCR and sequencing of partial N gene. We performed whole genome sequencing through a metagenomics approach. In Arezzo, we applied control measures indicated by national regulations and carried out an epidemiological investigation to trace the contacts between the infected cat, people and other animals in the 10 days preceding the onset of disease. We performed visual inspections, bioacoustics analyses and camera trapping to investigate a possible interface between cats and bats and performed active and passive surveillance in these animals to trace the source of infection. Italian WCBV retained high identity across the whole-genome with the only other isolate found in 2002 from a Russian bent-winged bat (Miniopterus schreibersii) (GB EF614258). We identified 11 contacts, six persons that received full PEP, plus a dog and four cats that underwent six months of quarantine. They all remain healthy one year passed exposure. We identified a group of bent-winged bats in a tunnel nearby the cat's house showing antibodies neutralizing WCBV across four sampling occasions, but no virus in salivary swabs. Bat carcasses from different species collected across the country were all negative. We described the first case of WCBV in a non-flying mammal, an Italian cat showing neurological signs and aggressive behaviour. This event highlights the lack of international guidelines against divergent lyssaviruses in the absence of preventive and therapeutic measures. Fortunately, we noticed no secondary cases and contacts remained healthy. The Italian WCBV retains high identity with the reference strain, showing no signs of geographical clustering or adaptation to a new host. Results from our investigation indicate bent-winged bats as the most probable source of infection, testifying the bat-human encroachment in urban areas and confirming that free-ranging cats are a potential hazard for public health other than for the conservation of bats. [ABSTRACT FROM AUTHOR]

Abstract: Vanadium compounds are able to interact with living cells exerting a variety of biological effects. The pentavalent form is the most stable and toxic form of the element. In systems in vitro pentavalent vanadium is an effective genotoxic agent, inducing DNA damage and chromosome malsegregation at low doses. On the other hand, no adequate in vivo data are available for the characterization of the genotoxic hazard following oral intake, the most relevant route of human exposure. In this study, the genotoxic effects produced by the oral intake of sodium ortho-vanadate (Na3VO4) were investigated. Male CD-1 mice were treated for 5 weeks with a range of concentrations of Na3VO4 in drinking water (0.75–1500mg/l). Both micronuclei and primary DNA lesions as detected by comet assay were assessed in several tissues. Statistically significant increases of micronuclei in bone marrow were observed in mice receiving the two highest concentrations of Na3VO4 (750 and 1500mg/l). A significant increase of comet tail length was observed in splenocytes of mice receiving Na3VO4 at 1500mg/l, whereas no effect was observed in bone marrow and testis cells. No treatment-related effect on sperm chromatin structure or on testis cell population was observed. The determination of vanadium content in mouse tissues at the end of treatment highlighted a very low internal exposure, especially in soft tissues. Overall, the results obtained indicate that the genotoxic activity of pentavalent vanadium is expressed in vivo only following high dose exposure, possibly as a consequence of the poor bioavailability of the element. [Copyright &y& Elsevier]

Prostaglandins (PG) are key mediators of diverse functions in the skin and several reports suggest that PG mediate post-inflammatory pigmentary changes through modulation of melanocyte dendricity and melanin synthesis. The proteinase-activated receptor 2 (PAR-2) is important for skin pigmentation because activation of keratinocyte PAR- 2 stimulates uptake of melanosomes through phagocytosis in a Rho-dependent manner. In this report, we show that activation of keratinocyte PAR-2 stimulates release of PGE2 and PGF2α and that PGE2 and PGF2α. act as paracrine factors that stimulate melanocyte dendricity. We characterized the expression of the EP and FP receptors in human melanocytes and show that human melanocytes express EP1 and EP3, and the FP receptor, but not EP2 and EP4. Treatment of melanocytes with EP1 and EP3 receptor agonists resulted in increased melanocyte dendricity, indicating that both EP1 and EP3 receptor signaling contribute to PGE2-mediated melanocyte dendricity. Certain EP3 receptor subtypes have been shown to increase adenosine 3',5',-cyclic monophosphate (cAMP) through coupling to Gs, whereas EP1 is known to couple to Gq to activate phospholipase C with elevation in Ca2+. The cAMP/protein kinase A system is known to modulate melanocyte dendrite formation through modulation of Rac and Rho activity. Neither PGF2α or PGE2 elevated cAMP in human melanocytes showing that dendricity observed in response to PGE2 and PGF2α is cAMP-independent. Our data suggest that PAR-2 mediates cutaneous pigmentation both through increased uptake of melanosomes by keratinocytes, as well as by release of PGE2 and PGF2α. that stimulate melanocyte dendricity through EP1, EP3, and FP receptors. [ABSTRACT FROM AUTHOR]

Recent work shows that the G-protein-coupled receptor proteinase activated receptor-2 activates signals that stimulate melanosome uptake in keratinocytes in vivo and in vitro . The Rho family of GTP-binding proteins is involved in cytoskeletal remodeling during phagocytosis. We show that proteinase-activated receptor-2 mediated phagocytosis in human keratinocytes is Rho dependent and that proteinase-activated receptor-2 signals to activate Rho. In contrast, Rho activity did not affect either proteinase-activated receptor-2 activity or mRNA and protein levels. We explored the signaling mechanisms of proteinase-activated receptor-2 mediated Rho activation in human keratinocytes and show that activation of proteinase-activated receptor-2, either through specific proteinase-activated receptor-2 activating peptides or through trypsinization, elevates cAMP in keratinocytes. Proteinase-activated receptor-2 mediated Rho activation was pertussis toxin insensitive and independent of the protein kinase A signaling pathway. These data are the first to show that proteinase-activated receptor-2 mediated phagocytosis is Rho dependent and that proteinase-activated receptor-2 signals to Rho and cAMP in keratinocytes. Because phagocytosis of melanosomes is recognized as an important mechanism for melanosome transfer to keratinocytes, these results suggest that Rho is a critical signaling intermediate in melanosome uptake in keratinocytes. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most frequent primary malignant tumour of bone and metastases occur in 30% of cases, the 5-year survival rate is 25–30%. Although pre- and post-operative chemotherapy has improved prognosis in osteosarcoma (OS), high toxicity and natural and acquired drug-resistance are the first cause of treatment failure. The identification of new predictive and therapeutic biomarkers may increase drug sensitivity and better control localized and metastatic disease. By the evidence that CXCR4 receptor by binding its ligand CXCL12 activates downstream critical endpoints for tumour malignancy, we first studied human OS progression correlating CXCR4 expression in OS biopsy with patient clinical data. By Real-time PCR and immunoistochemistry we found that high levels of CXCR4 gene and protein expression significantly correlated with OS progression, emphasizing the role of CXCR4/CXCL12 axis in tumour prognosis. This was supported by univariate analyses that showed a higher probability of local and/or systemic relapse in OS patients with a high CXCR4 gene expression and a significant increase of metastasis risk associated with an increasing score of CXCR4 protein staining intensity. Secondarily, to study the role of CXCR4 as a target for new therapeutic strategies, we evaluated the response of OS cells to the fully human CXCR4 antibody, MDX1338. In the study we also included AMD3100, the most studied CXCR4 antagonist. In CXCR4-positive OS cells cultured in CXCL12-rich BM-MCS-CM (bone marrow-derived mesenchymal stem conditioned medium), a decrease of cell proliferation up to 30%–40% of control was seen after drug exposure. However, an increase of apoptosis was seen in p53-positive U2OS and 143B after CXCR4 inhibitor incubation, while no changes were seen in treated SAOS-2 cells which also present a different labeling profile. The role of p53 in apoptotic response to CXCR4 inhibitors was confirmed by p53 silencing in U2OS cell line. Our data suggest that the response to anti-CXCR4 agents could be influenced by the genetic background and labeling profile which induces a different cross-talk between tumour cells and environment. The delay in cell cycle progression associated with increased apoptosis could sensitize p53-positive cells to conventional therapy and in vivo preclinical experiments are on going with the aim to suggest new combined target therapies in human OS. [ABSTRACT FROM AUTHOR]

Abstract We study the steady incompressible flow of a Bingham fluid in a thin T-like shaped domain, under the action of given external forces and with no-slip boundary condition on the whole boundary of the domain. This phenomenon is described by non linear variational inequalities. By letting the parameter describing the thickness of the thin domain tend to zero, we derive two uncoupled problems corresponding to the two branches of the T-like shaped structure. We then analyze and give a physical justification of the limit problem. [ABSTRACT FROM AUTHOR]

Dam-break waves are a major concern for communities and infrastructures in flood-prone areas. The impact of dam-break waves against rigid obstacles after propagation on a mobile bed is lacking both in experimental datasets and in numerical investigations aimed at assessing the capabilities and limitations of available morphodynamic models. To fill these gaps, a novel data set from experiments of dam-break waves propagating over an erodible bottom and impacting over a vertical wall is presented and compared with numerical simulations performed by the Saint Venant–Exner model. First, the effects of bottom mobility are discussed by comparison with the corresponding fixed bed condition. Then, supplementary conditions are investigated for different initial water levels and reservoir lengths. The comparison with the results of the numerical simulation shows that the relatively simple model employed is able to reproduce the general features of the process and the peak impact force with reasonable accuracy. • Dam-break waves impacting a wall are studied in fixed and mobile bed conditions. • A novel data set of laboratory experiments is provided. • The peak value of the impact force is slightly greater under mobile bed conditions. • The SVE numerical model reasonably predicts the general features of the phenomenon. [ABSTRACT FROM AUTHOR]

Abstract: The trace element vanadium interacts with living cells, in which it exerts a variety of biological effects depending on its chemical form and oxidation state. Tetravalent vanadium was shown to affect several genotoxicity end-points in vitro, but its genotoxic potential in vivo is not elucidated. In this study, the genotoxic effects induced in vivo by subacute oral exposure to vanadyl sulphate (VOSO4), a tetravalent vanadium salt, were investigated. To this aim male CD1 mice were administered with VOSO4 in drinking water over the dose range 2–1000mg/l for 5 weeks. The incidence of micronucleated blood reticulocytes was measured along treatment period. At the end of treatment, micronuclei in both blood reticulocytes and bone marrow polychromatic erythocytes were determined; in addition, DNA lesions detectable by comet assay were assessed in marrow and testicular cells. Tissue distribution of vanadium at sacrifice was determined by atomic absorption spectrometry. Comet assays and the analysis of micronuclei in polychromatic erythrocytes did not reveal treatment related effects. A slight increase in micronucleated reticulocytes, with no relationship with the administered dose, was observed in some treated groups. The determination of vanadium content in kidney, liver, spleen, bone, stomach, small intestine and testis highlighted low internal exposure, especially in soft tissues. Overall, data indicate scarce bioavailability for orally administered tetravalent vanadium, and lack of significant genotoxic potential in vivo. [Copyright &y& Elsevier]

Background Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly ‘GCTB-schedule’ (120 mg per 12/year, 1440 mg total dose/year) are lacking. Methods Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. Results Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6–45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13–76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9–115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7–15 months). Adverse events Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84–100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). Conclusions Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB. [ABSTRACT FROM AUTHOR]

Purpose: Our previous study suggested that the coiled coil domain-containing 55 gene (CCDC55), also named as NSRP1 (nuclear speckle splicing regulatory protein 1 (NSRP1)), was encompassed in a haplotype block spanning over the serotonin transporter (5-HTT) gene in patients with schizophrenia (SCZ). However, the neurobiological function of CCDC55 gene remains unknown. This study aims to uncover the potential role of CCDC55 in SCZ-associated molecular pathways. Experimental design : Using molecular cloning, sequencing and immune blotting to identify basic properties, yeast two-hybrid screening and glutathione S-transferase (GST) pull-down assay to test protein–protein interaction, and confocal laser scanning microscopy (CSLM) to show intracellular interaction of proteins. Principal findings : (i) CCDC55 is expressed as a nuclear protein in human neuronal cells; (ii) Protein–protein interaction analyses showed CCDC55 physically interacted with Ran binding protein 9 (RanBP9) and disrupted in schizophrenia 1 (DISC1); (iii) CCDC55 and RanBP9 co-localized in the nucleus of human neuronal cells; (iv) CCDC55 also interacted with the cannabinoid receptor 1 (CNR1), and with the brain cannabinoid receptor-interacting protein 1a (CNRIP1a); (v) CNR1 activation in differentiated human neuronal cells resulted in an altered RanBP9 localization. Conclusion : CCDC55 may be involved in a functional bridging between the CNR1 activation and the DISC1/RanBP9-associated pathways. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The aim of this work is to characterize the shape and the volume of the internal anal sphincter (IAS) in normal subjects by three-dimensional anorectal ultrasonography. Methods: Thirty-nine normal volunteer males (mean age 58.5±18.7) and 25 females (mean age 59.4±14.1) were submitted to anorectal ultrasonography. The tissue is defined by a semiautomatic procedure. Measurements of thickness, length and volume were assessed automatically. The software provides an average number of 57,600 thickness measurements, 360 length measurements for each zone (90 for each quadrant) and seven volume measurements (one for each anatomical area).The mean values of magnitudes were calculated for the entire volume in each quadrant and zone. Age and gender-related variations were analyzed. Results: In assessments of the whole tissue, only thickness was gender-related, with greater thickness for females (male thickness: 1.81±0.47mm, female thickness 2.16±0.57mm, P-value<0.01).In the distal zone: thickness, length and volume were all larger in females (for male and female respectively: 1.83±0.49mm vs 2.34±0.58mm, P-value<0.01, for the thickness; 10.87±2.10mm vs 12.18±2.21mm, P-value<0.02 for the length and 1501±605mm3 vs 2169±871mm3, P-value<0.01 for the volume). In the medial zone, only thickness was gender-related, with greater thickness in females (male thickness: 2.04±0.60mm, female thickness:2.44±0.74mm, P-value<0.02).The only variation observed in the proximal zone concerned length, larger in males (respectively: 11.27±2.84mm vs 9.55±2.43mm, P-value<0.02). The male population was significantly positively correlated with ageing for volume in the whole tissue (ρ =0.32, P-value<0.05), and for both thickness and volume in the medial zone (ρ =0.33, P-value<0.05 for thickness; ρ =0.39, P-value<0.02 for the volume). Conclusion: This new method is useful to understand both functional anal disorders and local damage which may affect only part of the muscle tissue. [Copyright &y& Elsevier]