Prognostic relevance of ALT-associated markers in liposarcoma: a comparative analysis

<p>Abstract</p> <p>Background</p> <p>Most cancers maintain telomeres by activating telomerase but a significant minority, mainly of mesenchymal origin, utilize an alternative lengthening of telomeres (ALT) mechanism.</p> <p>Methods</p> <p>In this study we comparatively analyzed the prognostic relevance of ALT in a monoinstitutional series of 85 liposarcoma patients as a function of the marker (ALT-associated promyelocytic leukemia bodies (APB) versus heterogeneous telomeres) used to classify the tumor.</p> <p>Results</p> <p>Independently of the detection approach, ALT proved to be a prognostic discriminant of increased mortality, although the prognostic relevance of the two markers appeared at different follow-up intervals (at 10 years for APB and 15 years for telomeres).</p> <p>Conclusions</p> <p>Overall, we confirmed ALT as an indicator of poor clinical outcome in this disease and provide the first evidence that the sensitivity of the ALT predictive power depends, at least in part, on the method used.</p

SECURITY RISK ANALYSIS AND EVALUATION OF INTEGRATING CUSTOMER ENERGY MANAGEMENT SYSTEMS INTO SMART DISTRIBUTION GRIDS

ABSTRAC

By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

Basal-like breast cancer is an aggressive tumor subtype with a poor response to conventional therapies. Tumor formation and relapse are sustained by a cell subset of Breast Cancer Stem Cells (BrCSCs). Here we show that miR-100 inhibits maintenance and expansion of BrCSCs in basal-like cancer through Polo-like kinase1 (Plk1) down-regulation. Moreover, miR-100 favors BrCSC differentiation, converting a basal like phenotype into luminal. It induces the expression of a functional estrogen receptor (ER) and renders basal-like BrCSCs responsive to hormonal therapy. The key role played by miR-100 in breast cancer free-survival is confirmed by the analysis of a cohort of patients' tumors, which shows that low expression of miR-100 is a negative prognostic factor and is associated with gene signatures of high grade undifferentiated tumors. Our findings indicate a new possible therapeutic strategy, which could make aggressive breast cancers responsive to standard treatments

Architecture, Services and Protocols for CRUTIAL

This document describes the complete specification of the architecture, services and protocols of the project CRUTIAL. The CRUTIAL Architecture intends to reply to a grand challenge of computer science and control engineering: how to achieve resilience of critical information infrastructures (CII), in particular in the electrical sector. In general lines, the document starts by presenting the main architectural options and components of the architecture, with a special emphasis on a protection device called the CRUTIAL Information Switch (CIS). Given the various criticality levels of the equipments that have to be protected, and the cost of using a replicated device, we define a hierarchy of CIS designs incrementally more resilient. The different CIS designs offer various trade offs in terms of capabilities to prevent and tolerate intrusions, both in the device itself and in the information infrastructure. The Middleware Services, APIs and Protocols chapter describes our approach to intrusion tolerant middleware. The CRUTIAL middleware comprises several building blocks that are organized on a set of layers. The Multipoint Network layer is the lowest layer of the middleware, and features an abstraction of basic communication services, such as provided by standard protocols, like IP, IPsec, UDP, TCP and SSL/TLS. The Communication Support layer features three important building blocks: the Randomized Intrusion-Tolerant Services (RITAS), the CIS Communication service and the Fosel service for mitigating DoS attacks. The Activity Support layer comprises the CIS Protection service, and the Access Control and Authorization service. The Access Control and Authorization service is implemented through PolyOrBAC, which defines the rules for information exchange and collaboration between sub-modules of the architecture, corresponding in fact to different facilities of the CII’s organizations. The Monitoring and Failure Detection layer contains a definition of the services devoted to monitoring and failure detection activities. The Runtime Support Services, APIs, and Protocols chapter features as a main component the Proactive-Reactive Recovery service, whose aim is to guarantee perpetual correct execution of any components it protects.Project co-funded by the European Commission within the Sixth Frame-work Programme (2002-2006

Identification by Virtual Screening and In Vitro Testing of Human DOPA Decarboxylase Inhibitors

Dopa decarboxylase (DDC), a pyridoxal 5′-phosphate (PLP) enzyme responsible for the biosynthesis of dopamine and serotonin, is involved in Parkinson's disease (PD). PD is a neurodegenerative disease mainly due to a progressive loss of dopamine-producing cells in the midbrain. Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide) is the most effective symptomatic treatment for PD. Although carbidopa and trihydroxybenzylhydrazine (the in vivo hydrolysis product of benserazide) are both powerful irreversible DDC inhibitors, they are not selective because they irreversibly bind to free PLP and PLP-enzymes, thus inducing diverse side effects. Therefore, the main goals of this study were (a) to use virtual screening to identify potential human DDC inhibitors and (b) to evaluate the reliability of our virtual-screening (VS) protocol by experimentally testing the “in vitro” activity of selected molecules. Starting from the crystal structure of the DDC-carbidopa complex, a new VS protocol, integrating pharmacophore searches and molecular docking, was developed. Analysis of 15 selected compounds, obtained by filtering the public ZINC database, yielded two molecules that bind to the active site of human DDC and behave as competitive inhibitors with Ki values ≥10 µM. By performing in silico similarity search on the latter compounds followed by a substructure search using the core of the most active compound we identified several competitive inhibitors of human DDC with Ki values in the low micromolar range, unable to bind free PLP, and predicted to not cross the blood-brain barrier. The most potent inhibitor with a Ki value of 500 nM represents a new lead compound, targeting human DDC, that may be the basis for lead optimization in the development of new DDC inhibitors. To our knowledge, a similar approach has not been reported yet in the field of DDC inhibitors discovery

AIRO Breast Cancer Group Best Clinical Practice 2022 Update

Introduction: Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice.Method: This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations.Results: An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders.Conclusions: Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine