Extremity exposure in nuclear medicine: preliminary results of a European study

The Work Package 4 of the ORAMED project, a collaborative project (2008-11) supported by the European Commission within its seventh Framework Programme, is concerned with the optimisation of the extremity dosimetry of medical staff in nuclear medicine. To evaluate the extremity doses and dose distributions across the hands of medical staff working in nuclear medicine departments, an extensive measurement programme has been started in 32 nuclear medicine departments in Europe. This was done using a standard protocol recording all relevant information for radiation exposure, i.e. radiation protection devices and tools. This study shows the preliminary results obtained for this measurement campaign. For diagnostic purposes, the two most-used radionuclides were considered: 99mTc and 18F. For therapeutic treatments, Zevalin® and DOTATOC (both labelled with 90Y) were chosen. Large variations of doses were observed across the hands depending on different parameters. Furthermore, this study highlights the importance of the positioning of the extremity dosemeter for a correct estimate of the maximum skin dose

Mechanisms of transcriptional regulation by SRF co-factors

Serum response factor (SRF) controls gene activation in response to changes in actin dynamics and mitogen-activated protein kinases. SRF has low intrinsic transcriptional activity and requires the recruitment of one of two families of co-activators: the MRTFs (myocardin-related transcription factors) and the TCFs (ternary complex factors). MRTFs are actin-binding proteins. Disruption of the actin-MRTF interaction is sufficient to induce MRTF nuclear accumulation and transcriptional activation. The TCF family are specifically activated by MAPK signalling. This thesis aims to elucidate how the SRF transcription network is controlled. The work presented encompasses two projects focused on each of the co-activator families. The regulation of MRTF shuttling from the cytoplasm to the nucleus is relatively well understood while its regulation once in the nucleus is still uncharacterized. The work demonstrates that nuclear MRTF activities are influenced by nuclear actin. Nuclear actin interferes with MRTF-DNA binding and target gene activation. In the presence of G-actin, nuclear MRTF can associate with target loci and recruit Pol II that, although traverses the gene body, does not generate stable mRNA. This inhibited state is accompanied by hypo-phosphorylation of the Pol II CTD. Dissociation of MRTF-actin interaction is required to re-establish Pol II phosphorylation and mRNA accumulation. The Erk-TCF signalling pathway was used to investigate how chromatin signatures are established in response to cues. Fibroblasts lacking all three TCFs, or reconstituted with mutant derivatives of the Elk-1 TCF were generated. Following Erk activation, chromatin immunoprecipitation and RNA-sequencing techniques, were employed to study the role of the TCFs in chromatin changes and transcriptional activation. It was possible to show that signal-induced chromatin changes occur in absence of transcription, and the specific chromatin signature requires Elk-1 DNA binding and phosphorylation. In addition analysis of the H3K27me3 mark demonstrated that Elk-1 activation is required to maintain a permissive chromatin landscape

Integration of transcriptional and metabolic control in macrophage activation

Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and stimulus-specific changes in gene expression programs accompanied by extensive rewiring of metabolism, with alterations in chromatin modifications providing one layer of integration of transcriptional and metabolic regulation. A systematic and mechanistic understanding of the mutual influences between signal-induced metabolic changes and gene expression is still lacking. Here, we discuss current evidence, controversies, knowledge gaps, and future areas of investigation on how metabolic and transcriptional changes are dynamically integrated during macrophage activation. The cross-talk between metabolism and inflammatory gene expression is in part accounted for by alterations in the production, usage, and availability of metabolic intermediates that impact the macrophage epigenome. In addition, stimulus-inducible gene expression changes alter the production of inflammatory mediators, such as nitric oxide, that in turn modulate the activity of metabolic enzymes thus determining complex regulatory loops. Critical issues remain to be understood, notably whether and how metabolic rewiring can bring about gene-specific (as opposed to global) expression changes

The use of Reamer–irrigator–aspirator in the management of long bone osteomyelitis: an update

Purpose: Reamer–irrigator–aspirator (RIA) is an innovative device that its indications have recently been expanded to the management of long bone infections. Methods: In this narrative review, we summarise the most important studies in the field and we present the current open questions pertaining to the use of RIA in the management of osteomyelitis of long bones. Results: The relevant literature is sparse and low quality. Nevertheless, the use of RIA for infected cases has yielded promising outcomes in specialised centres. Technical aspects that merit special attention in osteomyelitis of long bones are its inapplicability in small diameter long bones, the inadequate debridement of wide metaphyseal areas and the potential bleeding sequelae. The use of RIA in open fracture management to reduce infection risk has not gained acceptance. The antibiotic impregnated nails and rods constitute a complimentary strategy for the management of infections. Conclusions: The use of RIA for the management of long bone infections is an innovative and promising strategy. High quality studies are needed to shed light in its efficacy compared to conventional methods of management of osteomyelitis of long bones

NUCLEARE DA FISSIONE: STATO E PROSPETTIVE

Questo documento è stato redatto dal Comitato di Coordinamento sul nucleare da fissione e da altri colleghi ENEA esperti nel settore con l'obiettivo di effettuare lo 'stato dell'arte' e analizzare le prospettive di sviluppo del nucleare da fissione nel mondo, in Europa e in Italia. Esso vuole rappresentare solamente la base di partenza sulla quale sviluppare i necessari approfondimenti tematici, per un supporto più puntuale all'azione del Governo per il ritorno all'energia nucleare in Italia

Zc3h10 regulates adipogenesis by controlling translation and F-actin/mitochondria interaction

The commitment of mesenchymal stem cells to preadipocytes is stimulated by hormonal induction. Preadipocytes induced to differentiate repress protein synthesis, remodel their cytoskeleton, and increase mitochondrial function to support anabolic pathways. These changes enable differentiation into mature adipocytes. Our understanding of the factors that coordinately regulate the early events of adipocyte differentiation remains incomplete. Here, by using multipronged approaches, we have identified zinc finger CCCH-type containing 10 (Zc3h10) as a critical regulator of the early stages of adipogenesis. Zc3h10 depletion in preadipocytes resulted in increased protein translation and impaired filamentous (F)-actin remodeling, with the latter detrimental effect leading to mitochondrial and metabolic dysfunction. These defects negatively affected differentiation to mature adipocytes. In contrast, Zc3h10 overexpression yielded mature adipocytes with remarkably increased lipid droplet size. Overall, our study establishes Zc3h10 as a fundamental proadipogenic transcription factor that represses protein synthesis and promotes F-actin/mitochondria dynamics to ensure proper energy metabolism and favor lipid accumulation

Burkholderia Lethal Factor 1, a Novel Anti-Cancer Toxin, Demonstrates Selective Cytotoxicity in MYCN-Amplified Neuroblastoma Cells

Immunotoxins are being investigated as anti-cancer therapies and consist of a cytotoxic enzyme fused to a cancer targeting antibody. All currently used toxins function via the inhibition of protein synthesis, making them highly potent in both healthy and transformed cells. This non-specific cell killing mechanism causes dose-limiting side effects that can severely limit the potential of immunotoxin therapy. In this study, the recently characterised bacterial toxin Burkholderia lethal factor 1 (BLF1) is investigated as a possible alternative payload for targeted toxin therapy in the treatment of neuroblastoma. BLF1 inhibits translation initiation by inactivation of eukaryotic initiation translation factor 4A (eIF4A), a putative anti-cancer target that has been shown to regulate a number of oncogenic proteins at the translational level. We show that cellular delivery of BLF1 selectively induces apoptosis in neuroblastoma cells that display MYCN amplification but has little effect on non-transformed cells. Future immunotoxins based on this enzyme may therefore have higher specificity towards MYCN-amplified cancer cells than more conventional ribosome-inactivating proteins, leading to an increased therapeutic window and decreased side effects

Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer

Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion