Structure–function relationship and evolutionary history of the human selenoprotein M (SelM) found over-expressed in hepatocellular carcinoma

In humans we know 25 selenoproteins that play important roles in redox regulation, detoxification, immune-system protection and viral suppression. In particular, selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds, and can be implicated in calcium responses. However, it presents a redox motif (CXXU), where U is a selenocysteine, and may also function as redox regulator because its decreased or increased expression regulated by dietary selenium alters redox homeostasis. No data are reported in literature about its involvement in cancer but only in neurodegenerative diseases. In this paper we evaluated the SelM expression in two hepatoma cell lines, HepG2 and Huh7, compared to normal hepatocytes. The results suggested its involvement in hepatocellular carcinoma (HCC) as well as its possible use to follow the progression of this cancer as putative marker. The aim of this study has been to analyze the structure–function relationships of SelM. Hence, firstly we studied the evolutionary history of this protein by phylogenetic analysis and GC content of genes from various species. So, we modeled the three-dimensional structure of the human SelM evaluating its energetic stability by molecular dynamics simulations. Moreover, we modeled some of its mutants to obtain structural information helpful for structure-based drug design.     

ZnFe2O4‐C/LiFePO4‐CNT: A Novel High‐Power Lithium‐Ion Battery with Excellent Cycling Performance

An innovative and environmentally friendly battery chemistry is proposed for high power applications. A carbon‐coated ZnFe₂O₄ nanoparticle‐based anode and a LiFePO₄‐multiwalled carbon nanotube‐based cathode, both aqueous processed with Na‐carboxymethyl cellulose, are combined, for the first time, in a Li‐ion full cell with exceptional electrochemical performance. Such novel battery shows remarkable rate capabilities, delivering 50% of its nominal capacity at currents corresponding to ≈20C (with respect to the limiting cathode). Furthermore, the pre‐lithiation of the negative electrode offers the possibility of tuning the cell potential and, therefore, achieving remarkable gravimetric energy and power density values of 202 Wh kg^?1 and 3.72 W kg^?1, respectively, in addition to grant a lithium reservoir. The high reversibility of the system enables sustaining more than 10 000 cycles at elevated C‐rates (≈10C with respect to the LiFePO₄ cathode), while retaining up to 85% of its initial capacity.     

iPathology cockpit diagnostic station: validation according to College of American Pathologists Pathology and Laboratory Quality Center recommendation at the Hospital Trust and University of Verona

Background

Validation of digital whole slide images is crucial to ensure that diagnostic performance is at least equivalent to that of glass slides and light microscopy. The College of American Pathologists Pathology and Laboratory Quality Center recently developed recommendations for internal digital pathology system validation. Following these guidelines we sought to validate the performance of a digital approach for routine diagnosis by using an iPad and digital control widescreen-assisted workstation through a pilot study.

Methods

From January 2014, 61 histopathological slides were scanned by ScanScope Digital Slides Scanner (Aperio, Vista, CA). Two independent pathologists performed diagnosis on virtual slides in front of a widescreen by using two computer devices (ImageScope viewing software) located to different Health Institutions (AOUI Verona) connected by local network and a remote image server using an iPad tablet (Aperio, Vista, CA), after uploading the Citrix receiver for iPad. Quality indicators related to image characters and work-flow of the e-health cockpit enterprise system were scored based on subjective (high vs poor) perception. The images were re-evaluated two weeks apart.

Results

The whole glass slides encountered 10 liver: hepatocarcinoma, 10 renal carcinoma, 10 gastric carcinoma and 10 prostate biopsies: adenocarcinoma, 5 excisional skin biopsies: melanoma, 5 lymph-nodes: lymphoma. 6 immuno- and 5 special stains were available for intra- and internet remote viewing. Scan times averaged two minutes and 54 seconds per slide (standard deviation 2 minutes 34 seconds). Megabytes ranged from 256 to 680 (mean 390) per slide storage. Reliance on glass slide, image quality (resolution and color fidelity), slide navigation time, simultaneous viewers in geographically remote locations were considered of high performance score. Side by side comparisons between diagnosis performed on tissue glass slides versus widescreen were excellent showing an almost perfect concordance (0.81, kappa index).

Conclusions

We validated our institutional digital pathology system for routine diagnostic facing with whole slide images in a cockpit enterprise digital system or iPad tablet. Computer widescreens are better for diagnosing scanned glass slide that iPad. For urgent requests, iPad may be used. Legal aspects have to be soon faced with to permit the clinical use of this technology in a manner that does not compromise patient care.

     

Chemo-orientation responses in hymenopteran parasitoids induced by substrate-borne semiochemicals

Hymenopteran parasitoids can utilize substrate-borne semiochemicals released by conspecifics or by their hosts, increasing the likelihood of successful mating and host location. According to the literature, two substrate-borne chemo-orientation patterns can occur: (1) biased random searching, a non-directional reaction toward the chemicals (kinesis), and (2) trail-following searching, a directional response toward the source emitting the chemical compounds (taxis). These two different strategies can be adopted by parasitoids to locate hosts and mates. In host location, random searching is induced by allelochemicals indirectly associated with the host, whereas trail-following behavior is induced by allelochemicals directly emitted by the target organism. In mate finding, sex pheromones emitted by conspecifics can induce either the random searching or the trail-following behavior, although the spatial distribution of virgin conspecifics could be an important factor driving the evolution of substrate-borne chemo-orientation patterns. The chemical nature of substrate-borne semiochemicals has not yet been fully elucidated. Most studies have shown that crude extracts are biologically active for eliciting parasitoid arrestment response, but few studies have clearly characterized their chemical nature. However, experimental evidence indicates that cuticular lipids located in the external layer of insects’ bodies play a role in parasitoid–parasitoid and host–parasitoid communication. The ecological role of parasitoid chemo-orientation in host and mate location is discussed from a biological control perspective.     

Looking for long-term changes in hydroid assemblages (Cnidaria,Hydrozoa) in Alboran Sea (South-Western Mediterranean): a proposal of a monitoring point for the global warming

In the last 20–30 years, the temperature of the Mediterranean Sea has increased and global warming is allowing the establishment of tropical-affinity species into more temperate zones. Sessile communities are particularly useful as a baseline for ecological monitoring; however, a lack of historical data series exists for sessile marine organisms without commercial interest. Hydroids are ubiquitous components of the benthic sessile fauna on rocky shores and have been used as bio-indicators of environmental conditions. In this study on the benthic hydroid assemblages of the Chafarinas Islands (Alboran Sea, South-Western Mediterranean), we characterized the hydroid assemblages, identified the bathymetric gradients, and compared them with a previous study carried out in 1991. Hydroid assemblages showed a significant difference both between year and among depths. Furthermore, eight species not present in 1991 were found, including two possible new species and the tropical and subtropical species Sertularia marginata. Due to its strategic position at the entrance of the Mediterranean and the existence of previous data on hydroid assemblages, the Chafarinas Islands are proposed as a possible monitoring point for entrance of Atlantic tropical species into the Mediterranean Sea.     

Correlation between interaction strengths drives stability in large ecological networks

Food webs have markedly non‐random network structure. Ecologists maintain that this non‐random structure is key for stability, since large random ecological networks would invariably be unstable and thus should not be observed empirically. Here we show that a simple yet overlooked feature of natural food webs, the correlation between the effects of consumers on resources and those of resources on consumers, substantially accounts for their stability. Remarkably, random food webs built by preserving just the distribution and correlation of interaction strengths have stability properties similar to those of the corresponding empirical systems. Surprisingly, we find that the effect of topological network structure on stability, which has been the focus of countless studies, is small compared to that of correlation. Hence, any study of the effects of network structure on stability must first take into account the distribution and correlation of interaction strengths.     

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

Introduction

Pulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy.

Methods

Thirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A “good response” was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DL_CO) >15% and PaO₂ > 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved.

Results

Twenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease.

Conclusions

Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00573326","term_id":"NCT00573326"}}NCT00573326. Registered 13 December 2007.     

The current management of mycosis fungoides and Sézary syndrome and the role of radiotherapy: Principles and indications

Aim

To evaluate the current treatment of mycosis fungoides (MF) and Sézary syndrome (SS) focusing on the role of radiotherapy (RT), its principles and indications, and the perspectives of the novel irradiation technologies.

Background

MF and SS are rare lymphoproliferative diseases whose incidence is increasing. For a long time RT has been used as a single modality or in integrated treatment programs for these diseases.

Materials and methods

The latest systematic reviews, primary studies and new diagnostic and treatment guidelines on MF and SS were analyzed. Clinical outcomes together with the technical aspects and the role of RT were also evaluated.

Results

New data are available on pathogenesis, diagnostic criteria, classification and staging procedures for MF and SS and several local and systemic therapies are proposed. Localized RT can cure “minimal stage” MF while total skin electron beam irradiation (TSEI) may cure initial-stage disease and may offer important symptom relief (itch, erythroderma) in a more advanced setting. Despite its efficacy, RT is not largely used, mainly because of some technical difficulties but new RT technologies may be proposed to treat large skin surfaces.

Conclusions

New treatment programs offer good results, with median survival of more than 12 years in early-stage MF, but the median survival of 2.5 years or less in advanced stages is still a challenge. RT remains an option for all stages with a good cost/effectiveness ratio in a curative or palliative setting. New RT technologies can overcome some technical problems of treating large skin surfaces.     

Abacavir Induced T Cell Reactivity from Drug Na?ve Individuals Shares Features of Allo-Immune Responses

Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8⁺ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele (‘altered self-allele’) and create the potential for robust T cell responses.     

Emergence of Small-World Anatomical Networks in Self-Organizing Clustered Neuronal Cultures

In vitro primary cultures of dissociated invertebrate neurons from locust ganglia are used to experimentally investigate the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. At all the different stages of the culture''s development, identification of neurons'' and neurites'' location by means of a dedicated software allows to ultimately extract an adjacency matrix from each image of the culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main network''s characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graph''s micro- and meso-scale properties emerge. Finally, we identify the main physical processes ruling the culture''s morphological transformations, and embed them into a simplified growth model qualitatively reproducing the overall set of experimental observations.