9 research outputs found
Use of health apps and wearable devices : Survey among Italian associations for patient advocacy
No full textBackground: Technological tools such as Web-based social networks, telemedicine, apps, or wearable devices are becoming more widespread in health care like elsewhere. Although patients are the main users, for example, to monitor symptoms and clinical parameters or to communicate with the doctor, their perspective is seldom analyzed, and to the best of our knowledge, no one has focused on the patients’ health care advocacy associations’ point of view. Objective: The objective of this study was to assess patients’ health care advocacy associations’ opinions about the use, usefulness, obstacles, negative aspects, and impact of health apps and wearable devices through a Web-based survey. Methods: We conducted a Web-based survey through SurveyMonkey over nearly 3 months. Participants were contacted via an email explaining the aims of the survey and providing a link to complete the Web-based questionnaire. All the 20 items were mandatory, and the anonymized data were collected automatically into a database. Only fully completed questionnaires were considered for analysis. Results: We contacted 1998 patients’ health care advocacy associations; a total of 258 questionnaires were received back (response rate 12.91%), and 227 of the received questionnaires were fully completed (completion rate 88.0%). Informative apps, hospital apps for viewing medical reports or booking visits, and those for monitoring physical activity are the most used. They are considered especially useful to improve patients’ engagement and compliance with treatment. Wearable devices to check physical activity and glycemia are the most widespread considering, again, their benefits in increasing patients’ involvement and treatment compliance. For health apps and wearable devices, the main obstacles to their use are personal and technical reasons; the risk of overmedicalization is considered the most negative aspect of their constant use, while privacy and confidentiality of data are not rated a limitation. No statistical difference was found on stratifying the answers by responders’ technological level (P=.30), age (P=.10), and the composition of the association’s advisory board (P=.15). Conclusions: According to responders, health apps and wearable devices are sufficiently known and used and are considered potential supports for greater involvement in health management. However, there are still obstacles to their adoption, and the developers need to work to make them more accessible and more useful. The involvement of patients and their associations in planning services and products based on these technologies (as well as others) would be desirable to overcome these barriers and boost awareness about privacy and the confidentiality of data
Transparency in ovarian cancer clinical trial results : ClinicalTrials.gov versus PubMed, Embase and Google scholar
No full textBackground: In recent years the question of the lack of transparency in clinical research has been debated by clinicians, researchers, citizens and their representatives, authors and publishers. This is particularly important for infrequent cancers such as ovarian cancer, where treatment still gives disappointing results in the majority of cases. Our aim was to assess the availability to the public of results in ClinicalTrials.gov, and the frequency of non-publication of results in ClinicalTrials.gov and in PubMed, Embase and Google Scholar. We collected all trials on ovarian cancer identified as "completed status" in the ClinicalTrials.gov registry on 17 January 2017. We checked the availability of the results in ClinicalTrials.gov and systematically identified published manuscripts on results. Results: Out of 2725 trials on ovarian cancer identified, 752 were classified as "completed status". In those closed between 2008 and 2015, excluding phase I, the frequency of results in ClinicalTrials.gov was 35%. Of the 752 completed studies the frequency of published results in PubMed, Embase or Google Scholar ranged from 57.9% to 69.7% in the last years. Conclusions: These findings show a lack of transparency and credibility of research. Citizens or patients' representatives, with the medical community, should continuously support initiatives to improve the publication and dissemination of clinical study results
QUANTITATIVE LIPIDOMICS AND PROTEOMICS IN MEDICINAL CHEMISTRY
No full textLe scienze omiche sono attualmente in fase di sviluppo offrendo una nuova prospettiva dell'ambiente cellulare e dell'organismo. Tra queste, la genomica e la proteomica sono tra le più sviluppate. Al contrario, la lipidomica è ancora un campo emergente. L'importanza di fornire un forte approccio metodologico abbinato ad una rigorosa interpretazione dei dati è spiegata dalla recente scoperta del ruolo chiave dei lipidi come componenti strutturali e fonte energetica ma anche in molti processi biologici (secondi messaggeri, regolatori delle interazioni intercellulari e di carica superficiale, coinvolgimento in malattie metaboliche, cancro ecc.).
La spettrometria di massa, grazie ai recenti e significativi progressi, è il metodo analitico più adatto in molte delle scienze omiche nonostante la loro integrazione sia ancora agli inizi e sia necessaria un'attenta ottimizzazione dei protocolli. Tuttavia, considerata la complessità molecolare, solo una visione multi-omica può darci un quadro completo dei processi intra- ed extra-cellulari in condizioni fisiologiche e patologiche nonché in risposta ad un'esposizione ambientale o chimica per contribuire infine al campo della medicina di precisione.
Il progetto di ricerca qui presentato mira quindi a fornire prospettive di proteomica e lipidomica, sia come approccio singolo che integrato, a diverse domande di ricerca mediante spettrometria di massa ad alta risoluzione.
L'indagine sul proteoma cutaneo di topi glabri mi ha permesso di mostrare come il peptide endogeno β-alanil-L-istidina (carnosina) agisca in difesa dei danni UV-A. Infatti, diversi importanti sistemi proteici hanno mostrato un'alterazione del trattamento con UV-A tra cui il pathway di segnale del calcio, la funzione mitocondriale o l'espressione della sirtuina, che sono stati tutti ripristinati da un trattamento preventivo della pelle mediante un'applicazione topica di carnosina. Queste alterazioni proteomiche potrebbero derivare (almeno in parte) da ROS generati da UV-A, o/e dalla generazione di prodotti di ossidazione lipidica (HNE, acroleina) derivanti dalla perossidazione di acidi grassi polinsaturi. L'implicazione di tali agenti è enfatizzata dalla potente efficacia del trattamento nel ripristinare un normale profilo proteomico delle pelli trattate con UV-A, in accordo con la sua capacità di neutralizzare la formazione di addotti sulle proteine e la loro successiva modificazione, ripristinando così la loro funzione.
Passando alla lipidomica, l'importanza biologica recentemente dimostrata dagli esteri degli acidi grassi degli idrossiacidi grassi (FAHFA) ha richiesto l'ottimizzazione di un metodo su misura per la loro identificazione e quantificazione nella matrice umana. Infatti, crescenti evidenze sui ruoli fisiologici dei FAHFA, compresi quelli antinfiammatori, antidiabetici e immunomodulatori, motivano una più ampia caratterizzazione di questi lipidi come possibili biomarcatori e bersagli terapeutici per condizioni patologiche come il diabete o l'obesità. Tuttavia, la bassa concentrazione nei tessuti umani, la grande eterogeneità della struttura e il fatto che la maggior quantità di FAHFAs nelle cellule è incorporata nei trigliceridi sfidano gli attuali metodi analitici per la loro accurata identificazione e quantificazione. La preparazione dei campioni ottenuta e l'ottimizzazione del metodo strumentale hanno tuttavia permesso con successo di isolare, rilevare e quantificare per la prima volta FAHFA endogeni sul tessuto adiposo umano indicando alterazioni significative basate sullo stato metabolico (soggetti obesi insulino-sensibili o resistenti vs soggetti magri) e porzioni di tessuto adiposo (viscerale vs sottocutaneo). Questi risultati saranno utili per comprendere meglio le potenzialità biologiche di questi lipidi bioattivi nelle patologie metaboliche.
Infine, i due studi multi-omici condotti in questo percorso di dottorato hanno avuto rispettivamente lo scopo di valutare gli effetti molecolari dell'acido ialuronico a basso peso molecolare (LMW-HA) nel proteoma e lipidoma di fibroblasti dermici umani e di analizzare i cambiamenti del profilo lipidomico e proteomico indotti dal trattamento di prevenzione con γ-Orizanolo in ratti obesi.
LMW-HA ha mostrato un impatto sia sul profilo proteomico che lipidico, principalmente a una concentrazione pari allo 0.50%. I risultati di proteomica non solo sono stati confermati ma anche corroborati da quelli di lipidomica e dall’integrazione dei due approcci. Infatti, la funzionalità dei mitocondri, la maturazione delle cellule e il metabolismo dei lipidi si sono stati dimostrati in linea. Per quanto riguarda le modificazioni del lipidoma, abbiamo visto un particolare aumento di ceramidi, trigliceridi ed esteri del colesterolo, tutti coinvolti nell'idratazione della pelle e nel rinnovamento dell'epidermide sostenendo il ruolo benefico dell’ acido ialuronico a basso peso molecolare come ingrediente cosmetico. Tuttavia, il corretto equilibrio tra la loro sintesi e metabolismo è fondamentale per il benessere della pelle e ulteriori studi sono necessari per l’approfondimento di queste dinamiche.
La valutazione degli effetti del γ-Orizanolo (Orz), invece, ha fornito solo uno scarso numero di alterazioni significative plasmatiche sia nel proteoma che nel lipidoma probabilmente a causa della debolezza del modello animale. Sono dunque necessari ulteriori studi per confermare la rilevanza biologica di Orz mostrata finora principalmente da test biologici.
Per concludere, sebbene molte domande relative a questi temi di ricerca siano ancora senza risposta e altre omiche dovrebbero essere incluse in una visione integrativa (metabolomica ad esempio), durante questo percorso multidisciplinare di dottorato ho apprezzato la complessità e il valore dell’approccio omico nell'approfondire le nostre conoscenze in diversi campi di ricerca permettendo di avvicinarsi sempre più alla medicina di precisione, obiettivo finale di tutte le scienze omiche.The ‘omics sciences are currently in development offering a new and combined perspective of cellular and organismal environment. Among these, genomics and proteomics are among the most developed while lipidomics is still an emergent field. The importance to provide a strong methodological approach paired to a rigorous data interpretation is explained by the recent discovery of the lipids’ key role not only as structural components and energetic source but also in many biological processes (i.e., second messengers, regulators of inter-cellular interactions and of surface charge, involvement in metabolic diseases, cancer etc.).
Thanks to the recent significant advances, mass spectrometry is the most suitable analytical method in many of ‘omics sciences despite their integration is still at the beginning and a careful optimization of protocols is needed. Nevertheless, considering the molecular complexity, only a multi-omics vision can give a complete picture of intra- and extra-cellular processes in physiological and pathological conditions as well as in response to an environmental or chemical exposure to finally contribute to the field of precision medicine.
So, the work herein aims to provide proteomics and lipidomics perspectives, both as single and integrated approaches, to different research questions by high-resolution mass spectrometry.
At first, the investigation on skin hairless mice proteome allowed me to show how an endogenous peptide, β-alanil-L-histidine (a.k.a. carnosine), is acting in defense of UV-A damages. Indeed, several major protein systems shown an alteration by UV-A treatment including calcium signaling, mitochondrial function or sirtuin expression, which were all restored by a preventive treatment of the skins by a topical application of carnosine. These proteomics alterations could result (at least in part) from ROS generated by UV-A, or/and the generation of lipid oxidation products (HNE, acrolein) resulting from the peroxidation of polyunsaturated fatty acids in the irradiated skins. The implication of such agents is emphasized by the potent efficacy of carnosine in restoring a normal proteomic profile of UV-A-treated skins, in accordance with its ability to neutralize the formation of adducts on proteins and their subsequent modification, thereby restoring their function.
Moving to lipidomics, the biological importance recently demonstrated by fatty acid esters of hydroxy fatty acids (FAHFAs) asked for a tailored method optimization for their identification and quantification in human matrix. In fact, increasing evidence on the physiological roles of FAHFAs, including anti-inflammatory, anti-diabetic and immunomodulatory ones, motivates a more extensive characterization of these lipids as possible biomarkers and therapeutic targets for pathological conditions such as diabetes or obesity. Nevertheless, the low concentration in human tissues, the large structure heterogeneity and that the major amount of FAHFAs in cells is incorporated into triacylglycerols challenge current analytical methods for their accurate identification and quantification. The achieved samples’ preparation and instrumental method optimization successfully enabled to isolate, detect, and quantify endogenous FAHFAs for the first time on human adipose tissue revealing significant alterations based on metabolic status (obese insulin sensitive or resistant vs lean subjects) and adipose tissue portions (visceral vs subcutaneous). These results will be useful to better understand the biological potentiality of this bioactive lipids in metabolic pathologies.
Then, the two multi-omics studies herein conducted were aimed to evaluate molecular effects of low-molecular-weight hyaluronic acid (LMW-HA) in proteome and lipidome of normal human dermal fibroblasts and to analyze lipidome and proteome profile changes induced by γ-Oryzanol (Orz) prevention treatment in obese-induced rats, respectively.
LMW-HA showed an impact both on proteome and lipidome profile, mainly at 0.50 % of concentration. The proteomics results were not only confirmed but also corroborated by lipidomics and integratomics ones. Indeed, mitochondria functionality, cells maturation and lipids metabolism were concordantly demonstrated. About lipidome changes, we saw a particular increasing of ceramides, triacylglycerols and cholesterol esters involved in the skin moisturizing and epidermis renewal and so supporting the beneficial role of low-molecular weight as cosmetic ingredient. Nevertheless, the correct balance between their synthesis and degradation is essential for the skin wellness and further studies are necessary for the deepening of these dynamics.
The Orz’s effects assessment, instead, provided only marginal significant alterations both in plasma’s proteome and lipidome probably due to the weakness of the animal model. Further thoughts and experiments are needed to confirm the biological relevance of Orz mainly showed in biological tests so far.
To conclude, although a lot of questions related to these research topics are still unanswered and other omics should be included in an integrative vision (metabolomics for example), during this multidisciplinary PhD journey I appreciated the complexity and the value of omics sciences in deepening our knowledge about several research fields approaching more and more the precision medicine goal
Trends in the consumption of opioids for the treatment of severe pain in Europe, 1990–2016
No full textBackground: Over the last decades, consumption of opioids for the treatment of pain increased steadily in the United States, Australia, and a few European countries. To date, no study has analysed time trends in opioid consumption across Europe. Methods: We analysed data provided by International Narcotics Control Boards on the consumption of fentanyl, oxycodone, morphine, hydromorphone and pethidine in 40 European countries over the last decade. Trends in total opioid consumption from 1990 to 2016 in 22 selected European countries, the European Union (EU) as a whole, and, for comparison purpose, the United States, were analysed using the joinpoint regression analysis. Results: In 2014–2016, opioid use was >10,000 defined daily doses for statistical purposes (s-DDD) per 1,000,000 inhabitants die in Western/Northern countries, whereas it was <1000 s-DDD in Southern/Eastern ones. In most European countries, opioid consumption increased to a great extent between 2004–2006 and 2014–2016; it rose from 6,477 to 8,967 s-DDD (+38.4%) in the EU, and from 14,598 to 16,491 s-DDD (+13%) in the United States. The increase in opioid use was steady since the early to mid-1990s in most European countries and it slowed down after the mid- to late 2000s. In Denmark, Finland, France, Ireland, Switzerland, Poland and the EU, opioid use levelled off or declined over most recent years. Conclusions: Consumption of opioid analgesics sharply increased in most of European countries since the early to mid-1990s. This notwithstanding, in the mid-2010s there was still a more than 10-fold difference between the highest consumption in Western/Northern countries and the lowest one in Southern/Eastern countries. Significance: This study provides an updated and comprehensive analysis of time trends and geographic variations in opioid consumption use across European countries over the last three decades
Advanced quantitative proteomics to evaluate molecular effects of low-molecular-weight hyaluronic acid in human dermal fibroblasts
No full textHyaluronic acid (HA) is physiologically synthesized by several human cells types but it is also a widespread ingredient of commercial products, from pharmaceuticals to cosmetics. Despite its extended use, the precise intra- and extra-cellular effects of HA at low-molecular-weight (LWM-HA) are currently unclear. At this regard, the aim of this study is to in-depth identify and quantify proteome's changes in normal human dermal fibroblasts after 24 h treatment with 0.125, 0.25 and 0.50 % LMW-HA (20−50 kDa) respectively, vs controls. To do this, a label-free quantitative proteomic approach based on high-resolution mass spectrometry was used. Overall, 2328 proteins were identified of which 39 significantly altered by 0.125 %, 149 by 0.25 % and 496 by 0.50 % LMW-HA. Protein networking studies indicated that the biological effects involve the enhancement of intracellular activity at all concentrations, as well as the extracellular matrix reorganization, proteoglycans and collagen biosynthesis. Moreover, the cell's wellness was confirmed, although mild inflammatory and immune responses were induced at the highest concentration. The more complete comprehension of intra- and extra-cellular effects of LMW-HA here provided by an advanced analytical approach and protein networking will be useful to further exploit its features and improve current formulations
Integratomics of Human Dermal Fibroblasts Treated with Low Molecular Weight Hyaluronic Acid
No full textHyaluronic acid (HA) is a glycosaminoglycan very common in commercial products from pharmaceuticals to cosmetics due to its widespread distribution in humans and its diversified physico-chemical proprieties. Despite its extended use and preliminary evidence showing even also opposite activities to the native form, the precise cellular effects of HA at low-molecular-weight (LWM-HA) are currently unclear. The ‘omics sciences currently in development offer a new and combined perspective on the cellular and organismal environment. This work aims to integrate lipidomics analyses to our previous quantitative proteomics one for a multi-omics vision of intra-and extra-cellular impact of different concentrations (0.125, 0.25, and 0.50%) of LMW-HA (20–50 kDa) on normal human dermal fibroblasts by LC-high resolution mass spectrometry (LC-HRMS). Untargeted lipidomics allowed us to identify 903 unique lipids mostly represented by triacylglycerols, ceramides, and phosphatidylcholines. According to proteomics analyses, LMW-HA 0.50% was the most effective concentration also in the lipidome rearrangement especially stimulating the synthesis of ceramides involved in skin hydration and reparation, cell signaling, and energy balance. Finally, integrative analyses showed 25 nodes covering several intra-and extra-cellular functions. The more complete comprehension of intra-and extra-cellular effects of LMW-HA here pointed out will be useful to further exploit its features and improve current formulations even though further studies on lipids biosynthesis and degradation are necessary
The Burden of Opioid Adverse Events and the Influence on Cancer Patients’ Symptomatology
No full textContext: Opioids are frequently used for the treatment of moderate-to-severe pain and their use may produce a number of unwanted adverse events (AEs). Objectives: The objective of this study was to understand the burden of opioid-induced AEs in cancer patients with pain after the introduction of strong opioids (WHO Step III). Methods: This is a cohort study derived from a randomized controlled trial involving 498 cancer patients with pain who received strong opioids. During 28-day follow-up, we analyzed frequency, intensity, and changes over time of the main opioid-induced AEs; the influence of previous pain therapy on AEs; and the relationships between the presence of AEs and analgesic response. Results: After starting strong opioids, dry mouth, nausea, and vomiting immediately increased and persisted over time, constipation continued to increase, while drowsiness and confusion tended to decrease. Patients previously treated with weak opioids had more frequent and severe AEs. While at all observation points the percentage of patients without AEs was 37%–39%, considering all the five scheduled visits, from Day 3 to Day 28, 17% of patients never experienced any AEs, while 48% of patients had four or more concomitant AEs. Patients with no AEs experienced significantly lower pain intensity. Conclusion: Opioid introduction induces various AEs that persist over time and worse patients’ symptomatology. Moreover, there seems to be a different expression of the opioid toxicity among patients, and a possible interaction between AEs and the analgesic response. The balance between the opioids analgesic effect and induced toxicity is fundamental in deciding the best management for pain in cancer patients
Quantitative proteomics study of carnosine effect in an animal model of Western diet‐induced nonalcoholic fatty liver disease
No full textThe nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver
Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21
No full textThe Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue
