ADPIC y los Tratados Bilaterales de Inversión: la necesidad de encontrar una armonía en su aplicación

This paper analyzes the current international standards for the protection of intellectual property rights by international investment agreements with particular emphasis on bilateral investment treaties (BITs) and how these relate to TRIPS. It demonstrates that international standards for the protection of intellectual property rights after the entry into force of the TRIPS Agreement remain inconsistent. The TRIPS-plus standards as included in BITs erode the flexibilities provided for in the TRIPS Agreement. In doing so, this paper raises the necessity of clarifying the international legal framework in this respect, in order to allow these two bodies of law to coexist in a harmonious and coherent manner.El presente documento analiza las normas internacionales existentes sobre la protección de los derechos de propiedad intelectual en los acuerdos internacionales de inversión, con especial énfasis en los tratados bilaterales de inversión (TBI) y cómo se relaciona con el Acuerdo sobre los Aspectos de los Derechos de Propiedad Intelectual relacionados con el Comercio (ADPIC). El análisis demuestra que los estándares internacionales para la protección de los derechos de propiedad intelectual, después de la adopción del ADPIC, son inconsistentes. En el trabajo se analizan las normas ADPIC-Plus que han repercutido de manera sustancial sobre las flexibilidades previstas en el Acuerdo. En este trabajo se concluye sobre la necesidad de aclarar los parámetros jurídicos internacionales sobre el tema, y de esta manera asegurar la coexistencia armoniosa de las disposiciones acordadas en los TBI y ADPIC

Inferencing Progenitor and Explosion Properties of Evolving Core-collapse Supernovae from Zwicky Transient Facility Light Curves

We analyze a sample of 45 Type II supernovae from the Zwicky Transient Facility (ZTF) public survey using a grid of hydrodynamical models in order to assess whether theoretically-driven forecasts can intelligently guide follow up observations supporting all-sky survey alert streams. We estimate several progenitor properties and explosion physics parameters including zero-age-main-sequence (ZAMS) mass, mass-loss rate, kinetic energy, 56Ni mass synthesized, host extinction, and the time of explosion. Using complete light curves we obtain confident characterizations for 34 events in our sample, with the inferences of the remaining 11 events limited either by poorly constraining data or the boundaries of our model grid. We also simulate real-time characterization of alert stream data by comparing our model grid to various stages of incomplete light curves (t less than 25 days, t less than 50 days, all data), and find that some parameters are more reliable indicators of true values at early epochs than others. Specifically, ZAMS mass, time of explosion, steepness parameter beta, and host extinction are reasonably constrained with incomplete light curve data, whereas mass-loss rate, kinetic energy and 56Ni mass estimates generally require complete light curves spanning greater than 100 days. We conclude that real-time modeling of transients, supported by multi-band synthetic light curves tailored to survey passbands, can be used as a powerful tool to identify critical epochs of follow up observations. Our findings are relevant to identify, prioritize, and coordinate efficient follow up of transients discovered by Vera C. Rubin Observatory.Comment: 27 pages, 14 figures, Accepted to The Astrophysical Journa

Cluster analysis of higher-education competitiveness in selected European countries

The subject of research in this paper is higher-education competitiveness on account of its impact on the enhancement of social and economic competitiveness, as well as on the growth of human capital and creation of social knowledge. The purpose of this paper is to group the selected European countries according to higher-education competitiveness, by means of the hierarchical cluster analysis method, with a special focus on the position of Serbia. Higher-education competitiveness in the chosen countries is analysed by means of three indicators of competitiveness: the ratio of the number of students per number of inhabitants, the number of students per number of employed, as well as the amount of budgetary funds allocated per student. The research results indicate different higher-education competitiveness in the analysed countries and also the fact that, according to this analysis, Serbia is in the group of countries with low competitiveness of higher education

Oxaliplatin, 5-fluorouracil/leucovorin and epirubicin as first-line treatment in advanced gastric carcinoma: a phase II study

The association between oxaliplatin and 5-fluorouracil (5-FU) has been extensively reported to improve prognosis of gastric cancer patients. The present study is aimed at evaluating response rate and the toxicity profile of the association with oxaliplatin, 5-FU/lecovorin and epirubicin in gastric cancer patients with locally advanced or metastatic disease. Thirty-six patients have been enrolled and 35 evaluated. The treatment schedule was oxaliplatin (100 mg m−2), 5-FU (400 mg m−2), leucovorin (40 mg m−2) and epirubicin (60 mg m−2) intravenously. administered every 3 weeks for 6 months, for a total of 185 therapy cycles . Response rate and toxicity were assessed according to the international WHO criteria. Every patient received a mean of 5.3 therapy cycles in a day-hospital setting. Sixteen of 35 patients (46%) showed an objective response, two complete response and 14 partial response. Median time to progression was 33 weeks with an overall median survival of 49 weeks. During the study, anaemia grade 3 and neutropenia grade 3 were observed in 9 and 11% of patients respectively. A grade 3 periferic sensorial neuropathy was observed in 6% of patients. No life threatening or cardiac toxicity was recorded. The regimen used showed anticancer activity against gastric carcinoma, a tolerable toxicity profile and excellent patient compliance

Human Gastrointestinal Juices Intended for Use in In Vitro Digestion Models

The aim of this study was to characterise the individual human gastric and duodenal juices to be used in in vitro model digestion and to examine the storage stability of the enzymes. Gastroduodenal juices were aspirated, and individual variations in enzymatic activities as well as total volumes, pH, bile acids, protein and bilirubin concentrations were recorded. Individual pepsin activity in the gastric juice varied by a factor of 10, while individual total proteolytic activity in the duodenal juice varied by a factor of 5. The duodenal amylase activity varied from 0 to 52.6 U/ml, and the bile acid concentration varied from 0.9 to 4.5 mM. Pooled gastric and duodenal juices from 18 volunteers were characterised according to pepsin activity (26.7 U/ml), total proteolytic activity (14.8 U/ml), lipase activity (951.0 U/ml), amylase activity (26.8 U/ml) and bile acids (4.5 mM). Stability of the main enzymes in two frozen batches of either gastric or duodenal juice was studied for 6 months. Pepsin activity decreased rapidly and adjusting the pH of gastric juice to 4 did not protect the pepsin from degradation. Lipase activity remained stable for 4 months, however decreased rapidly thereafter even after the addition of protease inhibitors. Glycerol only marginally stabilised the survival of the enzymatic activities. These results of compositional variations in the individual gastrointestinal juices and the effect of storage conditions on enzyme activities are useful for the design of in vitro models enabling human digestive juices to simulate physiological digestion

The myeloperoxidase-derived oxidant HOSCN inhibits protein tyrosine phosphatases and modulates cell signalling via the mitogen-activated protein kinase (MAPK) pathway in macrophages

MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by hydrogen peroxide to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid) respectively. Specificity constants indicate that SCN− is a major substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. While HOCl and HOBr are powerful oxidizing agents, HOSCN is a less reactive, but more specific, oxidant which targets thiols and especially low pKa species. In the present study we show that HOSCN targets cysteine residues present in PTPs (protein tyrosine phosphatases) with this resulting in a loss of PTP activity for the isolated enzyme, in cell lysates and intact J774A.1 macrophage-like cells. Inhibition also occurs with MPO-generated HOCl and HOBr, but is more marked with MPO-generated HOSCN, particularly at longer incubation times. This inhibition is reversed by dithiothreitol, particularly at early time points, consistent with the reversible oxidation of the active site cysteine residue to give either a cysteine–SCN adduct or a sulfenic acid. Inhibition of PTP activity is associated with increased phosphorylation of p38a and ERK2 (extracellular-signal-regulated kinase 2) as detected by Western blot analysis and phosphoprotein arrays, and results in altered MAPK (mitogen-activated protein kinase) signalling. These data indicate that the highly selective targeting of some protein thiols by HOSCN can result in perturbation of cellular phosphorylation and altered cell signalling. These changes occur with (patho)physiological concentrations of SCN− ions, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage, particularly in smokers who have elevated plasma levels of SCN−

Selenium-containing amino acids are targets for myeloperoxidase-derived hypothiocyanous acid: determination of absolute rate constants and implications for biological damage

Elevated MPO (myeloperoxidase) levels are associated with multiple human inflammatory pathologies. MPO catalyses the oxidation of Cl−, Br− and SCN− by H2O2 to generate the powerful oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) respectively. These species are antibacterial agents, but misplaced or excessive production is implicated in tissue damage at sites of inflammation. Unlike HOCl and HOBr, which react with multiple targets, HOSCN targets cysteine residues with considerable selectivity. In the light of this reactivity, we hypothesized that Sec (selenocysteine) residues should also be rapidly oxidized by HOSCN, as selenium atoms are better nucleophiles than sulfur. Such oxidation might inactivate critical Sec-containing cellular protective enzymes such as GPx (glutathione peroxidase) and TrxR (thioredoxin reductase). Stopped-flow kinetic studies indicate that seleno-compounds react rapidly with HOSCN with rate constants, k, in the range 2.8×103–5.8×106 M−1·s−1 (for selenomethionine and selenocystamine respectively). These values are ~6000-fold higher than the corresponding values for H2O2, and are also considerably larger than for the reaction of HOSCN with thiols (16-fold for cysteine and 80-fold for selenocystamine). Enzyme studies indicate that GPx and TrxR, but not glutathione reductase, are inactivated by HOSCN in a concentration-dependent manner; k for GPx has been determined as ~5×105 M−1·s−1. Decomposed HOSCN did not induce inactivation. These data indicate that selenocysteine residues are oxidized rapidly by HOSCN, with this resulting in the inhibition of the critical intracellular Sec-dependent protective enzymes GPx and TrxR

Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min−1 were excluded. Study treatment consisted of docetaxel 75 mg m−2 (day 8) and gemcitabine 1000 mg m−2 (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42–74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3–4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1–9.2 months) and the median overall survival was 15 months (95% CI 11.2–18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease

The association of hydration status with physical signs, symptoms and survival in advanced cancer-The use of Bioelectrical Impedance Vector Analysis (BIVA) technology to evaluate fluid volume in palliative care: An observational study

Background Hydration in advanced cancer is a controversial area; however, current hydration assessments methods are poorly developed. Bioelectrical impedance vector analysis (BIVA) is an accurate hydration tool; however its application in advanced cancer has not been explored. This study used BIVA to evaluate hydration status in advanced cancer to examine the association of fluid status with symptoms, physical signs, renal biochemical measures and survival. Materials and methods An observational study of 90 adults with advanced cancer receiving care in a UK specialist palliative care inpatient unit was conducted. Hydration status was assessed using BIVA in addition to assessments of symptoms, physical signs, performance status, renal biochemical measures, oral fluid intake and medications. The association of clinical variables with hydration was evaluated using regression analysis. A survival analysis was conducted to examine the influence of hydration status and renal failure. Results The hydration status of participants was normal in 43 (47.8%), 'more hydrated' in 37 (41.1%) and 'less hydrated' in 10 (11.1%). Lower hydration was associated with increased symptom intensity (Beta = -0.29, p = 0.04) and higher scores for physical signs associated with dehydration (Beta = 10.94, p = 0.02). Higher hydration was associated with oedema (Beta = 2.55, p<0.001). Median survival was statistically significantly shorter in 'less hydrated' patients (44 vs. 68 days; p = 0.049) and in pre-renal failure (44 vs. 100 days; p = 0.003). Conclusions In advanced cancer, hydration status was associated with clinical signs and symptoms. Hydration status and pre-renal failure were independent predictors of survival. Further studies can establish the utility of BIVA as a standardised hydration assessment tool and explore its potential research application, in order to inform the clinical management of fluid balance in patients with advanced cancer