354 research outputs found
Some geometrical methods for constructing contradiction measures on Atanassov's intuitionistic fuzzy sets
Trillas et al. (1999, Soft computing, 3 (4), 197–199) and Trillas and Cubillo (1999, On non-contradictory input/output couples in Zadeh's CRI proceeding, 28–32) introduced the study of contradiction in the framework of fuzzy logic because of the significance of avoiding contradictory outputs in inference processes. Later, the study of contradiction in the framework of Atanassov's intuitionistic fuzzy sets (A-IFSs) was initiated by Cubillo and Castiñeira (2004, Contradiction in intuitionistic fuzzy sets proceeding, 2180–2186). The axiomatic definition of contradiction measure was stated in Castiñeira and Cubillo (2009, International journal of intelligent systems, 24, 863–888). Likewise, the concept of continuity of these measures was formalized through several axioms. To be precise, they defined continuity when the sets ‘are increasing’, denominated continuity from below, and continuity when the sets ‘are decreasing’, or continuity from above. The aim of this paper is to provide some geometrical construction methods for obtaining contradiction measures in the framework of A-IFSs and to study what continuity properties these measures satisfy. Furthermore, we show the geometrical interpretations motivating the measures
Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors
Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m(2) was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m(2)); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m(2), which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m(2))/gemcitabine 800 mg/m(2) d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types
Application of Drought Management Guidelines in Spain
The Spanish case study presents the drought planning process carried in the Tagus Basin. The presentation is structured in four parts: organizational, methodological, operational and public review components. The organizational component presents the framework and specific legislations and the organizations and institutions in Spain that work on drought preparedness and mitigation. The methodological component presents the analytical techniques used for drought risk analysis and management. The operational component describes the proposed structure for the drought management plan and presents the specific actions that are contemplated in it. The process review component identifies stakeholders that are involved in the decision making process and presents their views on the process
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Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism
Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato–thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto–striato–parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto–striato–cerebellar dysregulation in ASD
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic
The prognosis for patients with metastatic melanoma remains very poor. Constitutive
signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis,
poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032),
suggesting its potential as a molecular target. We recently designed a series of isoseleno- and
isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects
of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of
five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1
(IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and
the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a
short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover
their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1
induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays.
Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as
decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as
survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies
further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it
acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis
by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and
WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032
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