Technology transfer from HEP computing to the medical field: overview and application to dosimetry

We show how nowadays it is possible to achieve the goal of accuracy and fast computation response in radiotherapic dosimetry using MonteCarlo methods, together with a grid computing model. We present a complete, fully functional prototype system for brachytherapy, entirely based on open source software systems originally developed for High Energy Physics experiments. It integrates a Geant4-based simulation component, an AIDA-based dosimetric analysis, a web-based user interface, and distributed processing either on a local computing farm or on geographically spread nodes. Thanks to the object-oriented approach adopted for the architecture, the work presented can be easily extended to become a general purpose dosimetric system, capable to address all radiotherapic techniques. An extension for application to dosimetric studies for IMRT is in progress

Incidence of temporomandibular joint clicking in adolescents with and without unilateral posterior cross-bite: a 10-year follow-up study

Among different malocclusions, posterior cross-bite is thought to have a strong impact on the correct functioning of the masticatory system. The association between unilateral posterior cross-bite (UPCB) and temporomandibular joint (TMJ) clicking, however, remains still controversial. The aim of this study was to investigate whether the presence of UCPB during early adolescence increases the risk of reporting TMJ clicking after a long-term follow-up. A longitudinal survey design was carried out in a group of 12-year-old young adolescents, who were examined at baseline for TMJ clicking sounds and unilateral posterior cross-bite. After 10 years, 519 subjects could be reached by a telephone survey. Standardised questions were used to collect self-reported TMJ sounds and to determine whether participants had received an orthodontic treatment. Logistic regression analysis revealed a significant association between unilateral posterior cross-bite and subjectively reported TMJ clicking (odds ratio = 6·0; 95% confidence limits = 3·4-10·8; P < 0·0001). The incidence of TMJ clicking was 12%. At a ten-year follow-up, self-reports of TMJ clicking were significantly associated with the presence of UPCB at baseline, but not with the report of having received an orthodontic treatment. Within the limitation of this study, the presence of unilateral posterior cross-bite in young adolescents may increase the risk of reporting TMJ sounds at a 10-year follow-up. The provision of an orthodontic treatment, however, does not appear to reduce the risk of reporting TMJ sounds

Synergistic effects of atomic oxygen and UV radiation on carbon/carbon plates at different attitude positions

Atomic oxygen (AtOx) is a major component of the space environment between 200 and 800 km (LEO-low Earth orbit region) and is the principal source of erosion for exposed aerospace structures. The damage to surface materials is proportional to the AtOx fluence, which depends on altitude, exposure time, orbital inclination, and solar activity, and it is caused by the formation of volatile oxides which do not adhere to the surface; furthermore, the mass loss may also be worsened by UV radiation, which increases the chemical degradation of the exposed material. Carbon/carbon (C/C) is an advanced ceramic composite that is frequently found as a base component of thermal protection systems (TPS), rocket nozzles, or other spacecraft subsystems. In this work, a simulation of the AtOx/UV synergistic effects on C/C plates exposed at different attitude positions were carried out by experimental tests performed at the Aerospace Systems Laboratory (LSA-Sapienza University of Rome) by means of an Atomic Oxygen OS-Prey RF plasma source, which also included a high-power UV-ray generator. The present experimental plan was built on the activity developed during recent years at LSA concerning the study of C/C materials for protecting aerospace structures from thermal shock in re-entry missions. The tests were conceived by considering a fixed time of exposure with a base fluence of 7.6 x 1019 n.s./cm2, as evaluated from the erosion of the reference samples exposed to AtOx flux at a normal incidence; the simulation of the different attitude positions was then analyzed, also considering the simultaneous effect of UV radiation. The results of the aging ground test suggest the following: (i) C/C oxidation in LEO must be taken into full consideration in the TPS design with reference to protective coating solutions, (ii) the LEO environment simulation is closely related to AtOx/UV combined irradiation, as well as to the spacecraft's in-orbit attitude

Oncogenic roles of GOLPH3 in the physiopathology of cancer

Golgi phosphoprotein 3 (GOLPH3), un effettore del fosfatidilinositolo 4-fosfato [PI (4) P] al Golgi, è necessaria per il mantenimento della struttura del nastro del Golgi, il traffico di vescicole e la glicosilazione del Golgi. GOLPH3 è stato convalidato come oncoproteina combinando la genomica integrativa con l'analisi clinopatologiche e funzionali. È spesso amplificato in diversi tipi di tumori solidi tra cui melanoma, cancro ai polmoni, cancro al seno, glioma e cancro del colon-retto. La sovraespressione di GOLPH3 è correlata a una prognosi infausta in più tipi di tumore, compreso il 52% dei tumori al seno e dal 41% al 53% del glioblastoma. I ruoli di GOLPH3 nella tumorigenesi possono essere correlati a diverse attività cellulari, tra cui: (i) regolazione del traffico dal Golgi alla membrana plasmatica e contributo a fenotipi secretori maligni; (ii) controllare l'internalizzazione e il riciclaggio di molecole di segnalazione chiave o aumentare la glicosilazione delle glicoproteine ​​rilevanti per il cancro; e (iii) influenzare la risposta al danno al DNA e il mantenimento della stabilità genomica. Qui riassumiamo le attuali conoscenze sui percorsi oncogeni che coinvolgono GOLPH3 nel cancro umano, l'influenza di GOLPH3 sul metabolismo del tumore e sullo stroma circostante e il suo possibile ruolo nella formazione di metastasi tumorali.Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation

Synergic stimulation of serotonin 5-HT1A receptor and &#945;2-adrenoceptors for neuropathic pain relief: Preclinical effects of 2-substituted imidazoline derivatives

Neuropathic pain affects millions of people causing disability and impairing quality of life. Commonly used analgesics are generally characterized by limited therapeutic outcomes. The serotonin 5-HT1A receptor and the α2 adrenergic receptors are involved in central nociceptive mechanisms with a pivotal role in the inhibitory descending pain pathway. Since their stimulation may modulate the nervous signaling altered by neuropathies, the purpose of the present research is the study of the combined activation of 5-HT1A and α2 receptors by rationally designed imidazoline ligands ((S)-(-)-1 and 2-5) in a rat model of neuropathic pain (chronic constriction injury - CCI). On day 14 after nerve damage, the acute administration per os (p.o.) of low doses of (S)-(-)-1 (0.1-1mg/kg) was able to significantly increase the pain threshold to mechanical noxious stimuli for more than 1h. (S)-(-)-1 efficacy was confirmed by the decrease of spontaneous pain evaluated as hind limb weight bearing alterations. The clinically-used compound gabapentin (100mg/kg p.o.) induced a pain relieving effect similar to (S)-(-)-1 administered at 100 fold lower dose. In the same model, the selected analogues, compounds 2-5 (1mg/kg p.o.) were effective 30min after administration. In particular, 5 fully reverted the CCI-induced hypersensitivity. The pain relieving activity of 5 was significantly prevented by the selective 5-HT1A receptor antagonist WAY 100635 (1mg/kg intraperitoneally, i.p.) and, at a lesser extent, by the α2 antagonist yohimbine (3mg/kg i.p.). A novel pharmacodynamic approach to the treatment of neuropathic pain is presented

Optical observations for energetic characterization of in-orbit explosion: the FREGAT-SB case

Over the past years, the constant increase of space debris and inactive satellites is the root cause of catastrophic events, such as collision between a debris and active satellites. One of the events that might generate a large number of debris is the in-orbit explosion. Within this complex framework, it is of paramount importance to use a monitoring and surveillance system in order to understand the number and the distribution of fragments, in an area around the Earth extremely populated by man-made object. This entails a growing international interest in Space Surveillance and Tracking (SST), where optical observation reaches an interesting method to obtain information of orbital objects. In this paper, the Sapienza Space Systems and Space Surveillance Laboratory (S5Lab) presents the results of an observative campaign focused on the energetical characterization of the explosion and the monitoring of the fragments, which have been generated by a low orbit explosion of the third Russian stage rocket FREGAT-SB (ID 37756). The event occurred on 08.05.2020 between 04:00 and 06:00 UTC time. Through the observatory system Sapienza Coupled University Debris Observatory (SCUDO) located in Collepardo (FR, Italy), a certain number of images have been collected. The observation strategy was focused on the orbital plane to try to estimate the number of these fragments and their distribution. Once the astrometry phase to retrieve the measures in terms of right ascension and declination was performed, a first analysis is carried on to understand whether or not the fragments are already present in the North American Aerospace Defense Command (NORAD) catalogue. The ones that are not catalogued could be FREGAT’s fragments. The next energetic characterization method is based on a tangential impulse assignment in agreement with isotropic explosion and the evolution of fragments’ cloud, where the important variations, to a first approximation, are on semiaxes and eccentricity. As a result of this procedure, an association between the impulse and the measure takes place. The analysis of the angular distance between original body and the fragments over the time is carried out, in order to validate this method. Moreover, a magnitude estimation procedure is shown. All these results are compared with those obtained with the NORAD assignment

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved

COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes

Congenital disorders of glycosylation (CDG) comprise a family of human multisystemic diseases caused by recessive mutations in genes required for protein N-glycosylation. More than 100 distinct forms of CDGs have been identified and most of them cause severe neurological impairment. The Conserved Oligomeric Golgi (COG) complexmediates tethering of vesicles carrying glycosylation enzymes across the Golgi cisternae. Mutations affecting human COG1, COG2 and COG4-COG8 cause monogenic forms of inherited, autosomal recessive CDGs.We have generated a Drosophila COG7-CDG model that closely parallels the pathological characteristics of COG7-CDG patients, including pronounced neuromotor defects associated with altered N-glycome profiles. Consistent with these alterations, larval neuromuscular junctions of Cog7 mutants exhibit a significant reduction in bouton numbers. We demonstrate that the COG complex cooperates with Rab1 and Golgi phosphoprotein 3 to regulate Golgi trafficking and that overexpression of Rab1 can rescue the cytokinesis and locomotor defects associated with loss of Cog7. Our results suggest that the Drosophila COG7-CDG model can be used to test novel potential therapeutic strategies by modulating trafficking pathways

Y RNA: an overview of their role as potential biomarkers and molecular targets in human cancers

Y RNA are a class of small non-coding RNA that are largely conserved. Although their discovery was almost 40 years ago, their function is still under investigation. This is evident in cancer biology, where their role was first studied just a dozen years ago. Since then, only a few contributions were published, mostly scattered across different tumor types and, in some cases, also suffering from methodological limitations. Nonetheless, these sparse data may be used to make some estimations and suggest routes to better understand the role of Y RNA in cancer formation and characterization. Here we summarize the current knowledge about Y RNA in multiple types of cancer, also including a paragraph about tumors that might be included in this list in the future, if more evidence becomes available. The picture arising indicates that Y RNA might be useful in tumor characterization, also relying on non-invasive methods, such as the analysis of the content of extracellular vesicles (EV) that are retrieved from blood plasma and other bodily fluids. Due to the established role of Y RNA in DNA replication, it is possible to hypothesize their therapeutic targeting to inhibit cell proliferation in oncological patients

Non-coding RNAs and endometrial cancer

Non-coding RNAs (ncRNAs) are involved in the regulation of cell metabolism and neoplastic transformation. Recent studies have tried to clarify the significance of these information carriers in the genesis and progression of various cancers and their use as biomarkers for the disease; possible targets for the inhibition of growth and invasion by the neoplastic cells have been suggested. The significance of ncRNAs in lung cancer, bladder cancer, kidney cancer, and melanoma has been amply investigated with important results. Recently, the role of long non-coding RNAs (lncRNAs) has also been included in cancer studies. Studies on the relation between endometrial cancer (EC) and ncRNAs, such as small ncRNAs or micro RNAs (miRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), antisense RNAs (asRNAs), small nuclear RNAs (snRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), competing endogenous RNAs (ceRNAs), lncRNAs, and long intergenic ncRNAs (lincRNAs) have been published. The recent literature produced in the last three years was extracted from PubMed by two independent readers, which was then selected for the possible relation between ncRNAs, oncogenesis in general, and EC in particular