Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties

Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the (99)mTc-labeled cyclic peptide beta Ala-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2 with that of the linear analog beta Ala-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of beta Ala, and the resulting pz-peptide conjugates were reacted with the fac-[Tc-99m(CO)(3)](+) moiety. The Tc-99m(CO)(3)-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic Tc-99m(CO)(3)-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear Tc-99m(CO)(3)-pz-peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle(4),DPhe(7))-alpha MSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively)

Thermal cycling effects on the durability of a pultruded GFRP material for off-shore civil engineering structures

AbstractThis paper investigates the effects of thermal cycles on the structural integrity of a pultruded Glass Fibre Reinforced Polymer (GFRP). Through a critical review of current literature alongside a comprehensive experimental campaign, the material’s response to cyclic thermal loading has been ascertained, defined by the rate of degradation of its physical, mechanical and visco-elastic properties. Matching sets of both dry and soaked samples conditioned in distilled water for 224days. Freeze–thaw cycling of both dry and soaked samples was conducted between 20°C and −10°C for a total of 300 cycles. Computed Tomography scanning (CT-scan) was undertaken to assess the microstructural physical changes throughout freeze–thaw cycling. After exposure, GFRP samples exhibited a minor decrease in glass transition temperature (Tg) which indicated minor structural degradation. Dry GFRP sample’s mechanical response exhibited negligible changes in both tensile and in-plane shear properties. However, as a result of the higher induced thermal stresses, soaked samples showed a significant degradation of their tensile and shear strengths. Yet, the soaked material’s stiffness remained largely unaffected due to the potential reversible nature of plasticization, which acts to increase the material’s molecular mobility when initially moisture-saturated, but is later recovered as the soaked samples lose moisture throughout freeze–thaw cycling

Computational approaches in antibody-drug conjugate optimization for targeted cancer therapy

WOS: 000444683500007PubMed ID: 30068276Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second-and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme [IF/00578/2014]; European Social Fund; Programa Operacional Potencial Humano; Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]; European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme [CENTRO-01-0145-FEDER-000008]; European Regional Development Fund (ERDF), COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation; Portuguese national funds via FCT [POCI-01-0145-FEDER-007440]; FCT [FCT-SFRH/BPD/97650/2013]; Fundacao para a Ciencia e Tecnologia (FCT), Portugal [UID/Multi/04349/2013]Irina S. Moreira acknowledges support by the Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme - IF/00578/2014 (co-financed by European Social Fund and Programa Operacional Potencial Humano), and a Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]. This work was also financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000008: Brain-Health 2020, and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-007440. Rita Melo acknowledges support from the FCT (FCT-SFRH/BPD/97650/2013). This work has been partially supported by the Fundacao para a Ciencia e Tecnologia (FCT), Portugal, through the UID/Multi/04349/2013 project in Centre for Nuclear Sciences and Technologies (C2TN)

Functionalization of Ruthenium(II) terpyridine complexes with cyclic RGD peptides to target integrin receptors in cancer cells

The lack of selectivity for cancer cells and the resulting negative impact on healthy tissue is a severe drawback of actual cancer chemotherapy. Tethering of cytotoxic drugs to targeting vectors such as peptides, which recognize receptors overexpressed on the surface of tumor cells, is one possible strategy to overcome such a problem. The pentapeptide cyc(RGDfK) targets the integrin receptor αvβ3, important for tumor growth and metastasis formation. In this work, two terpyridine based Ru(II) complexes were prepared and for the first time conjugated to cyc(RGDfK) via amide bond formation resulting in a monomeric and a dimeric bioconjugate. Both Ru(II) complexes bind strongly and selectively to integrin αvβ3, with the dimeric molecule displaying a 20-fold higher affinity to the receptor than the monomeric one. However, the cytotoxicity of the complexes and related bioconjugates against human A549 and SKOV-3 cell lines is still not sufficient for application as anticancer agents. Nevertheless, considering the high selectivity for integrin receptor αvβ3, the synthesis of Ru-based bioconjugates with cyc(RGDfK) paves a promising way towards the design of effective targeted anticancer agents

The effects of large-sided soccer training games and pitch size manipulation on time-motion profile, spatial exploration and surfaxe área: Tactical opportunities

Analysis of the physical, technical and physiological variations induced through the use of different soccer game formats have been widely discussed. However, the coaching justification for the specific use of certain game formats based on individual and collective spatial awareness is unclear. As a result, the purpose of this study was to analyze 11 versus 11 game formats conducted across two pitch sizes (half-size: 54 m × 68 m vs full-size: 108 m × 68 m) to identify effects of time–motion profiles, individual exploration behavior and collective organization. A total of 10 amateur soccer players from the same team (23.39 ± 3.91 years old) participated in this study. Data position of the players was used to calculate the spatial exploration index and the surface area. Distances covered in different speeds were used to observe the time–motion profile. The full-size pitch dimensions significantly contributed to greater distances covered via running (3.86–5.52 m s−1) and sprinting (>5.52 m s−1). Total distance and number of sprints were also significantly greater in the full-size pitch as compared to the half-size pitch. The surface area covered by the team (half-size pitch: 431.83 m2 vs full-size pitch: 589.14 m2) was significantly larger in the full-size pitch condition. However, the reduced half-size pitch significantly contributed to a greater individual spatial exploration. Results of this study suggest that running and sprinting activities increase when large, full-size pitch dimensions are utilized. Smaller surface area half-size pitch contributes to a better exploration of the pitch measured by spatial exploration index while maintaining adequate surface area coverage by the team. In conclusion, the authors suggest that the small half-size pitch is more appropriate for low-intensity training sessions and field exploration for players in different positions. Alternatively, the large full-size pitch is more appropriate for greater physically demanding training sessions with players focused on positional tactical behavio

Public awareness and engagement in relation to the coastal oil spill in northeast Brazil

Social media data is a rich source of information to assess human activities in catastrophic events. Here, we use social media data to understand how the 2019 Brazilian oil spill influenced social attitudes. Data were collected from the globally popular Instagram platform between August 1, 2019 and March 1, 2020. First, we manually identified the 5 most popular (portuguese language) hashtags related to the oil spill #oleonononordeste;#desastreambiental;#ma rsemoleo;#sosnordeste;#ma rsempetroleo. In the sequence, we collected information on captions, post metadata and users associated with posts retrieved using the selected hashtags. We identified a total of 7,413 posts. These posts were grouped in topics: government (47.76%), protest (24.37%), volunteers (24.45%), biodiversity (0.003%), origin (0.006%), tourism (0.008%) and others (0.016%). All topics had the peak of posts in October and November 2019. Nevertheless, interest in the oil spill was temporary, with most posts appearing in the 2-4 months after the beginning of the disaster. Our findings illustrate the enormous potential of using social media data for understanding and monitoring human engagement with environmental disasters, but also suggest that conservationists and environmental groups may only have a limited 'window of opportunity' to engage and mobilize public support for remediation and restoration efforts.Peer reviewe

Perturbed Angular Correlation Study of the Static and Dynamic Aspects of Cadmium and Mercury Atoms Inside and Attached to a C-60 Fullerene Cage

30 keV Cd-111m and 50 keV Hg-199m beams from ISOLDE were used to implant on preformed targets of C-60 with a thickness of 1 mg cm(-2). Endofullerene compounds, viz. Cd-111m@C-60 and Hg-199m@C-60 formed during implantation were separated by filtration through micropore filter paper followed by solvent extraction. Dried samples of the endofullerene compounds were counted for the time differential perturbed angular correlation (TDPAC) measurement using the coincidence of the 151-245 keV cascade of Cd-111m and the 374 158 keV cascade of Hg-199m on a six LaBr3(Ce) detector system coupled with digital electronics. The results for 111mCd@C60 indicate a single static component (27%) and a fast relaxing component (73%), the latter implying that the cadmium atom moves rapidly inside the cage at room temperature. The quadrupole interaction frequency and asymmetry parameter of the cadmium atom occupying the static site in C60 are omega(Q) = 8.21(36) Mrad s(-1) and eta = 0.41(9), respectively. The fast relaxation constant is 0.0031(4) ns(-1). Similarly, mercury atoms also exhibit a single static and a fast component. The static site has a quadrupole frequency omega(Q) = 283.0(12.4) Mrad s-1 and eta = 0 with a fraction of 30%. The fast relaxation constant is 0.045(8) ns(-1) with a fraction of 70%, very similar to that of cadmium

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

International audienc

Physical Activity Is Associated With Improved Eating Habits During the COVID-19 Pandemic

The aim of this study was to analyze the association between physical activity andeating habits during the COVID-19 pandemic among Brazilian adults. A sample of1,929 participants answered an online survey, however 1,874 were included in theanalysis. The impact of the COVID-19 pandemic on eating habits was assessedinquiring about participants’ intake of fruits, vegetables, fried foods, and sweetsduring the pandemic. Physical activity was assessed by asking participants abouttheir weekly frequency, intensity and number of minutes/hours engaging in structuredphysical activities per week. Participants were then stratified into categories based onmoderate-to-vigorous intensity (0–30; 31–90; 91–150; 151–300; and >300 min/week)and into active (≥150 min) or inactive (<150 min). Increased sweets consumption wasthe most commonly reported change to eating habits (42.5%), followed by an increase inthe consumption of vegetables (26.6%), fruits (25.9%), and fried foods (17.9%). Physicalactivity practice was related to lower consumption of fried foods (OR = 0.60; p < 0.001)and sweets (OR = 0.53; p < 0.001). A cluster analysis revealed subjects with higherthe level of physical activity was more likely to follow a healthy diet (p < 0.001). Thus,physical activity was positively associated with healthier eating habits. Health authoritiesmust recommend regular physical as a strategy to improve overall health during theCOVID-19 pandemic. Future studies should address the physical activity interventionsto improve health status during a pandemic

Increased Screen Time Is Associated With Alcohol Desire and Sweetened Foods Consumption During the COVID-19 Pandemic

Background: Elevated screen time has been associated with addictive behaviors, such as alcohol and sugar intake and smoking. Considering the substantial increase in screen time caused by social isolation policies, this study aimed to analyze the association of increased screen time in different devices during the COVID-19 pandemic with consumption and increased desire of alcohol, smoking, and sweetened foods in adults. Methods: A sample of 1,897 adults with a mean age of 37.9 (13.3) years was assessed by an online survey, being composed by 58% of women. Participants were asked whether screen time in television, cell phone, and computer increased during the pandemic, as well as how much time is spent in each device. Closed questions assessed the frequency of alcohol and sweetened food consumption, smoking, and an increased desire to drink and smoke during the pandemic. Educational level, age, sex, feeling of stress, anxiety, depression, and use of a screen device for physical activity were covariates. Binary logistic regression models considered adjustment for covariates and for mutual habits. Results: Increased television time was associated with increased desire to drink (OR = 1.46, 95% CI: 1.12; 1.89) and increased sweetened food consumption (OR = 1.53, 95% CI: 1.18; 1.99), while an increase in computer use was negatively associated with consumption of alcohol (OR = 0.68, 95% CI: 0.53; 0.86) and sweetened foods (OR = 0.78, 95% CI: 0.62; 0.98). Increased cell phone time was associated with increased sweetened food consumption during the pandemic (OR = 1.78, 95% CI: 1.18; 2.67). Participants with increased time in the three devices were less likely to consume sweetened foods for ≥5 days per week (OR = 0.63, 95% CI: 0.39; 0.99) but were twice as likely to have sweetened food consumption increased during pandemic (OR = 2.04, 95% CI: 1.07; 3.88). Conclusion: Increased screen time was differently associated with consumption and desire for alcohol and sweets according to screen devices. Increased time in television and cell phones need to be considered for further investigations of behavioral impairments caused by the pandemic