Molecular modelling and experimental studies of the interactions between biomolecules and nanostructured inorganic materials

In this study the interactions of biomacromolecules with different inorganic nanostructured materials were investigated using experimental and theoretical approaches. A deeper understanding on the fundamental steps involved for such interactions is very important for the fields of nanotechnology, medicine and biotechnology. In nanotechnology biomolecules like DNA have often been considered as templates for the scaffolding of nanoparticles. TEM observations of DNA molecules with Au55 cluster indicated the formation of equidistant gold nanowires. Interestingly the nanowires were composed of such dimensions that indicated that the Au55 cluster initially used was reduced to the size of a cluster with 13 gold atoms. In order to understand the formation of gold nanowires, various molecular modelling techniques were employed. Based on molecular mechanics simulations, it was found that Au55 cluster energetically prefers to interact with the major groove of B-DNA whereas Au13 prefers to associate with the major grooves of A-DNA. It is not clear how the reduction of Au55 to Au13 occurs however it is assumed that it is influenced by the dramatic alterations occurring in the groove geometry during B-DNA to A-DNA transition. The formation of gold nanowires is determined by the equidistant decoration of Au13 clusters around the major grooves of A-DNA. Molecular dynamics simulations indicated that the aggregation of such DNA-gold complexes leads to the formation of nanowires which are separated from each other almost 0.5 nm. The ability of Au55 to interact with the major grooves of B-DNA led to further investigations on the potential of this gold cluster as an anticancer drug. Gold-based compounds have not been studied as extensively as other metal-based drugs like platinum derivatives which have been employed as chemotherapeutic agents for many years in medical oncology. A variety of human cancer and healthy cell lines have been employed for investigating sensitivity towards Au55 and cisplatin. In vitro cytotoxicity assays performed by a colourimetric-based method (MTT) have indicated that generally Au55 is more toxic and efficient than cisplatin. Especially the cisplatin resistant metastatic melanoma cell lines exhibited the highest sensitivity towards Au55. Apoptotic or necrotic death influenced by Au55 was investigated by performing a fluorometric assay which measures the induction of the apoptotic proteins caspases 3 and 7. The effect of Au55 was different among the five cell lines investigated. In the case of the osteosarcoma cell line U-2OS induction of caspases 3 and 7 in the presence either of Au55 or cisplatin was observed indicating apoptosis being triggered. In the other four different cell lines the induction of caspases either in the presence of Au55 or cisplatin was similar to the controls. This indicates that these cells could be dying either by necrosis, or apoptosis is induced through a caspase-independent pathway. Further information on the cellular localisation and possible target has been investigated by measuring the distribution of radioactive gold cluster in various cellular fractions of the BLM cell line. It has been found that slightly higher amount of Au55 was located in the chromosomal DNA rather than in the cytoplasmic fraction. The Au55 was strongly bound to the chromosomal DNA with a very small fraction of it being present in the nuclear proteins. This has indicated that DNA is one of the main cellular targets however it is not certain whether such an interaction is directly related to the cytotoxic effect of Au55. The gold cluster could possibly damage the chromosomal DNA in the presence of H2O2 as indicated by the conversion of supercoiled plasmid DNA into open-circular form by agarose gel electrophoresis. Molecular docking simulations have shown the energetic preference of this agent for AATT sequences which is different to the GG and AG preference of cisplatin. Finally protein-gold cluster interactions could also play an important role on the cytotoxic effect of Au55. In vitro cytotoxicity assays in the presence of albumin have shown an increase in the IC50 values indicating a sequestering effect of albumin protein. Molecular docking simulations suggest the interaction of Au55 with specific cystein residues of human albumin. Nanostructured inorganic materials have been considered very important in the field of biotechnology with major applications aiming towards the immobilisation or purification of biomolecules such as proteins and amino acids. In this study the interactions of three different amino acids with a zeolite structure have been investigated using molecular modelling. MD simulations have been performed in the presence of water molecules with Phe, Lys and Glu being placed around the structure of zeolite beta. The simulations have indicated that amino acids energetically prefer to interact with the surface of the zeolite-beta rather being placed inside the pores or in the bulk. MD simulations clearly indicate the preference of Phe to adsorb through the formation of hydrogen bonds with the O atoms of the zeolite structure. The amino acids Lys and Glu have indicated a lower preference as the formation of fewer hydrogen bonds with the zeolite surface has been exhibited. This is in aggreement with experimental studies reported in the literature. Nevertheless MD simulations have not been able to distinguish any differences on the adsorption behavior of Glu and Lys

Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia

Identification of an optimal prolactin threshold to determine prolactinoma size using receiver operating characteristic analysis

Prolactinomas represent the most common type of secretory pituitary neoplasms, with a therapeutic management that varies considerably based on tumour size and degree of hyperprolactinemia. The aim of the current study was to evaluate the relationship between serum prolactin (PRL) concentrations and prolactinoma size, and to determine a cut-off PRL value that could differentiate micro- from macro-prolactinomas. A retrospective cohort study of 114 patients diagnosed with prolactinomas between 2007 and 2017 was conducted. All patients underwent gadolinium enhanced pituitary MRI and receiver operating characteristic (ROC) analyses were performed. 51.8% of patients in this study were men, with a mean age at the time of diagnosis of 42.32 ± 15.04 years. 48.2% of the total cohort were found to have microadenomas. Baseline serum PRL concentrations were strongly correlated to tumour dimension (r = 0.750, p = 0.001). When performing the ROC curve analysis, the area under the curve was 0.976, indicating an excellent accuracy of the diagnostic method. For a value of 204 μg/L (4338 mU/L), sensitivity and specificity were calculated at 0.932 and 0.891, respectively. When a cut off value of 204 μg/L (4338 mU/L) was used, specificity was 93.2%, and sensitivity 89.1%, acceptable to reliably differentiate between micro- and macro- adenomas

Principal components analysis based control of a multi-dof underactuated prosthetic hand

<p>Abstract</p> <p>Background</p> <p>Functionality, controllability and cosmetics are the key issues to be addressed in order to accomplish a successful functional substitution of the human hand by means of a prosthesis. Not only the prosthesis should duplicate the human hand in shape, functionality, sensorization, perception and sense of body-belonging, but it should also be controlled as the natural one, in the most intuitive and undemanding way. At present, prosthetic hands are controlled by means of non-invasive interfaces based on electromyography (EMG). Driving a multi degrees of freedom (DoF) hand for achieving hand dexterity implies to selectively modulate many different EMG signals in order to make each joint move independently, and this could require significant cognitive effort to the user.</p> <p>Methods</p> <p>A Principal Components Analysis (PCA) based algorithm is used to drive a 16 DoFs underactuated prosthetic hand prototype (called CyberHand) with a two dimensional control input, in order to perform the three prehensile forms mostly used in Activities of Daily Living (ADLs). Such Principal Components set has been derived directly from the artificial hand by collecting its sensory data while performing 50 different grasps, and subsequently used for control.</p> <p>Results</p> <p>Trials have shown that two independent input signals can be successfully used to control the posture of a real robotic hand and that correct grasps (in terms of involved fingers, stability and posture) may be achieved.</p> <p>Conclusions</p> <p>This work demonstrates the effectiveness of a bio-inspired system successfully conjugating the advantages of an underactuated, anthropomorphic hand with a PCA-based control strategy, and opens up promising possibilities for the development of an intuitively controllable hand prosthesis.</p

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) <= 2 cm: Study Protocol for a Prospective Observational Study

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017–2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach

the city and the river . stirrings

Με αφορμή τα αντιπλημμυρικά έργα που απαιτούνται, επιχειρείται ο επαναπροσδιορισμός της σχέση της πόλης της Άρτας με την παραποτάμια περιοχή του Άραχθου που την περιβάλλει. Λειτουργώντας αντίθετα με την λογική του εγκιβωτισμού, κατά την διάρκεια της πλημμύρας, το ποτάμι ανακτά το παλιό εύρος του. Προστατεύοντας με τις ελάχιστες παρεμβάσεις την ανθρώπινη παρουσία, τονίζουμε το χαρακτηριστικό της διαρκούς μεταβολής και την αίσθηση του εφήμερου. Το πέρασμα του νερού και του ανθρώπου γίνεται αντιληπτό σαν ίχνος αποτυπωμένο στη βλάστηση και το ανάγλυφο. Με αυτόν τον τρόπο ενεργοποιείται η λειτουργία της μνήμης, μια διαδικασία που βρίσκει το αποκορύφωμά της, στην συλλογική έκφανση της, καθώς κατά την διάρκεια της τεχνητής πλημμύρας που προκαλεί ο περιοδικός έλεγχος του υπερχειλιστή του φράγματος, θεσμοθετείται μια νέα δημόσια γιορτή, ενισχύοντας τη συνοχή της πόλης και δίνοντας ταυτόχρονα το έναυσμα για την πολιτισμική, εκπαιδευτική και οικονομική ανάπτυξη της. Τα παραπάνω συνδυάστηκαν με την χωροθέτηση της αναγκαίας επέκτασης του πολεοδομικού σχεδίου και την διευθέτηση της κυκλοφοριακής λειτουργίας, με βασικές επιδιώξεις, την συσχέτιση του καινούργιου τμήματος της πόλης με το ιστορικό της κέντρο, την ανάδειξη ενός τμήματος του ποταμού σε συνδετικό κρίκο ανάμεσα στα δύο μέρη και την αποσυμφόρηση του περιφερειακού δρόμου ο οποίος παρουσιάζει αυξημένη κίνηση και αποτελεί εμπόδιο στην προσέγγιση της παραποτάμιας περιοχής. Τέλος, σε μια προσπάθεια να δώσουμε μια λογική οργάνωσης στις λαβυρινθώδεις διαδρομές και την αποσπασματική αναγνώριση τυχαίων στιγμιότυπων της πόλης, εντυπώσεις που δημιουργεί ο φαινομενικά άναρχος τρόπος ανάπτυξης του πολεοδομικού ιστού, ορίζουμε δύο πεζοδρομημένες διαδρομές. Αυτές παρουσιάζουν διαφορετικά ποιοτικά χαρακτηριστικά , ξεκινούν και τελειώνουν ωστόσο στο ποτάμι, το οποίο για μία ακόμη φορά μετατρέπεται σε καίριο συντελεστή της ενίσχυσης της συνεκτικότητας της πόλης.The present project attempts to redefine the relationship between the town of Arta and the riparian zone of Araxthos, the river that surrounds it, given the fact that flood control measures because of the dam, consisted an important aspect. The basic idea was the return of the water in its initial riverbed during the flood by avoiding the encasement scenario. Thus we manage with the town boundary were most of our proposals lie on, leaving the riparian zone free of constructions and adding only paths were needed. Water and man become aware only as traces, when they are not really there, upon the vegetation and the topography. emphasizing the constant change and the sense of the ephemeral. The range of the area thought determined large scale interventions, so they had to be able to play multiple roles in the town’s reality, with most important the continuity of public space in the river front, as well as the need for a wide park besides the river arc. Aiming to make spaces that would bring people closer we started by the activation of the collective memory. To achieve that we came up with the idea of reversing the ‘flood – problem’ into an advantage by causing it ourselves. Therefore, the man made flood is going to establish a new public festival that is going to strengthen the cohesion between the civilians and constitute the trigger for cultural, educational and economic progress. Besides focusing on the river zone the project took two more directions to achieve its goal. The most important was the urban plan expansion that needed to be reconsidered as well as the connections and the traffic operation. The second one was the impact of the river arc upon the town planning. The river embraces the city so we proposed a sort of organization that stems of its topography by creating two axis that would organize the heart of the town and reveal the way towards the water.Κατερίνα ΜπουλουγούραΜαρία Τσώλ

Use of Long-Acting Injectable Antipsychotics in a Clinical Sample of Community-Dwelling Patients with Schizophrenia-Spectrum Disorders in Rural Greece

Data on the use of long-acting injectable antipsychotics (LAIs) in rural community mental healthcare settings are scarce. This study aimed to investigate the prescription patterns of LAIs in a clinical sample of patients with schizophrenia-spectrum disorders in rural Greece. All patients with schizophrenia-spectrum disorders who regularly attend the Mobile Mental Health Unit of the prefectures of Ioannina and Thesprotia (MMHU I-T) in northwestern Greece were included in the study. The sample consists of 87 patients (59 males and 28 females) with a mean age of 54.4 years and a mean illness duration of 28 years. Most patients (72.4%) received antipsychotic monotherapy, and nearly 30% received an LAI formulation, mostly a second-generation LAI (20 of 26 patients, 76.9%). The treatment regimen comprised benzodiazepines in one-third of the patients and antidepressants in one-quarter. There was no statistically significant association between treatment regimen and the clinical and demographic variables studied, except for biological sex (female). The percentage of patients treated with LAIs in this study was almost three times higher than the rate previously reported in Greece and is higher than the rates reported in other countries. Patients with schizophrenia-spectrum disorders in rural Greece may have adequate access to innovative treatment with second-generation LAIs. Further research is needed to demonstrate the cost-effectiveness of LAI treatment in rural communities and to elucidate the factors associated with such treatment

The annual incidence of Langerhans cell histiocytosis among adults living in Greece

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a variable clinical course and outcome. Although there are some data regarding its incidence in children, such information in adults is lacking. To address the actual annual LCH incidence among adults, we prospectively recorded, during a 12-month period, any new case with a definitive histological diagnosis of LCH, among persons aged 18 and older living in Greece. Fourteen new cases were recorded corresponding to an annual incidence of 1.58 per million population. Female to male ratio was 1.34, and mean age at diagnosis was 43.5 years

Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival : A Systematic Review and Meta-Analysis

The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53-1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24-3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease