Whither Magnetic Hyperthermia? A Tentative Roadmap

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.This work was supported by the NoCanTher project, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 685795. The authors acknowledge support from the COST Association through the COST actions "RADIOMAG" (TD1402) and "MyWAVE" (CA17115). D.O., A.S.-O. and I.R.-R. acknowledge financial support from the Community of Madrid under Contracts No. PEJD-2017-PRE/IND-3663 and PEJ-2018-AI/IND-11069, from the Spanish Ministry of Science through the Ramon y Cajal grant RYC2018-025253-I and Research Networks RED2018-102626-T, as well as the Ministry of Economy and Competitiveness through the grants MAT2017-85617-R, MAT2017-88148R and the "Severo Ochoa" Program for Centers of Excellence in R&D (SEV-2016-0686). M.B. and N.T.K.T. would like to thank EPSRC for funding (grant EP/K038656/1 and EP/M015157/1) and AOARD (FA2386-171-4042) award. This work was additionally supported by the EMPIR program co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation program, grant no. 16NRM04 "MagNaStand". The work was further supported by the DFG grant CRC "Matrix in Vision" (SFB 1340/1 2018, no 372486779, project A02)

Dynamic Chromatin Organization during Foregut Development Mediated by the Organ Selector Gene PHA-4/FoxA

Central regulators of cell fate, or selector genes, establish the identity of cells by direct regulation of large cohorts of genes. In Caenorhabditis elegans, foregut (or pharynx) identity relies on the FoxA transcription factor PHA-4, which activates different sets of target genes at various times and in diverse cellular environments. An outstanding question is how PHA-4 distinguishes between target genes for appropriate transcriptional control. We have used the Nuclear Spot Assay and GFP reporters to examine PHA-4 interactions with target promoters in living embryos and with single cell resolution. While PHA-4 was found throughout the digestive tract, binding and activation of pharyngeally expressed promoters was restricted to a subset of pharyngeal cells and excluded from the intestine. An RNAi screen of candidate nuclear factors identified emerin (emr-1) as a negative regulator of PHA-4 binding within the pharynx, but emr-1 did not modulate PHA-4 binding in the intestine. Upon promoter association, PHA-4 induced large-scale chromatin de-compaction, which, we hypothesize, may facilitate promoter access and productive transcription. Our results reveal two tiers of PHA-4 regulation. PHA-4 binding is prohibited in intestinal cells, preventing target gene expression in that organ. PHA-4 binding within the pharynx is limited by the nuclear lamina component EMR-1/emerin. The data suggest that association of PHA-4 with its targets is a regulated step that contributes to promoter selectivity during organ formation. We speculate that global re-organization of chromatin architecture upon PHA-4 binding promotes competence of pharyngeal gene transcription and, by extension, foregut development

Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors

<p>Abstract</p> <p>Background</p> <p>Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established - namely, the Swarm Rat Chondrosarcoma (SRC) - and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy.</p> <p>Methods</p> <p>To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC.</p> <p>Results</p> <p>The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression.</p> <p>Conclusion</p> <p>This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that thymosin-β4 may have a role in chondrosarcoma metastasis.</p

Immediate Post-concussion and Cognitive Testing: Ceiling Effects, Reliability, and Implications for Interpretation

OBJECTIVE: The most commonly used computerized neurocognitive test in concussion assessment and management, Immediate Post-concussion and Cognitive Testing (ImPACT), has demonstrated varying and sometimes concerning levels of test-retest reliability. This study aimed to further examine ImPACT\u27s psychometric qualities and whether ceiling effects may suppress its reliability. METHOD: A total of 300 consecutively selected ImPACT score reports for students attending a secondary school between 2010 and 2015 were reviewed. Test-retest reliabilities for composite scores and subscales were computed using Pearson product moment correlations (r) and intraclass correlation coefficients. To examine the potential influence of ceiling effects, we conducted frequency analyses of scores falling at, or near, the maximum possible score. RESULTS: A total of 92 score reports met inclusion criteria. Test-retest reliabilities ranged from 0.42 to 0.69 for composite scores and 0.19 to 0.71 for subscales. Subscales comprising the Verbal and Visual Memory composites evidenced the most prominent ceiling effects. CONCLUSIONS: Obtained test-retest reliabilities were consistent with a large segment of the literature and add to concerns about ImPACT\u27s reliability. Furthermore, at least in a select sample, this study identified sizeable ceiling effects that likely diminish the reliability of some composite scores. To mitigate the risk of false-negative errors on post-injury testing, ImPACT users should be cognizant of such ceiling effects. Supplemental, or alternative, approaches to protect against underestimating baseline functioning also warrant consideration

An iron-oxide nanoparticle with therapeutic capability in Magnetic Fluid Hyperthermia and diagnostic capability in MRI and MPI

M55 belongs to a class of innovative nanomaterials, constituted by doped ferrite, with potential application in tumor therapy, as agents for Magnetic Fluid Hyperthermia (MFH), and in diagnosis, as contrast agents for MRI and MPI. Interestingly, such nanomaterials are characterized by a self-limiting temperature that can be modulated by adjusting the composition of the nanomaterial itself. M55 was coated with a double shell of citrate and glucose. We demonstrated that it has good capability as contrast agent for MRI and MPI. Moreover we tested its biocompatibility in a triple negative human breast cancer line and its efficacy as MFH agent in the same cell line. Despite relatively low SAR values in water solution, this agents was highly efficient in decreasing cell viability after two MFH treatments. Finally, we demonstrated that it can be useful to label cells for cell tracking in MPI. Although preliminary, these results are encouraging and push toward in vivo tests of such material.&nbsp

Doped Ferrite Nanoparticles Exhibiting Self-Regulating Temperature as Magnetic Fluid Hyperthermia Antitumoral Agents, with Diagnostic Capability in Magnetic Resonance Imaging and Magnetic Particle Imaging

Simple Summary Hyperthermia, a limited increase in tumor tissue temperature up to a maximum of 45 degrees C, has long been used in cancer treatment, either as a stand-alone therapy or in conjunction with chemo-/radiotherapy. Among the different physical procedures used, a particularly promising technique is magnetic fluid hyperthermia (MFH): this consists of the local administration of magnetic nanoparticles, followed by the application of alternating magnetic fields. One concern with this technique is the possibility of damage to healthy peritumoral tissue. The present study investigates innovative nanoparticles with self-regulating temperature, which should reduce this risk and thus mark a significant step forward in MFH. In an experimental model of aggressive breast cancer, we demonstrated a substantial reduction of tumor growth rate by using an experimental MFH protocol, transferable to clinical practice. These innovative nanomaterials present the added advantage of allowing non-invasive monitoring of temperature, by magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). This paper reports a comprehensive investigation of a magnetic nanoparticle (MNP), named M55, which belongs to a class of innovative doped ferrite nanomaterials, characterized by a self-limiting temperature. M55 is obtained from M48, an MNP previously described by our group, by implementing an additional purification step in the synthesis. M55, after citrate and glucose coating, is named G-M55. The present study aimed to demonstrate the properties of G-M55 as a diagnostic contrast agent for MRI and magnetic particle imaging (MPI), and as an antitumoral agent in magnetic fluid hyperthermia (MFH). Similar specific absorption rate values were obtained by standard MFH and by an MPI apparatus. This result is of interest in relation to the application of localized MFH by MPI apparatus. We demonstrated the biocompatibility of G-M55 in a triple-negative human breast cancer line (MDA-MB-231), and its efficacy as an MFH agent in the same cell line. We also demonstrated the efficacy of MFH treatment with G-M55 in an experimental model of breast cancer. Overall, our results pave the way for the clinical application of G-M55 as an MFH agent in breast cancer therapy, allowing not only efficient treatment by both standard MFH apparatus and MPI but also temperature monitoring

Zero valent iron core–iron oxide shell nanoparticles as small magnetic particle imaging tracers

Nanoparticle tracers with small sizes and large magnetization are critical for biomedical imaging and especially for magnetic particle imaging (MPI). Small size is important for accessing future intracellular and neurological in vivo applications Here, we sho