Handling of Doubtful WBC Scintigraphies in Patients with Suspected Prosthetic Joint Infections

Abstract: Despite the application of EANM recommendations for radiolabelled white-blood-cells (WBC) scintigraphy, some cases still remain doubtful based only on visual analysis. The aim of this study was to investigate the role of semi-quantitative analysis and bone marrow scan (BMS) in solving doubtful cases. We retrospectively evaluated all [99mTc]HMPAO-WBC scintigraphies performed, in the last 7 years, for a suspected monolateral prosthetic joint infection (PJI). In doubtful cases, we used five different thresholds of increase of target-to-background (T/B) ratio, between delayed and late images, as criteria of positivity (5%, 10%, 15%, 20% and 30%). BMS were also analysed and sensitivity, specificity and accuracy of different methods were calculated according to final diagnosis. The sensitivity, specificity and accuracy were, respectively, 77.8%, 43.8% and 53.0% for the cut-off at 5%; 72.2%, 66.7% and 68.2% for the cut-off at 10%; 66.7%, 75.0% and 72.7% for the cut-off at 15%; 66.7%, 85.4% and 80.3% for the cut-off at 20%; 33.3%, 93.8% and 77.3% for the cut-off at 30%. BMS provided a significantly higher diagnostic performance than 5%, 10% and 15% thresholds. Conversely, we did not observe any statistically significant difference between BMS and the cut-off of more than 20%. Therefore, doubtful cases should be analysed semi-quantitatively. An increase in T/B ratio of more than 20% between delayed and late images, should be considered as a criterion of positivity, thus avoiding BMS

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

Immunotherapy against the amyloid-beta (Abeta) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of Abeta, and yet be capable of eliciting antibodies that recognize Abeta fibrils and neurotoxic Abeta oligomers but not the physiological monomeric species of Abeta. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide Abeta1-15 (Abeta15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(Abeta15)n polypeptides bearing one, four, or eight copies of Abeta15 were constructed and injected into mice in combination with alum, an adjuvant approved for human use. All three polypeptides were found to be immunogenic, yet eliciting antibodies with distinct recognition specificities. The anti-Trx(Abeta15)4 antibody, in particular, recognized Abeta42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to Abeta. We have also demonstrated that anti-Trx(Abeta15)4, which binds to human AD plaques, markedly reduces Abeta pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained Abeta fragment repeat and identify Trx(Abeta15)4 as a promising new tool for AD immunotherapy

C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition

Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients' samples and by in silico analysis on an independent patient cohort from Taylor's platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients' risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring

Diagnostic and prognostic potential of the proteomic profiling of serum-derived extracellular vesicles in prostate cancer

Extracellular vesicles (EVs) and their cargo represent an intriguing source of cancer biomarkers for developing robust and sensitive molecular tests by liquid biopsy. Prostate cancer (PCa) is still one of the most frequent and deadly tumor in men and analysis of EVs from biological fluids of PCa patients has proven the feasibility and the unprecedented potential of such an approach. Here, we exploited an antibody-based proteomic technology, i.e. the Reverse-Phase Protein microArrays (RPPA), to measure key antigens and activated signaling in EVs isolated from sera of PCa patients. Notably, we found tumor-specific protein profiles associated with clinical settings as well as candidate markers for EV-based tumor diagnosis. Among others, PD-L1, ERG, Integrin-β5, Survivin, TGF-β, phosphorylated-TSC2 as well as partners of the MAP-kinase and mTOR pathways emerged as differentially expressed endpoints in tumor-derived EVs. In addition, the retrospective analysis of EVs from a 15-year follow-up cohort generated a protein signature with prognostic significance. Our results confirm that serum-derived EV cargo may be exploited to improve the current diagnostic procedures while providing potential prognostic and predictive information. The approach proposed here has been already applied to tumor entities other than PCa, thus proving its value in translational medicine and paving the way to innovative, clinically meaningful tools

Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy

Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC. \uc2\ua9 2012 Macmillan Publishers Limited. All rights reserved

The European venture capital landscape: an EIF perspective. Volume II: Growth patterns of EIF-backed startups

Start-up growth is often treated as a stylised fact, despite an extensive research body composed of divergent theories and empirical findings. Against this background, this work contributes to the literature by analysing a hand-collected dataset of 2,951 EIF-backed VC start-ups. Section 2 briefly reviews the relevant literature and 3 discusses data and methods. Section 4 uses descriptive statistics to explore average and median growth trends of start-ups, following an EIF-backed VC investment. Section 5 employs a latent class cluster analysis to establish a taxonomy of start-up growth profiles, characterised by speed and bias towards sales or patenting. The observed growth patterns, described in section 6, are typically idiosyncratic and persistent. However, a series of factors affecting growth mode can be evidenced. In particular, this paper finds that the geographic distribution of outperforming start-ups hints at national and regional factors acting as enablers for different typologies of successful growth. Implications for research and practice are discussed

The European venture capital landscape: an EIF perspective. Volume IV: The value of innovation for EIF-backed startups

The creation of value through innovation is among the defining traits of new technology-driven ventures. In this paper we contribute to the literature by investigating the value of innovations for start-ups supported by EIF in the years 1996 to 2014, as measured through patent applications. The paper is structured around two main parts. The first part presents a series of descriptive statistics on EIF's VC investee patent portfolio and discusses some of the strategic aspects of patenting, such as timing and geographical coverage. The second part develops an econometric model to estimate the Euro-value of innovations based on patent renewal data, following the seminal work of Pakes and Schankerman (1984). We observe that start-ups are efficient at transforming financial capital obtained through VC financing into innovative capital. On average, for every Euro of EIF-supported VC financing, start-ups generated 2.74 Euro of private innovation value

The European venture capital landscape: an EIF perspective. Volume V: The economic impact of VC investments supported by the EIF

This paper examines the impact of venture capital (VC) investments supported by the EIF on the financial growth and performance of young and innovative firms. Using a novel dataset covering European start-ups supported by VC in the years 2007 to 2014, we generate a counterfactual group of non-VCbacked firms through a combination of exact and propensity score matching. To offset the relatively limited set of observables allowed by our data, we estimate treatment propensity using a series of innovative measures based on machine learning, network theory, and satellite imagery analysis. Our results document the positive effects of EIF-supported VC investments on start-up performance, as measured through various financial indicators (e.g. assets, revenue, employment). We find that VC financing enables start-ups to prioritise long-term growth, trading off short- to medium-term profitability if necessary. Overall, our work provides meaningful evidence towards the positive effects of EIF-supported VC investment on the financial growth of young and innovative businesses in Europe

The real effects of EU loan guarantee schemes for SMEs: A pan-European assessment

This paper provides a pan-European assessment of EU credit guarantees to SMEs. Synthesizing past research, it investigates the firm-level economic impact of over 360,000 guaranteed loans under the EU MAP and CIP programmes from 2002 to 2016. These loans represented a total amount of EUR 22bn spanning 19 European countries - approximately 60% of all loan amounts guaranteed under these programmes. The paper reports estimates of the average treatment effect on the treated of these loans on the financial growth and survivability of firms, through a comparison against SMEs that were not supported by these programmes. Guaranteed loans are found to positively affect the growth of firms' assets (by 7 to more than 35%), the share of intangible assets (by one third of the initial share in Italy and the Nordic countries), sales (by 6 to 35%), employment (by 8 to 30%), and lower their probability to default (by 4 to 5%). The paper decomposes these effects by size, age, industry, and discusses implications

The Economic Impact of EU Guarantees on Credit to SMEs – Evidence from CESEE Countries

This paper estimates the economic impact at final beneficiary level of the Multi-Annual Programme for enterprises and entrepreneurship EU SME Guarantee Facility in Central, Eastern and South-Eastern European (CESEE) Countries in the period 2005-2012. Data on SME beneficiaries has been collected from administrative records and enriched with information on firms' financial accounts taken from the Orbis database. The paper combines propensity scores and difference-in-differences estimation in order to evaluate the effect of having received a MAP-guaranteed SME loan on firm performance (employment, production, profitability and factor productivity) against a control group of comparable firms. Our results offer several insights. We find that the EU SME Guarantee Facility in the CESEE region had, on average, a significant positive effect on firms' employment: beneficiary firms were able to increase their workforce by 17.3%, compared to the control groups, within the first 5 years following the issuance of the guaranteed loan. Moreover, by the fifth year after the signature date, the turnover of MAP beneficiaries had increased by 19.6%, compared to non-beneficiary companies. However, MAP beneficiaries faced a temporary setback in productivity, with respect to their peers, an effect that could be due to allocative inefficiencies following the MAP-induced increase in their production factors. Such gap was, however, partially absorbed over the medium run. By breaking down our sample by country, signature year, size and age classes, we observe that micro and young SMEs have benefited the most from MAP-guaranteed loans in terms of economic additionality. Overall, our findings suggest that the EU SME Guarantee Facility has been successful in bringing significant positive effects on beneficiary firms in CESEE Countries