Highlights of New Strategies to Increase the Efficacy of Transition Metal Complexes for Cancer Treatments

Although important progress has been made, cancer still remains a complex disease to treat. Serious side effects, the insurgence of resistance and poor selectivity are some of the problems associated with the classical metal-based anti-cancer therapies currently in clinical use. New treatment approaches are still needed to increase cancer patient survival without cancer recurrence. Herein, we reviewed two promising-at least in our opinion-new strategies to increase the efficacy of transition metal-based complexes. First, we considered the possibility of assembling two biologically active fragments containing different metal centres into the same molecule, thus obtaining a heterobimetallic complex. A critical comparison with the monometallic counterparts was done. The reviewed literature has been divided into two groups: the case of platinum; the case of gold. Secondly, the conjugation of metal-based complexes to a targeting moiety was discussed. Particularly, we highlighted some interesting examples of compounds targeting cancer cell organelles according to a third-order targeting approach, and complexes targeting the whole cancer cell, according to a second-order targeting strategy

Functional neurological disorders as seen by a cohort of general practitioners in Northern Italy: evidence from an online survey

General practitioners (GPs) provide primary care and advise their patients on which diagnostic and therapeutic pathways they judge most appropriate. For patients with functional neurological disorders (FND), receiving a proper explanation of diagnosis by their GP from the very beginning may drastically improve prognosis. Novel approaches to the diagnosis and treatment of FND have important implications for effective management. The aim of this study was to investigate Italian GP opinion and knowledge about FND in light of new approaches to the illness. To do this, we evaluated the responses to a 13-item web-based survey completed by 133 GPs practicing in northern Italy. Psychological terms to describe FND were more frequently used than functional neurological disorder and mental illness was considered an important predictor of diagnosis. Referral to a neurologist rather than to a psychiatrist was largely preferred, while physiotherapy consultation was seldom recognized as a valuable approach to treating FND. Overall, the survey findings suggest that knowledge about novel approaches to FND is somewhat lacking. Currently, GPs appear to be transitioning from a classical psychological view of the disorder toward a more modern conceptualization, in which neurobiological, psychological, and social factors all play an important role. Professional education during this transition would be an advantageous way to optimize physician management of FND and to enhance diagnosis, explanation, and management across primary and secondary care pathways

Hedonicity in functional motor disorders: a chemosensory study assessing taste

The aim of this study was to explore hedonicity to basic tastes in patients with functional motor disorders (FMDs) that are often associated with impairment in emotional processing. We recruited 20 FMD patients and 24 healthy subjects, matched for age and sex. Subjects were asked to rate the hedonic sensation (i.e., pleasant, neutral, and unpleasant) on a\u2009-\u200910 to +10 scale to the four basic tastes (sweet, sour, salty, and bitter) at different concentrations, and neutral stimuli (i.e., no taste stimulation) by means of the Taste Strips Test. Anxiety, depression, and alexithymia were assessed. FMD patients rated the highest concentration of sweet taste (6.7\u2009\ub1\u20092.6) as significantly more pleasant than controls (4.7\u2009\ub1\u20092.5, p\u2009=\u20090.03), and the neutral stimuli significantly more unpleasant (patients:\u2009-\u20090.7\u2009\ub1\u20090.4, controls: 0.1\u2009\ub1\u20090.4, p\u2009=\u20090.013). Hedonic ratings were not correlated to anxiety, depression, or alexithymia scores. Hedonic response to taste is altered in FMD patients. This preliminary finding might result from abnormal interaction between sensory processing and emotional valence

The Gravity Effect of Topography: A Comparison among Three Different Methods

In this paper, three different methods for computing the terrain correction have been compared. The terrain effect has been accounted for by using the standard right parallelepiped closed formula, the spherical tesseroid and the flat tesseroid formulas. Particularly, the flat tesseroid approximation is obtained by flattening the top and the bottom sides of the spherical tesseroid. Its gravitational effect can be computed as the gravitational effect of a polyhedron, i.e. a three-dimensional body with flat polygonal faces, straight edges and sharp corners or vertices. These three methods have been applied in the context of a Bouguer reduction scheme. Two tests were devised in the Alpine area in order to quantify possible discrepancies. In the first test, the terrain correction has been evaluated on a grid of points on the DTM. In the second test, Bouguer gravity anomalies were computed on sparse observed gravity data points. The results prove that the three methods are practically equivalent even in an area of rough topography though, in the second test, the Bouguer anomalies obtained by using the tesseroid and the flat tesseroid formulas have slightly smaller RMSs than the one obtained by applying the standard right parallelepiped formula

CI-CD practices at SKA

The Square Kilometre Array (SKA) is an international effort to build two radio interferometers in South Africa and Australia forming one Observatory monitored and controlled from global headquarters (GHQ) based in the United Kingdom at Jodrell Bank. SKA is highly focused on adopting CI/CD practices for its software development. CI/CD stands for Continuous Integration & Delivery and/or Deployment. This paper analyses the CI/CD practices selected by the Systems Team (a specialised agile team devoted to developing and maintaining the tools that allow continuous practices) in relation to a specific software system of the SKA telescope, i.e. the Local Monitoring and Control (LMC) of the Central Signal Processor (CSP), from now on called CSP.LMC. CSP is the SKA element with the aim to process the data coming from the receivers in order to be used for scientific analysis. To achieve this, it is composed of several instruments, called subsystems, such as the Correlator Beam Former (CBF), the Pulsar Search (PSS) and the Pulsar Timing (PST). CSP.LMC communicates to the Telescope Manager (the software front-end to control the telescope operations) all the required information to monitor the CSP's subsystems and the interface to configure them and send the commands needed to perform an observation. In other words, CSP.LMC permits the TM to monitor and control CSP as a single entity

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare fatal autorecessive disease. Halter et al. report outcomes from all known haematopoietic stem cell transplantations worldwide from sibling or unrelated donors for MNGIE between 2005 and 2011. In some of the recipients, correction of the underlying metabolic defect results in gradual clinical improvemen

Anti-Angiogenic Therapy Induces Integrin-Linked Kinase 1 Up-Regulation in a Mouse Model of Glioblastoma

BACKGROUND: In order to improve our understanding of the molecular pathways that mediate tumor proliferation and angiogenesis, and to evaluate the biological response to anti-angiogenic therapy, we analyzed the changes in the protein profile of glioblastoma in response to treatment with recombinant human Platelet Factor 4-DLR mutated protein (PF4-DLR), an inhibitor of angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: U87-derived experimental glioblastomas were grown in the brain of xenografted nude mice, treated with PF4-DLR, and processed for proteomic analysis. More than fifty proteins were differentially expressed in response to PF4-DLR treatment. Among them, integrin-linked kinase 1 (ILK1) signaling pathway was first down-regulated but then up-regulated after treatment for prolonged period. The activity of PF4-DLR can be increased by simultaneously treating mice orthotopically implanted with glioblastomas, with ILK1-specific siRNA. As ILK1 is related to malignant progression and a poor prognosis in various types of tumors, we measured ILK1 expression in human glioblastomas, astrocytomas and oligodendrogliomas, and found that it varied widely; however, a high level of ILK1 expression was correlated to a poor prognosis. CONCLUSIONS/SIGNIFICANCE: Our results suggest that identifying the molecular pathways induced by anti-angiogenic therapies may help the development of combinatorial treatment strategies that increase the therapeutic efficacy of angiogenesis inhibitors by association with specific agents that disrupt signaling in tumor cells

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients

The LANDSUPPORT geospatial decision support system (S-DSS) vision: Operational tools to implement sustainability policies in land planning and management

Nowadays, there is contrasting evidence between the ongoing continuing and widespread environmental degradation and the many means to implement environmental sustainability actions starting from good policies (e.g. EU New Green Deal, CAP), powerful technologies (e.g. new satellites, drones, IoT sensors), large databases and large stakeholder engagement (e.g. EIP-AGRI, living labs). Here, we argue that to tackle the above contrasting issues dealing with land degradation, it is very much required to develop and use friendly and freely available web-based operational tools to support both the implementation of environmental and agriculture policies and enable to take positive environmental sustainability actions by all stakeholders. Our solution is the S-DSS LANDSUPPORT platform, consisting of a free web-based smart Geospatial CyberInfrastructure containing 15 macro-tools (and more than 100 elementary tools), co-designed with different types of stakeholders and their different needs, dealing with sustainability in agriculture, forestry and spatial planning. LANDSUPPORT condenses many features into one system, the main ones of which were (i) Web-GIS facilities, connection with (ii) satellite data, (iii) Earth Critical Zone data and (iv) climate datasets including climate change and weather forecast data, (v) data cube technology enabling us to read/write when dealing with very large datasets (e.g. daily climatic data obtained in real time for any region in Europe), (vi) a large set of static and dynamic modelling engines (e.g. crop growth, water balance, rural integrity, etc.) allowing uncertainty analysis and what if modelling and (vii) HPC (both CPU and GPU) to run simulation modelling 'on-the-fly' in real time. Two case studies (a third case is reported in the Supplementary materials), with their results and stats, covering different regions and spatial extents and using three distinct operational tools all connected to lower land degradation processes (Crop growth, Machine Learning Forest Simulator and GeOC), are featured in this paper to highlight the platform's functioning. Landsupport is used by a large community of stakeholders and will remain operational, open and free long after the project ends. This position is rooted in the evidence showing that we need to leave these tools as open as possible and engage as much as possible with a large community of users to protect soils and land