Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba ¼ S–C6H4–COO) bound to gold(I)-phosphane fragments through a thiolate group [(h-C5H5)2TiMe(m-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(h-C5H5)2TiMe(m-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(h-C5H5)2Ti {OC(O)-4-C6H4-P(Ph2)AuCl}2] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds

Lipid-based nanostructures as a strategy to enhance curcumin bioaccessibility: behavior under digestion and cytotoxicity assessment

The aim of this study was to evaluate the behavior of different lipid-based nanostructures during in vitro digestion, in particular on curcumins bioaccessibility, and to access their potential toxicity. Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions (NE) were submitted to harmonized static in vitro digestion and their cytotoxicity and cellular transport were evaluated using Caco-2 cell line. NE presented the highest curcumins bioaccessibility followed by NLC and SLN, 71.1%, 63.7% and 53.3%, respectively. Free fatty acids percentage increased in the following order: NLC ? NE < SLN. Non-digested nanostructures and excipients presented no cytotoxicity; however, digested NE and NLC presented cytotoxicity due to MCT oil, which presented cytotoxicity after digestion. The apparent permeability coefficient of NLC was higher than SLN and NE. These results showed that lipid-based nanostructures physical state and composition have a high influence on particles' behavior during digestion, and on their cytotoxicity/intestinal permeability, and highlights the importance of conducting cytotoxicity assessments after in vitro digestion. This work contributes to a better understanding of the behavior of lipid-based nanostructures under digestion/adsorption, and this knowledge will be useful in design of nanostructures that afford both safety and an increased bioactive compounds bioavailability.Acknowledgments Raquel F. S. Goncalves acknowledge the Foundation for Science and Technology (FCT) for her fellowship (SFRH/BD/140182/2018) . This study was supported by Foundation for Science and Technology (FCT) under the scope of Project PTDC/AGRTEC/5215/2014, the strategic funding of UIDB/04469/2020 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020Programa Operacional Regional do Norte. Funding from INTERFACE Programme through the Innovation, Technology and Circular Economy Fund (FITEC) and iNova4Health, a program also financially supported by Fundacao para a Ciencia eTecnologia, is also gratefully acknowledged.info:eu-repo/semantics/publishedVersio

How can I integrate iEEG recordings with patients’ brain anatomy?

Preparing intracranial electroencephalography (iEEG) datasets for analysis presents a unique set of methodological challenges that are absent in non-invasive investigative techniques. Because iEEG is primarily used in epilepsy patients with varying brain pathologies, the main challenges pertain to variability in electrode coverage and therefore the regions of the brain from which electrophysiological recordings can be obtained. In this chapter, we outline how to efficiently integrate the raw anatomical images and electrophysiological recordings during preprocessing, allowing iEEG datasets to be analyzed in an anatomically precise and consistent way

Custom-molded headcases have limited efficacy in reducing head motion for fMRI

Effectively minimizing head motion continues to be a challenge for the collection of functional magnetic resonance imaging (fMRI) data. The development of individual-specific custom molded headcases have been offered as a promising solution to minimizing motion during data collection, but to date, only a single published investigation into their efficacy exists in the literature. That study found headcases to be effective in reducing motion during short resting state fMRI scans (Power et al, 2019). In the present work, we examine the efficacy of these same headcases in reducing motion for a larger group of participants engaged in naturalistic scanning paradigms that consist of long movie-watching scans (~20-45min), as well as speaking aloud inside the MRI. Unlike previous work, we find no reliable reduction in head motion during movie viewing when comparing participants with headcases to those who were simply situated with foam pillows or foam pillows with medical tape. Surprisingly, we also find that for those wearing headcases, head motion is worse while talking relative to those situated with just foam pillows. These differences appear to be driven by large brief rotations of the head as well as translations in the z-plane as participants speak. Smaller, constant head movements appear equivalent with or without headcases. The largest reductions in head motion are observable when participants were situated with both foam pillows and medical tape, consistent with recent work by Kraus and colleagues (2019). Altogether, this work suggests that in a non-clinical, non-developmental population, custom-molded headcases may provide limited efficacy in reducing head motion beyond existing tools available to researchers. We hope this work can help improve the quality of custom headcases, motivate the investigation of additional solutions, as well as help researchers make more informed decisions about their data acquisition procedures

Synchronized affect in shared experiences strengthens social connection

People structure their days to experience events with others. We gather to eat meals, watch TV, and attend concerts together. What constitutes a shared experience and how does it manifest in dyadic behavior? The present study investigates how shared experiences - measured through emotional, motoric, and cognitive alignment - promote social bonding. We recorded facial expressions of participants as they watched four episodes of a TV show for a total of four hours with another participant. After each episode, participants rated their impressions of each character and reported how connected they felt to their viewing partner. We found that participants displayed temporally and spatially synchronized emotional facial expressions and the amount of synchrony predicted perceived social connection between viewing partners. Dyads who shared similar impressions of characters also reported feeling more connected. We found that all three of these processes independently contributed to a latent factor of a shared experience that predicted social connection with temporal synchrony explaining the most variance. Our findings suggest that the development of interpersonal affiliations in shared experiences emerges from shared affective experiences comprised of multiple synchronous processes and demonstrate that these complex interpersonal processes can be studied in a holistic and unified framework leveraging naturalistic experimental designs

Effective Elimination of Cancer Stem Cells by Magnetic Hyperthermia

Cancer stem cells (CSCs) are a subpopulation of cancer cells that have stem cell-like properties and are thought to be responsible for tumor drug resistance and relapse. Therapies that can effectively eliminate CSCs will, therefore, likely inhibit tumor recurrence. The objective of our study was to determine the susceptibility of CSCs to magnetic hyperthermia, a treatment that utilizes superparamagnetic iron oxide nanoparticles placed in an alternating magnetic field to generate localized heat and achieve selective tumor cell kill. SPIO NPs having a magnetite core of 12 nm were used to induce magnetic hyperthermia in A549 and MDA-MB-231 tumor cells. Multiple assays for CSCs, including side population phenotype, aldehyde dehydrogenase expression, mammosphere formation, and <i>in vivo</i> xenotransplantation, indicated that magnetic hyperthermia reduced or, in some cases, eliminated the CSC subpopulation in treated cells. Interestingly, conventional hyperthermia, induced by subjecting cells to elevated temperature (46 °C) in a water bath, was not effective in eliminating CSCs. Our studies show that magnetic hyperthermia has pleiotropic effects, inducing acute necrosis in some cells while stimulating reactive oxygen species generation and slower cell kill in others. These results suggest the potential for lower rates of tumor recurrence after magnetic hyperthermia compared to conventional cancer therapies