A framework for deriving semantic web services

Web service-based development represents an emerging approach for the development of distributed information systems. Web services have been mainly applied by software practitioners as a means to modularize system functionality that can be offered across a network (e.g., intranet and/or the Internet). Although web services have been predominantly developed as a technical solution for integrating software systems, there is a more business-oriented aspect that developers and enterprises need to deal with in order to benefit from the full potential of web services in an electronic market. This ‘ignored’ aspect is the representation of the semantics underlying the services themselves as well as the ‘things’ that the services manage. Currently languages like the Web Services Description Language (WSDL) provide the syntactic means to describe web services, but lack in providing a semantic underpinning. In order to harvest all the benefits of web services technology, a framework has been developed for deriving business semantics from syntactic descriptions of web services. The benefits of such a framework are two-fold. Firstly, the framework provides a way to gradually construct domain ontologies from previously defined technical services. Secondly, the framework enables the migration of syntactically defined web services toward semantic web services. The study follows a design research approach which (1) identifies the problem area and its relevance from an industrial case study and previous research, (2) develops the framework as a design artifact and (3) evaluates the application of the framework through a relevant scenario

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

Tumoral CD105 is a novel independent prognostic marker for prognosis in clear-cell renal cell carcinoma

International audienceBackground: Angiogenesis is essential for tumour growth and metastasis. There are conflicting reports as to whether microvessel density (MVD) using the endothelial marker CD105 (cluster of differentiation molecule 105) in clear-cell renal cell carcinomas (ccRCC) is associated with prognosis. Recently, CD105 has been described as a RCC cancer stem cell marker.Methods: A total of 102 ccRCC were analysed. Representative tumour sections were stained for CD105. Vascularity (endothelial CD105) was quantified by MVD. The immunohistochemistry analysis detected positive (if present) or negative (if absent) CD105 tumoral staining. This retrospective population-based study was evaluated using Kaplan–Meier method, t-test and Cox proportional hazard model.Results: We found that the expression of endothelial CD105 (MVD) negatively correlated with nuclear grade (P<0.001), tumour stage (P<0.001) and Leibovitch score (P<0.001), whereas the expression of tumoral CD105 positively correlated with these three clinicopathological factors (P<0.001). In multivariate analysis, tumoral CD105 was found to be an independent predictor of poor overall survival (P=0.002).Conclusions: We have shown for the first time that tumoral CD105 is an independent predictive marker for death risk and unfavourable prognosis in patients with ccRCC after curative resection

Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis

Background: The mechanism by which c-Myc exerts its oncogenic functions is not completely clear and different hypotheses are still under investigation. The knowledge of the capacity of c-Myc to bind exclusively E-box sequences determined the discrepancy between, on the one hand, genomic studies showing the binding of c-Myc to all active promoters and, on the other hand, the evidence that only 60% or less of the binding sites have E-box sequences. Main body: In this review, we provide support to the hypothesis that the cooperation of c-Myc with transcriptional cofactors mediates c-Myc-induced cellular functions. We produce evidence that recently identified cofactors are involved in c-Myc control of survival mechanisms of cancer cells. Conclusion: The identification of new c-Myc cofactors could favor the development of therapeutic strategies able to compensate the difficulty of targeting c-Myc

Optical Control of Metabotropic Glutamate Receptors

G-protein coupled receptors (GPCRs), the largest family of membrane signaling proteins, respond to neurotransmitters, hormones and small environmental molecules. The neuronal function of many GPCRs has been difficult to resolve because of an inability to gate them with subtype-specificity, spatial precision, speed and reversibility. To address this, we developed an approach for opto-chemical engineering native GPCRs. We applied this to the metabotropic glutamate receptors (mGluRs) to generate light-agonized and light-antagonized “LimGluRs”. The light-agonized “LimGluR2”, on which we focused, is fast, bistable, and supports multiple rounds of on/off switching. Light gates two of the primary neuronal functions of mGluR2: suppression of excitability and inhibition of neurotransmitter release. The light-antagonized “LimGluR2block” can be used to manipulate negative feedback of synaptically released glutamate on transmitter release. We generalize the optical control to two additional family members: mGluR3 and 6. The system works in rodent brain slice and in zebrafish in vivo, where we find that mGluR2 modulates the threshold for escape behavior. These light-gated mGluRs pave the way for determining the roles of mGluRs in synaptic plasticity, memory and disease

Exploring risk of falls and dynamic unbalance in cerebellar ataxia by inertial sensor assessment

Background. Patients suffering from cerebellar ataxia have extremely variable gait kinematic features. We investigated whether and how wearable inertial sensors can describe the gait kinematic features among ataxic patients. Methods. We enrolled 17 patients and 16 matched control subjects. We acquired data by means of an inertial sensor attached to an ergonomic belt around pelvis, which was connected to a portable computer via Bluetooth. Recordings of all the patients were obtained during overground walking. From the accelerometric data, we obtained the harmonic ratio (HR), i.e., a measure of the acceleration patterns, smoothness and rhythm, and the step length coefficient of variation (CV), which evaluates the variability of the gait cycle. Results. Compared to controls, patients had a lower HR, meaning a less harmonic and rhythmic acceleration pattern of the trunk, and a higher step length CV, indicating a more variable step length. Both HR and step length CV showed a high effect size in distinguishing patients and controls (p &lt; 0.001 and p = 0.011, respectively). A positive correlation was found between the step length CV and both the number of falls (R = 0.672; p = 0.003) and the clinical severity (ICARS: R = 0.494; p = 0.044; SARA: R = 0.680; p = 0.003). Conclusion. These findings demonstrate that the use of inertial sensors is effective in evaluating gait and balance impairment among ataxic patients

Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses

Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases that modulates cell growth, apoptosis, proliferation and development. HIPK2 has several well-characterised tumour suppressor roles, but recent studies suggest it can also contribute to tumour progression, although the underlying mechanisms are unknown. Herein, we have identified novel crosstalk between HIPK2 and the cytoprotective transcription factor NRF2. We show that HIPK2 is a direct transcriptional target of NRF2, identifying a functional NRF2 binding site in the HIPK2 gene locus and demonstrating for the first time a transcriptional mode of regulation for this kinase. In addition, HIPK2 is required for robust NRF2 responsiveness in cells and in vivo. By using both gain-of-function and loss-of-function approaches, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2. Our results have uncovered a new downstream effector of HIPK2, NRF2, which is frequently activated in human tumours correlating with chemoresistance and poor prognosis. Furthermore, our results suggest that modulation of either HIPK2 levels or activity could be exploited to impair NRF2-mediated signalling in cancer cells, and thus sensitise them to chemotherapeutic drugs.Oncogene advance online publication, 10 July 2017; doi:10.1038/onc.2017.221.</p

A protective role for autophagy in vitiligo

A growing number of studies supports the existence of a dynamic interplay between energetic metabolism and autophagy, whose induction represents an adaptive response against several stress conditions. Autophagy is an evolutionarily conserved and a highly orchestrated catabolic recycling process that guarantees cellular homeostasis. To date, the exact role of autophagy in vitiligo pathogenesis is still not clear. Here, we provide the first evidence that autophagy occurs in melanocytes and fibroblasts from non-lesional skin of vitiligo patients, as a result of metabolic surveillance response. More precisely, this study is the first to reveal that induction of autophagy exerts a protective role against the intrinsic metabolic stress and attempts to antagonize degenerative processes in normal appearing vitiligo skin, where melanocytes and fibroblasts are already prone to premature senescence

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

Background: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants: A total of 150 mRCC patients with rapidly PD on first- line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarco- matoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Pro- gression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations: Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 ever- olimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second- line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary: The present work collected data about 150 patients affected by meta- static renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases