Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

Driving the refactoring of Java Enterprise applications by evaluating the distance between application elements

Java Enterprise Applications (JEAs) are complex systems composed using various technologies that in turn rely on languages other than Java, such as XML or SQL. Given the complexity of these applications, the need to reverse engineer them in order to support further development becomes critical. In this paper we show how it is possible to split a system into layers and how is possible to interpret the distance between application elements in order to support the refactoring of JEAs. The purpose of this paper is to explore ways to provide suggestions about the refactoring operations to perform on the code by evaluating the distance between layers and elements belonging those layers. We split JEAs into layers by considering the kinds and the purposes of the elements composing the application. We measure distance between elements by using the notion of the shortest path in a graph. Also we present how to enrich the interpretation of the distance value with enterprise pattern detection in order to refine the suggestion about modifications to perform on the code.

The Interplay of Power and Trust in Platform Ecosystems of the Enterprise Application Software Industry

In recent years, the formerly oligopolistic Enterprise Application Software (EAS) industry began to disintegrate into focal inter-firm networks with one huge, powerful, and multi-national plat-form vendor as the center, surrounded by hundreds or even thousands of small, niche players that act as complementors. From a theoretical point of view, these platform ecosystems may be governed by two organizing principles - trust and power. However, it is neither from a practical nor from a theoretical perspective clear, how trust and power relate to each other, i.e. whether they act as complements or substitutes. This study tries to elaborate our understanding of the relationship of trust and power by exploring their interplay using multi-dimensional conceptual-izations of trust and power, and by investigating potential dynamics in this interplay over the course of a partnership. Based on an exploratory multiple-case study of seven dyadic partner-ships between four platform vendors, and seven complementors, we find six different patterns of how trust and power interact over time. These patterns bear important implications for the suc-cessful management of partnerships between platform vendors and complementors, and clarify the theoretical debate surrounding the relationship of trust and power.

Active implementation strategy of CONSORT adherence by a dental specialty journal improved randomized clinical trial reporting.

OBJECTIVE To describe a novel CONsolidated Standards of Reporting Trials (CONSORT) adherence strategy implemented by the American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO) and to report its impact on the completeness of reporting of published trials. STUDY DESIGN AND SETTING The AJO-DO CONSORT adherence strategy, initiated in June 2011, involves active assessment of randomized clinical trial (RCT) reporting during the editorial process. The completeness of reporting CONSORT items was compared between trials submitted and published during the implementation period (July 2011 to September 2013) and trials published between August 2007 and July 2009. RESULTS Of the 42 RCTs submitted (July 2011 to September 2013), 23 were considered for publication and assessed for completeness of reporting, seven of which were eventually published. For all published RCTs between 2007 and 2009 (n = 20), completeness of reporting by CONSORT item ranged from 0% to 100% (Median = 40%, interquartile range = 60%). All published trials in 2011-2013, reported 33 of 37 CONSORT (sub) items. Four CONSORT 2010 checklist items remained problematic even after implementation of the adherence strategy: changes to methods (3b), changes to outcomes (6b) after the trial commenced, interim analysis (7b), and trial stopping (14b), which are typically only reported when applicable. CONCLUSION Trials published following implementation of the AJO-DO CONSORT adherence strategy completely reported more CONSORT items than those published or submitted previously.

Prioritizing – the task strategy of the powerful?

Previous research has shown that power increases focus on the main goal when distractor information is present. As a result, high-power people have been described as goal-focused. In real life, one typically wants to pursue multiple goals at the same time. There is a lack of research on how power affects how people deal with situations in which multiple important goals are present. To address this question, 158 participants were primed with high or low power or assigned to a control condition, and were asked to perform a dual-goal task with three difficulty levels. We hypothesized and found that high-power primed people prioritize when confronted with a multiple-goal situation. More specifically, when task demands were relatively low, power had no effect; participants generally pursued multiple goals in parallel. However, when task demands were high, the participants in the high-power condition focused on a single goal whereas participants in the low-power condition continued using a dual-task strategy. This study extends existing power theories and research in the domain of goal pursuit.

Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome

We report on a father and daughter with hand-foot-genital syndrome (HFGS) with typical skeletal and genitourinary anomalies due to a 14-residue polyalanine expansion in HOXA13. This is the largest (32 residues) polyalanine tract so far described for any polyalanine mutant protein. Polyalanine expansion results in protein misfolding, cytoplasmic aggregation and degradation; however, HOXA13 polyalanine expansions appear to act as loss of function mutations in contrast to gain of function for HOXD13 polyalanine expansions. To address this paradox we examined the cellular consequences of polyalanine expansions on HOXA13 protein using COS cell transfection and immunocytochemistry. HOXA13 polyalanine expansion proteins form cytoplasmic aggregates, and distribution between cytoplasmic aggregates or the nucleus is polyalanine tract size-dependent. Geldanamycin, an Hsp90 inhibitor, reduces the steady-state abundance of all polyalanine-expanded proteins in transfected cells. We also found that wild-type HOXA13 or HOXD13 proteins are sequestered in HOXA13 polyalanine expansion cytoplasmic aggregates. Thus, the difference between HOXA13 polyalanine expansion loss-of-function and HOXD13 polyalanine expansion dominant-negative effect is not the ability to aggregate wild-type group 13 paralogs but perhaps to variation in activities associated with refolding, aggregation or degradation of the proteins.

Cleavage of IgG1 and IgG3 by gingipain K from Porphyromonas gingivalis may compromise host defense in progressive periodontitis

Degradation of immunoglobulins is an effective strategy of bacteria to evade the immune system. We have tested whether human IgG is a substrate for gingipain K of Porphyromonas gingivalis and found that the enzyme can hydrolyze subclass 1 and 3 of human IgG. The heavy chain of IgG(1) was cleaved at a single site within the hinge region, generating Fab and Fc fragments. IgG(3) was also cleaved within the heavy chain, but at several sites around the CH2 region. Investigation of the enzyme kinetics of IgG proteolysis by gingipain K, using FPLC- and isothermal titration calorimetry-based assays followed by Hill plots, revealed non-Michaelis-Menten kinetics involving a mechanism of positive cooperativity. In ex vivo studies, it was shown that gingipain K retained its IgG hydrolyzing activity in human plasma despite the high content of natural protease inhibitors; that IgG(1) cleavage products were detected in gingival crevicular fluid samples from patients with severe periodontitis; and that gingipain K treatment of serum samples from patients with high antibody titers against P. gingivalis significantly hindered opsonin-dependent phagocytosis of clinical isolates of P. gingivalis by neutrophils. Altogether, these findings underline a biological function of gingipain K as an IgG protease of pathophysiological importance.

Prediction and prevention of schizophrenia: what has been achieved and where to go next?

In modern medicine, vigorous efforts are being made in the prediction and prevention of diseases. Mental disorders are suitable candidates for the application of this program. The currently known neurobiological and psychosocial risk indicators for schizophrenia do not have a predictive power sufficient for selective prevention in asymptomatic patients at risk. However, once predictive basic and later pre-psychotic high risk symptoms of psychosis develop into the five-year initial prodrome, the impending outbreak of the disease can be predicted with high accuracy. Research findings suggest a differential strategy of indicated prevention with cognitive behavioral therapy in early initial prodromal states and low dosage atypical antipsychotics in late initial prodromal states. The most important future tasks are the improvement of the predictive power by risk enrichment and stratification, as well as the confirmation of the existing and the development of new prevention strategies, with a stronger focus on the etiology of the disorder. In addition, the prediction and prevention approach would benefit from the inclusion of risk symptoms in the DSM-5 criteria.

Favourable prognostic value of antibodies anti-HSP20 in patients with cystic echinococcosis: a differential immunoproteomic approach

Seeking biomarkers reflecting disease development in cystic echinococcosis (CE), we used a proteomic approach linked to immunological characterisation for the identification of respective antigens. Two-dimensional gel electrophoresis (2-DE) of sheep hydatid fluid, followed by immunoblot analysis (IB) with sera from patients with distinct phases of disease, enabled us to identify by mass spectrometry heat shock protein 20 (HSP20) as a potential marker of active CE. Using IB, antibodies specific to the 34 kDa band of HSP20 were detected in sera from 61/95 (64%) patients with CE, but not in sera from healthy subjects. IB revealed anti-HSP20 antibodies in a higher percentage of sera from patients with active disease than in sera from patients with inactive disease (81 vs. 24%; P = 10(-4)). These primary results were confirmed in a long-term follow-up study after pharmacological and surgical treatment. Herewith anti-HSP20 antibody levels significantly decreased over the course of treatment in sera from patients with cured disease, relative to sera from patients with progressive disease (P = 0.017). Thus, during CE, a comprehensive strategy of proteomic identification combined with immunological validation represents a promising approach for the identification of biomarkers useful for the prognostic assessment of treatment of CE patients.