Low-Intensity Light-Responsive Anticancer Activity of Platinum(II) Complex Nanocolloids on 2D and 3D In Vitro Cancer Cell Model

none8This study aimed to evaluate the therapeutic efficacy of low-intensity visible light responsive nanocolloids of a Pt-based drug using a 2D and three-dimensional (3D) in vitro cancer cell model. Biocompatible and biodegradable polymeric nanocolloids, obtained using the ultrasonication method coupled with Layer by Layer technology, were characterized in terms of size (100 ± 20 nm), physical stability, drug loading (78%), and photoactivation through spectroscopy studies. The in vitro biological effects were assessed in terms of efficacy, apoptosis induction, and DNA-Pt adducts formation. Biological experiments were performed both in dark and under visible light irradiation conditions, exploiting the complex photochemical properties. The light-stimuli responsive nanoformulation gave a significant enhancement in drug bioactivity. This allowed us to achieve satisfying results by using nanomolar drug concentration (50 nM), which was ineffective in darkness condition. Furthermore, our nanocolloids were validated in 3D in vitro spheroids using confocal microscopy and cytofluorimetric assay to compare their behavior on culture in 2D monolayers. The obtained results confirmed that these nanocolloids are promising tools for delivering Pt-based drugs.This study was supported by “Tecnopolo di Nanotecnologia e Fotonica per la Medicina di Precisione” (TECNOMED)-FISR/MIUR-CNR: delibera CIPE n.3449 del 7/08/2017, CUP: B83B17000010001; “Tecnopolo per la Medicina di precisione” (TecnoMed Puglia) - Regione Puglia: DGR n.2117 del 21/11/2018, CUP: B84I18000540002.openViviana Vergaro; Francesca Baldassarre; Federica De Castro; Danilo Migoni; Maria Michela Dell’Anna; Piero Mastrorilli; Francesco Paolo Fanizzi; Giuseppe CiccarellaVergaro, Viviana; Baldassarre, Francesca; DE CASTRO, Federica; Danilo, Migoni; Michela Dell’Anna, Maria; Mastrorilli, Piero; Fanizzi, Francesco Paolo; Ciccarella, Giusepp

The Zn-Nonsulphides district of Bongarà (Northern Peru)

The Bongarà complex of deposits consists of a stratabound Pb-Zn Nonsulphide/Sulphide mineralization located in the Amazonas District, near the Yambrasbamba village (Peru) [1]. The deposits (Mina Grande, Mina Chica, and Rio Cristal) are hosted by Mesozoic limestone (Toarcian) of the Pucarà Group (Condorsinga Fm.), locally dolomitized and brecciated. The primary mineralization is considered a MVT, similar to the San Vicente deposit in Central Peru. There are multiple distinct ore concentrations scattered over a large area; the mineralization appears to be open-space filling and/or manto replacement associated with karstification. The economic value is currently considered as related to the concentrations of nonsulphide Zn minerals [2]. The Mina Grande deposit consists of several, partly exploited mineralized areas, where the ore consists of masses of nonsulphides (mainly hydrozincite>>smithsonite) mixed with brown soil. The mineralized body is 1.5 km long, 0.4 km wide, and extends to depths of 20 to 60 m below surface. The economic mineralization is concentrated in karstic cavities and earthy-looking mantos. The zinc “oxides” form a residual cap along the crest of an anticlinal structure [1]. This mineralization can be classified as belonging to Type 3 (residual in karsts cavities) among the supergene nonsulphide deposits [3]. The Rio Cristal prospect [1] is probably the most extensive area of zinc mineralization occurring at Bongarà to date. Diamond drilling has encountered both near-surface primary base metal sulphides (only in traces), and oxidized mineralization at depths of over 50 m down-hole, with grades of up to 20 to 30% Zn. The mineralization occurs in a sigmoidal zone, approximately 1.5 km long by 0.5 km wide. Several sub-horizontal manto-like bodies have been detected, which dominantly consist of masses of orange-brown and white zinc “oxides”, which include smithsonite, hydrozincite, cerussite and Fe-hydroxides. A mineralogical, petrographic, and isotope geochemical study of the Bongarà complex of deposits is being conducted by our research group. The ore grade is quite high (up to 35% Zn), with the metal mostly contained in hydrozincite (Mina Grande), smithsonite and hemimorphite (Rio Cristal). To calculate the temperature of smithsonite precipitation at Rio Cristal, a mean δ18O value has been considered between those of rain- and groundwater in the area. To calculate the temperature of calcite (and co-genetic hydrozincite) at Mina Grande, the mean δ18O annual value of the meteoric water (IAEA) has been considered. The temperatures resulting from stable isotopes geochemistry are comparable with the mean annual temperature values in the Bongarà district (21-23°C). At Bongarà there is considerable economic potential both for nonsulphides (occurring in the surficial karst network throughout the whole district, as at Mina Grande) and for sulphides (along several structures detected in the Rio Cristal area). The supergene mineralization is possibly related to weathering episodes (Tertiary to Recent) occurring under a climate not very different from today. References: [1] Wright C (2010) NI 43-101 Technical Report: 102 pp. [2] Boni M and Mondillo N (2015) Ore Geology Reviews 67: 208-233. [3] Hitzman MW et al (2003) Econ Geol 98: 685-714

Combining methane clumped and bulk isotopes, temporal variations in molecular and isotopic composition, and hydrochemical and geological proxies to understand methane’s origin in the Ronda peridotite massifs (Spain)

In serpentinised peridotite and ultramafic rock systems, methane (CH4) origin is frequently considered abiotic, but variable microbial and thermogenic components can also exist. Typically, the origin of CH4 is studied using bulk, 13C/12C and 2H/H isotopic composition, molecular gas composition, occasionally radiocarbon (14C), microbiology and geological context. Recent advances in CH4-clumped isotope methods have yielded novel insights into the formation of CH4: nonetheless, their interpretation in natural gas samples is often uncertain and requires additional research. Here, we study the origin of the gas released in hyperalkaline (pH > 10) springs in the Ronda Peridotite Massifs (southern Spain), combining bulk and clumped CH4 isotopes with molecular gas composition, hydrochemical (Total Organic Carbon and Platinum Group Elements in water), geothermal and geo-structural data. Five springs analysed in 2014 have been re-examined for changes in gas chemistry over time, and three newly discovered gas-bearing springs are analysed for the first time. Regardless of whether springs have microbial or abiotic isotopic fingerprints, we find that bulk CH4 isotopes are fairly stable over a seven-year period. This suggests that the CH4 source(s) or postgenetic processes (such as oxidation and diffusion) have not undergone significant temporal changes. Major variations in H2 and CH4 concentrations in certain springs may be the result of changes in gas pressure and migration intensity. Paired CH4 clumped isotopes (Δ12CH2D2 - Δ13CH3D) were analysed in two bubbling springs, where the presence of CH4 can be interpreted as non-microbial based on 13C enrichment, absence of 14C, and the presence of ethane and propane. However, these isotopes are in disequilibrium, which prevents the quantification of the gas formation temperature. Within the Δ12CH2D2 - Δ13CH3D diagram, the data lie within both the microbialgenic zone, suggested by previous authors, and the abiotic zone that results combining data from laboratory gas synthesis and other natural gas samples. Therefore, attributing a microbial origin to CH4 based only on clumped isotopes is less definite than previously assumed. The amount of Total Organic Carbon appears to be correlated with the origin of CH4, as it is higher in 13Cdepleted CH4 samples and lower in 13C-enriched samples. Palladium (Pd) and Rhodium (Rh) dissolved in water (the more soluble Platinum Group Elements) can be a proxy for the chromitite ore deposits contained in plagioclase tectonite layers throughout the investigated area, which may act as catalysts for abiotic CO2 hydrogenation. Clumped isotope disequilibrium and the reported absence of diffuse CH4-bearing fluid inclusions in the peridotites appear to rule out high temperature gas genesis in post-magmatic inclusions. These observations, along with the moderate temperatures at the base of the peridotite massifs and the consistent occurrence of gasEuropean Regional Development Fund (FEDER)Junta de AndalucíaUniversidad de MálagaFunding charge open access: University of Malaga / CBU

Combining methane clumped and bulk isotopes, temporal variations in molecular and isotopic composition, and hydrochemical and geological proxies to understand methane's origin in the Ronda peridotite massifs (Spain)

In serpentinised peridotite and ultramafic rock systems, methane (CH4) origin is frequently considered abiotic, but variable microbial and thermogenic components can also exist. Typically, the origin of CH4 is studied using bulk, 13C/12C and 2H/H isotopic composition, molecular gas composition, occasionally radiocarbon (14C), microbiology and geological context. Recent advances in CH4-clumped isotope methods have yielded novel insights into the formation of CH4: nonetheless, their interpretation in natural gas samples is often uncertain and requires additional research. Here, we study the origin of the gas released in hyperalkaline (pH > 10) springs in the Ronda Peridotite Massifs (southern Spain), combining bulk and clumped CH4 isotopes with molecular gas composition, hydrochemical (Total Organic Carbon and Platinum Group Elements in water), geothermal and geo-structural data. Five springs analysed in 2014 have been re-examined for changes in gas chemistry over time, and three newly discovered gas-bearing springs are analysed for the first time. Regardless of whether springs have microbial or abiotic isotopic fingerprints, we find that bulk CH4 isotopes are fairly stable over a seven-year period. This suggests that the CH4 source(s) or postgenetic processes (such as oxidation and diffusion) have not undergone significant temporal changes. Major variations in H2 and CH4 concentrations in certain springs may be the result of changes in gas pressure and migration intensity. Paired CH4 clumped isotopes (Δ12CH2D2 - Δ13CH3D) were analysed in two bubbling springs, where the presence of CH4 can be interpreted as non-microbial based on 13C enrichment, absence of 14C, and the presence of ethane and propane. However, these isotopes are in disequilibrium, which prevents the quantification of the gas formation temperature. Within the Δ12CH2D2 - Δ13CH3D diagram, the data lie within both the microbialgenic zone, suggested by previous authors, and the abiotic zone that results combining data from laboratory gas synthesis and other natural gas samples. Therefore, attributing a microbial origin to CH4 based only on clumped isotopes is less definite than previously assumed. The amount of Total Organic Carbon appears to be correlated with the origin of CH4, as it is higher in 13C-depleted CH4 samples and lower in 13C-enriched samples. Palladium (Pd) and Rhodium (Rh) dissolved in water (the more soluble Platinum Group Elements) can be a proxy for the chromitite ore deposits contained in plagioclase tectonite layers throughout the investigated area, which may act as catalysts for abiotic CO2 hydrogenation. Clumped isotope disequilibrium and the reported absence of diffuse CH4-bearing fluid inclusions in the peridotites appear to rule out high temperature gas genesis in post-magmatic inclusions. These observations, along with the moderate temperatures at the base of the peridotite massifs and the consistent occurrence of gas along tectonic contacts between serpentinised (H2-bearing) peridotite and carbon-bearing rocks, are compatible with the theory of low-temperature CO2 hydrogenation

Stress echo 2020 : the international stress echo study in ischemic and non-ischemic heart disease

Background: Stress echocardiography (SE) has an established role in evidence-based guidelines, but recently its breadth and variety of applications have extended well beyond coronary artery disease (CAD). We lack a prospective research study of SE applications, in and beyond CAD, also considering a variety of signs in addition to regional wall motion abnormalities. Methods: In a prospective, multicenter, international, observational study design, > 100 certified high-volume SE labs (initially from Italy, Brazil, Hungary, and Serbia) will be networked with an organized system of clinical, laboratory and imaging data collection at the time of physical or pharmacological SE, with structured follow-up information. The study is endorsed by the Italian Society of Cardiovascular Echography and organized in 10 subprojects focusing on: contractile reserve for prediction of cardiac resynchronization or medical therapy response; stress B-lines in heart failure; hypertrophic cardiomyopathy; heart failure with preserved ejection fraction; mitral regurgitation after either transcatheter or surgical aortic valve replacement; outdoor SE in extreme physiology; right ventricular contractile reserve in repaired Tetralogy of Fallot; suspected or initial pulmonary arterial hypertension; coronary flow velocity, left ventricular elastance reserve and B-lines in known or suspected CAD; identification of subclinical familial disease in genotype-positive, phenotype- negative healthy relatives of inherited disease (such as hypertrophic cardiomyopathy). Results: We expect to recruit about 10,000 patients over a 5-year period (2016-2020), with sample sizes ranging from 5,000 for coronary flow velocity/ left ventricular elastance/ B-lines in CAD to around 250 for hypertrophic cardiomyopathy or repaired Tetralogy of Fallot. This data-base will allow to investigate technical questions such as feasibility and reproducibility of various SE parameters and to assess their prognostic value in different clinical scenarios. Conclusions: The study will create the cultural, informatic and scientific infrastructure connecting high-volume, accredited SE labs, sharing common criteria of indication, execution, reporting and image storage of SE to obtain original safety, feasibility, and outcome data in evidence-poor diagnostic fields, also outside the established core application of SE in CAD based on regional wall motion abnormalities. The study will standardize procedures, validate emerging signs, and integrate the new information with established knowledge, helping to build a next-generation SE lab without inner walls

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

SARS-CoV-2 Breakthrough Infections: Incidence and Risk Factors in a Large European Multicentric Cohort of Health Workers

The research aimed to investigate the incidence of SARS-CoV-2 breakthrough infections and their determinants in a large European cohort of more than 60,000 health workers

A Lei da Mediação de Conflitos: estudos sobre a sua aplicação

Financiamento de MEDLaw - FCT UIDB/04112/2020.Os dez anos de vigência da Lei da Mediação em Portugal constituíram o mote para a compilação nesta obra de diversos estudos empírico-dogmáticos sobre a sua aplicação, analisando-se questões prementes como a voluntariedade ou obrigatoriedade da mediação, a executoriedade do acordo de mediação e a Convenção de Singapura, as exigências processuais e a suspensão dos prazos de prescrição e caducidade com o recurso à mediação, a organização associativa dos mediadores e a importância da sua formação, o funcionamento dos sistemas públicos de mediação, bem como novas áreas de aplicação da mediação, em especial no domínio administrativo e na recuperação extrajudicial de empresas, e ainda a relevância do desenvolvimento científico sobre este meio de resolução de conflitos. Ao regulamentar num único diploma, pela primeira vez no nosso ordenamento jurídico, a mediação pública e privada, a Lei n.º 29/2013, de 19 de abril, constituiu um marco legislativo. Dez anos volvidos, importava refletir sobre a sua aplicação prático-jurídica, norteados pelo objetivo de promover o estudo e a efetiva implementação da mediação de conflitos em Portugal. Esta obra constitui o output desenvolvido no âmbito do projeto de investigação MEDLAW, com o apoio da Fundação para a Ciência e Tecnologia, no âmbito do financiamento base atribuído ao polo de Leiria do Instituto Jurídico Portucalense, com a ref. UIDB/04112/2020.info:eu-repo/semantics/publishedVersio

IgE to cross-reactive carbohydrate determinants (CCD) in childhood: Prevalence, risk factors, putative origins

background IgE antibodies to cross-reactive carbohydrate determinants (CCD) are usually clinically irrelevant but they can be a cause of false positive outcomes of allergen-specific IgE tests in vitro. their prevalence and levels have been so far cross-sectionally examined among adult allergic patients and much less is known about their origins and relevance in childhood. methods we examined CCD with a cross-sectional approach in 1263 Italian pollen allergic children (panallergen in paediatrics, PAN-PED), as well as with a longitudinal approach in 612 german children (Multicenter allergy Study, MAS), whose cutaneous and IgE sensitization profile to a broad panel of allergen extracts and molecules was already known. the presence and levels of IgE to CCD were examined in the sera of both cohorts using bromelain (MUXF3) as reagent and a novel chemiluminescence detection system, operating in a solid phase of fluorescently labelled and streptavidin-coated paramagnetic microparticles (NOVEOS, HYCOR, USA). resultsIgE to CCD was found in 22% of the Italian pollen allergic children, mainly in association with an IgE response to grass pollen. children with IgE to CCD had higher total IgE levels and were sensitized to more allergenic molecules of Phleum pratense than those with no IgE to CCD. among participants of the German MAS birth cohort study, IgE to CCD emerged early in life (even at pre-school age), with IgE sensitization to group 1 and 4 allergen molecules of grasses, and almost invariably persisted over the full observation period.ConclusionsOur results contribute to dissect the immunological origins, onset, evolution and risk factors of CCD-sIgE response in childhood, and raise the hypothesis that group 1 and/or 4 allergen molecules of grass pollen are major inducers of these antibodies through an antigen-specific, T-B cell cognate interaction.IgE antibodies to CCD in childhood, tested in the PAN-PED (cross-sectional approach) and MAS (longitudinal approach) cohorts, are as follows: (1) very frequent in patients with pollen allergy (22%, 275/1263), (2) associated with strong and broad IgE response to grass pollen, (3) emerging with IgE sensitization to grass group 1 and 4 allergens, (4) can start very early in life (positive IgE seen in second year of life) and (5) once started, are almost invariably persistent.imag