Radiobiological model for β-emitter radiopharmaceutical therapy in dynamic cell cultures in the framework of the ISOLPHARM project

In medical physics and radiobiology, the most common method to probe the efficacy of radiation therapy approaches in vitro is the cell survival trial. Recently, the traditional procedure for external beams has been extended by some groups to targeted radionuclides. In parallel, the bioengineering state of the art allows for the use of 3D tissue-mimicking scaffolds to obtain realistic cell cultures in dynamic conditions. The aim of this study is to implement a mathematical model for the assessment of β-emitting radiopharmaceuticals, considering their molecular kinetics in vitro and how it affects the radiation delivery to cells. The molecular transitions will be assumed to fulfill the definition of Markov processes, while the cell survival will depend on the DNA damage, in competition with a logistic growth. The solutions of the resulting differential system will be evaluated by means of numerical examples. This work belongs to the framework of the ISOLPHARM project, headed by INFN-LNL, which has the aim of developing innovative radiopharmaceuticals exploiting the Isotope Separation On-Line (ISOL) at the SPES facility

Monte Carlo based dosimetry using PET/CT and SPECT/CT imaging in radiopharmaceutical therapy in the context of the ISOLPHARM project

The ISOLPHARM project has the aim of producing a set of innovative, high specific activity, carrier-free radioisotopes for target radionuclide therapy exploiting the ISOL technique at the SPES facility of INFN-LNL. The success of a particular radiopharmaceutical cancer treatment relies on an accurate assessment of the tissue response and toxicity. Since biological effects are mediated by the absorbed dose, which is defined as the energy absorbed per unit mass of tissue, internal dosimetry is of funda- mental importance because it allows for the maximization of the therapeutic effect while minimizing the radiation burden to other organs. This thesis work consists in the calculation of internal absorbed dose, following radiopharmaceutical treatments — e.g. with 18 F, 111 In or 111 Ag — by means of different Monte Carlo based approaches (using the Geant4 software) coupled with PET/CT and SPECT/CT images of mice acquired by the ISOLPHARM group. Il progetto ISOLPHARM nasce con lo scopo di produrre una serie di radioisotopi innovativi per l’utilizzo in terapia radiofarmaceutica sfruttando la tecnica ISOL nella facility SPES di INFN-LNL. Il successo di un trattamento radiofarmaceutico su un tumore dipende da un’accurata valutazione della risposta del tessuto e della tossicità. Poiché gli effetti biologici sono mediati dalla dose assorbita, definita come energia assorbita per unità di massa del tessuto, la dosimetria interna è d’importanza fondamentale per permettere la massimizzazione dell’effetto terapeutico minimizzando l’irraggiamento degli altri organi. Il lavoro di tesi consiste nel calcolo della dose assorbita internamente a seguito di trattamenti radiofarmaceutici — per esempio con 18 F, 111 In o 111 Ag — avvalendosi di diversi approcci basati sul metodo Monte Carlo (utilizzando il software Geant4) abbinato a immagini PET/CT o SPECT/CT murine acquisite dal gruppo ISOLPHARM

Innovazione tecnologica e nuovi lavori nel settore medico - ospedaliero

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Radiobiological model for β-emitter radiopharmaceutical therapy in dynamic cell cultures in the framework of the ISOLPHARM project

In medical physics and radiobiology, the most common method to probe the efficacy of radiation therapy approaches in vitro is the cell survival trial. Recently, the traditional procedure for external beams has been extended by some groups to targeted radionuclides. In parallel, the bioengineering state of the art allows for the use of 3D tissue-mimicking scaffolds to obtain realistic cell cultures in dynamic conditions. The aim of this study is to implement a mathematical model for the assessment of β-emitting radiopharmaceuticals, considering their molecular kinetics in vitro and how it affects the radiation delivery to cells. The molecular transitions will be assumed to fulfill the definition of Markov processes, while the cell survival will depend on the DNA damage, in competition with a logistic growth. The solutions of the resulting differential system will be evaluated by means of numerical examples. This work belongs to the framework of the ISOLPHARM project, headed by INFN-LNL, which has the aim of developing innovative radiopharmaceuticals exploiting the Isotope Separation On-Line (ISOL) at the SPES facility

The novel therapeutic application of ketamine in the context of abuse potential and liability: a critical issue for old and new drugs.

La ketamina \ue8 stata sviluppata come sostituta della fenciclidina e, come essa, si \ue8 dimostrata un potente \u201canestetico dissociativo\u201d. Tuttavia, i pazienti hanno spesso riportato \u201cemergence phenomena\u201d durante il risveglio (Ashton, 1998). La ketamina ha altri importanti usi medici. In particolare, alcuni studi clinici hanno mostrato che una sua singola infusione induce una rapida risposta antidepressiva nei soggetti con depressione maggiore (Berman et al., 2000). Tuttavia, la selezione di possibili farmaci ketamine-like dovrebbe anche basarsi su una appropriata valutazione dei suoi effetti indesiderati (Burgdorf et al., 2013). Pertanto, una precoce identificazione e caratterizzazione delle reazioni avverse da ketamina pu\uf2 essere utile al fine di definire i composti pi\uf9 appropriati da introdurre nella pratica clinica. Tra l\u2019altro, proprio quegli effetti che hanno limitato l'uso clinico della ketamina ne hanno favorito l'uso a scopo ricreativo (Morgan e Curran, 2011). Il sistema di farmacovigilanza (FV) svolge un ruolo importante per studiare il profilo di sicurezza dei farmaci. Inoltre, l'ultima legislazione europea di FV ha modificato la definizione di reazione avversa da farmaco (ADR) al fine di comprendere effetti nocivi e non voluti derivanti anche da abuso, errore terapeutico, esposizione professionale, misuso, overdose e uso off-label di un farmaco ("Sezione 7" della scheda di segnalazione italiana). L'obiettivo principale di questo progetto di ricerca era quello di capire come la FV potesse fornire informazioni sul profilo di sicurezza della ketamina come antidepressivo, sul suo abuso e sulla \u201cabuse liability\u201d dei farmaci. Dapprima si sono analizzati alcuni studi clinici sull'uso antidepressivo della ketamina; dei 14 studi selezionati sono state considerate le ADR, ma purtroppo non \ue8 stato possibile eseguire una revisione sistematica o meta-analisi. Con la seconda analisi si sono analizzate le schede contenuti nel database dell'OMS al fine di confrontare il profilo di sicurezza della ketamina se utilizzata a dosi sub-anestetiche o anestetiche. Nonostante i diversi dosaggi, in entrambi i gruppi le ADR sono risultate correlate a disturbi psichiatrici e disturbi del sistema nervoso. Per avere informazioni sull'abuso di ketamina, in primo luogo, \ue8 stato analizzato il database italiano di FV per valutare l'impatto della nuova definizione di ADR e si sono trovate solo 2 schede riferite all'abuso di ketamina; solo in un caso era stata selezionata la "Sezione 7". \uc8 stato poi analizzato il database dell\u2019OMS. Sono state estratte 202 schede e anche in questo caso si \ue8 rilevato che le reazioni pi\uf9 comuni riguardavano disturbi del sistema nervoso, disturbi psichiatrici e disturbi renali e urinari. In conclusione, questa ricerca ha dimostrato che, in letteratura non si trovano dati sufficienti riguardanti la sicurezza da ketamina come antidepressivo sia a breve che a lungo termine tanto che non \ue8 possibile eseguire revisioni sistematiche o meta-analisi. Tuttavia, l'analisi delle segnalazioni spontanee che \ue8 stata condotta ha confermato che anche basse dosi di ketamina provocano ADR che coinvolgono disturbi nervosi e psichiatrici. D'altra parte, la sorveglianza post-marketing non ha fornito molti risultati riguardanti l\u2019abuso di ketamina nonostante l'introduzione della nuova definizione di ADR. Nell'ambito della PV, sono necessarie alcune implementazioni al fine di poter fornire pi\uf9 supporto e informazioni utili sulla \u201cabuse liability\u201d di un farmaco.Ketamine was developed as a replacement for phencyclidine and like it ketamine was shown to be a potent \u201cdissociative anaesthetic\u201d. However, patients often reported \u2018emergence phenomena\u2019 during recovering from ketamine anaesthesia (Ashton, 1998). Ketamine has other important medical uses. In particular, some clinical studies showed that its single infusion induced a rapid antidepressant response in subjects with Major Depression Disorder (Berman et al., 2000). However, the selection of candidates should also be based on an appropriate evaluation of undesired ketamine-like effects (Burgdorf et al., 2013). Thus, an early identification and characterization of ketamine adverse drug reactions (ADRs) may be relevant, along with preclinical and clinical abuse liability studies as requested by regulatory agencies, in order to define the most appropriate compounds to be introduced in clinical practice. In fact, precisely those effects that limited the clinical use of ketamine made the drug appealing to recreational drug users and the its recreational use has increased over recent years in the world (Morgan and Curran, 2011). The pharmacovigilance (PV) system may play a role to study the safety profile of a drug. The monitoring of spontaneous suspected ADR reports represents a key component of the integrated systems of PV. Furthermore, the latest European PV legislation amended the definition of ADR in order to comprise noxious and unintended effects resulting also from abuse, medication errors, misuse, occupational exposure, off-label use and overdose (in the Italian reporting form: \u201cSection 7\u201d). The main objective of this research project was to study how the data collected from PV reports can provide information on the use of ketamine as an antidepressant as well as on its abuse. A critical analysis was then carried out on the information obtained regarding ketamine to determine the PV contribution might offer in the context of abuse liability. Clinical trials regarding the antidepressant use of ketamine were analysed. The ADRs reported in fourteen studies were considered, but, unfortunately, it was impossible to carry out a systematic review or meta-analysis. The second analysis considered the reports in the WHO database in order to compare the safety profile of ketamine when used at sub-anaesthetic or anaesthetic doses. Most of the ADRs in both groups were related to \u201cpsychiatric disorders\u201d, followed by \u201cnervous system disorders\u201d. To obtain information regarding ketamine abuse, two analyses were performed. First, the database of the Italian PV Network was analysed to assess the impact of the new definition of ADR. In database, there were 2 ADR reports referred to ketamine abuse. Only in one case \u201cSection 7\u201d was filled in. In the final analysis, the WHO database was analysed to detect the reports referring to ketamine abuse. 202 reports were extracted; the apparatus most commonly involved was nervous system disorders, followed by psychiatric disorders and renal/urinary disorders. In conclusion, the results of this research have shown that in literature there is not enough data on safety of ketamine as an antidepressant with the result that it is not possible to create a safety profile relating to either its short or long term use. However, the analysis of spontaneous reports confirmed that even low doses of ketamine cause ADRs involving nervous and psychiatric disorders. On the other hand, post-marketing surveillance based on spontaneous reporting has not revealed any significant new information concerning the abuse of ketamine. In fact, despite the new definition of ADR, reports of ketamine abuse in Italy and worldwide have not increased. In the area of PV, some further implementations are necessary in order to provide more support and more useful information concerning drug abuse liability

Normalizing Spontaneous Reports into MedDRA: some Experiments with MagiCoder

Text normalization into medical dictionaries is useful to support clinical task. A typical setting is Pharmacovigilance (PV). The manual detection of suspected adverse drug reactions (ADRs) in narrative reports is time consuming and Natural Language Processing (NLP) provides a concrete help to PV experts. In this paper we carry on experiments for testing performances of MagiCoder, an NLP application designed to extract MedDRA terms from narrative clinical text. Given a narrative description, MagiCoder proposes an automatic encoding. The pharmacologist reviews, (possibly) corrects, and then validates the solution. This drastically reduces the time needed for the validation of reports with respect to a completely manual encoding. In previous work we mainly tested MagiCoder performances on Italian written spontaneous reports. In this paper, we include some new features, change the experiment design, and carry on more tests about MagiCoder. Moreover, we do a change of language, moving to English documents. In particular, we tested MagiCoder on the CADEC dataset, a corpus of manually annotated posts about ADRs collected from social media

From narrative descriptions to MedDRA: automagically encoding adverse drug reactions

The collection of narrative spontaneous reports is an irreplaceable source for the prompt detection of suspected adverse drug reactions (ADRs). In such task qualified domain experts manually revise a huge amount of narrative descriptions and then encode texts according to MedDRA standard terminology. The manual annotation of narrative documents with medical terminology is a subtle and expensive task, since the number of reports is growing up day-by-day. Natural Language Processing (NLP) applications can support the work of people responsible for pharmacovigilance. Our objective is to develop NLP algorithms and tools for the detection of ADR clinical terminology. Efficient applications can concretely improve the quality of the experts\u2019 revisions. NLP software can quickly analyze narrative texts and offer an encoding (i.e., a list of MedDRA terms) that the expert has to revise and validate. MagiCoder, an NLP algorithm, is proposed for the automatic encoding of free-text descriptions into MedDRA terms. MagiCoder procedure is efficient in terms of computational complexity. We tested MagiCoder through several experiments. In the first one, we tested it on a large dataset of about 4500 manually revised reports, by performing an automated comparison between human and MagiCoder encoding. Moreover, we tested MagiCoder on a set of about 1800 reports, manually revised ex novo by some experts of the domain, who also compared automatic solutions with the gold reference standard. We also provide two initial experiments with reports written in English, giving a first evidence of the robustness of MagiCoder w.r.t. the change of the language. For the current base version of MagiCoder, we measured an average recall and precision of and , respectively. From a practical point of view, MagiCoder reduces the time required for encoding ADR reports. Pharmacologists have only to review and validate the MedDRA terms proposed by the application, instead of choosing the right terms among the 70\u202fK low level terms of MedDRA. Such improvement in the efficiency of pharmacologists\u2019 work has a relevant impact also on the quality of the subsequent data analysis. We developed MagiCoder for the Italian pharmacovigilance language. However, our proposal is based on a general approach, not depending on the considered language nor the term dictionary

Adolescent lifestyle behaviors, coping strategies and subjective wellbeing during the COVID-19 pandemic: an online student survey

Adolescence represents a critical period for rapid psychophysical and socio-cognitive changes, with implications for health and wellbeing in later life. From this perspective, the manifestation of unhealthy lifestyles and dysfunctional behaviors may reflect a change in wellbeing requiring alertness and prompt intervention. This study investigated lifestyle behaviors and coping strategies among Italian adolescents, also in relation to the ongoing COVID-19 pandemic, and whether they would predict a change in subjective wellbeing

Resonant Laser Ionization and Fine-Structure Study of Silver in an Ablation Plume

We report on a laser photo-ionization study of silver in relation to the Selective Production of Exotic Species (SPES) project at INFN-LNL in the offline laser laboratory. In this study, two dye lasers and an ablation laser operating at 10 Hz are used alongside a time-of-flight mass spectrometer (TOF-MS). Isotopic separation of the natural, stable isotopes 107Ag and 109Ag was clearly observed in the TOF signal. Resonant photo-ionization of silver was achieved with the use of the scheme 4d105s 2S1/2→ 4d105p 2Po3/2→ 4d106d 2D3/2 with transition wavelengths of 328.163 nm and 421.402 nm, respectively. Doppler-suppressed spectroscopy of these transition lines was performed in an ablation plume. Doppler broadening with collinear injection of excitation lasers and the effect of the linewidths of the excitation lasers were investigated. The fine-structure splitting of the level 4d106d 2D (J = 5/2 and J = 3/2) was confirmed to be 186 ± 2 pm, corresponding to 314 ± 3 GHz