174 research outputs found
Nomogramma clinico-patologico predittivo dello stato mutazionale di BRAF nel tumore del colon-retto metastatico
Negli ultimi anni i progressi ottenuti nel trattamento del carcinoma del colon-retto metastatico (mCRC) hanno prolungato notevolmente lâaspettativa di vita dei pazienti, con valori mediani di sopravvivenza che oggi sono vicini ai 30 mesi. Ha certamente contribuito a questo risultato lâintroduzione di alcuni farmaci a bersaglio molecolare, tra cui gli anticorpi monoclonali anti-epidermal growth factor receptor (EGFR). PoichĂŠ non tutti i pazienti ottengono beneficio da tali farmaci, è oggi necessario selezionare la popolazione da trattare attraverso lâanalisi dello stato mutazionale dei geni RAS (KRAS e NRAS). I pazienti che presentano una mutazione a carico di questi geni non traggono beneficio dal ricevere i farmaci anti-EGFR e devono quindi essere esclusi dal trattamento.
Il ruolo della mutazione V600E del gene BRAF, mutuamente esclusiva con le mutazioni di RAS, nel predire la risposta ai farmaci anti-EGFR è tuttâora dibattuto e gli studi a riguardo non risultano conclusivi, anche a causa della bassa incidenza di questa mutazione nel mCRC (circa 10%). Tutti gli studi concordano invece sul valore prognostico negativo di questa mutazione che si associa a una sopravvivenza mediana di circa dodici mesi. Conoscere lo stato mutazionale di BRAF è un valore aggiunto nella scelta del miglior iter terapeutico per ogni paziente, spingendo a scegliere un trattamento di partenza piĂš aggressivo quando possibile e a ponderare con molta attenzione interventi di resezione secondaria, spesso non risolutivi. Tuttavia, il test di BRAF non è disponibile nĂŠ comunemente eseguito in tutte le realtĂ cliniche, con sensibili differenze geografiche.
In letteratura sono riportate delle caratteristiche clinico-patologiche che si osservano piĂš frequentemente nei mCRC BRAF mutati. Tuttavia, la forza dellâassociazione tra ogni singola caratteristica e la mutazione di BRAF in un modello multivariato non è mai stata valutata.
Lâobiettivo di questa tesi è quello di costruire un nomogramma predittivo dello stato mutazionale di BRAF nei pazienti con tumore del colon-retto RAS wild-type, partendo dalle caratteristiche clinico-patologiche associate alla mutazione.
Sono state analizzate due ampie popolazioni di pazienti con mCRC, una popolazione training (TP) e una popolazione di validazione (VP) di cui erano disponibili dati clinici e patologici inclusi i risultati delle analisi mutazionali dei geni RAS e BRAF. Eâ stato creato un database specifico selezionando le caratteristiche giĂ presenti in letteratura associate alla mutazione V600E del gene BRAF: sesso, etĂ , performance status (secondo ECOG), sede del tumore primitivo, precedente resezione del tumore primitivo, istologia mucinosa, grado di differenziazione, tempo allâinsorgenza delle metastasi (sincrono o metacrono), numero di siti metastatici alla diagnosi, metastasi peritoneali, metastasi ai linfonodi a distanza, metastasi polmonari.
Nei 596 pazienti della TP 281 erano RAS wild-type (47%); 54 BRAFV600E mutati (9.1%) e le due mutazioni erano sempre mutuamente esclusive. Nella popolazione RAS wild-type i fattori predittivi della mutazione di BRAF erano la sede destra del tumore primitivo (OR: 7.80, 95% CI 3.05-19.92); il sesso femminile (OR: 2.90, 95% CI 1.14-7.37) e lâistologia mucinosa (OR: 4.95, 95% CI 1.90-12.90). Questi fattori si replicavano alla cross-validazione interna con tassi rispettivamente al 100%, 93% e 98%. Sulla base di queste evidenze è stato quindi costruito il nomogramma predittivo: i pazienti con sede destra del tumore primitivo, sesso femminile e istologia mucinosa avevano lâ81% di probabilitĂ di avere la mutazione BRAF. Allâanalisi ROC lâaccuratezza predittiva del nomogramma era alta (AUC: 0.812, SE: 0.034) con una sensibilitĂ dellâ81.2% e una specificitĂ del 72.1%.
Nei 508 pazienti della VP 262 erano RAS wild-type (51.6%) e 49 BRAFV600E mutati (9.6%). La sede destra del tumore primitivo, il sesso femminile e lâistologia mucinosa si sono confermati fattori predittivi indipendenti della mutazione di BRAF. Il nomogramma predittivo derivato nella TP è stato quindi applicato alla VP. Anche nella VP, allâanalisi ROC, lâaccuratezza predittiva del nomogramma è stata alta (AUC=0.811, SE: 0.041), con una sensibilitĂ del 73.5% e una specificitĂ dellâ80.3%, senza nessuna differenza significativa tra le prestazioni predittive del nomogramma nelle due popolazioni (p=1.0).
In conclusione, tre semplici caratteristiche ampiamente disponibili consentono di predire lo stato mutazionale di BRAF con alta sensibilità e specificità . Sebbene il test molecolare resti chiaramente il gold standard per stabilire se un mCRC è BRAF mutato o meno, questo strumento può essere estremamente utile laddove il test non sia effettivamente disponibile o non venga adottato su larga scala
FlexKnot and Gaussian Process for 21 cm global signal analysis and foreground separation
The cosmological 21 cm signal is one of the most promising avenues to study
the Epoch of Reionization. One class of experiments aiming to detect this
signal is global signal experiments measuring the sky-averaged 21 cm brightness
temperature as a function of frequency. A crucial step in the interpretation
and analysis of such measurements is separating foreground contributions from
the remainder of the signal, requiring accurate models for both components.
Current models for the signal (non-foreground) component, which may contain
cosmological and systematic contributions, are incomplete and unable to capture
the full signal. We propose two new methods for extracting this component from
the data: Firstly, we employ a foreground-orthogonal Gaussian Process to
extract the part of the signal that cannot be explained by the foregrounds.
Secondly, we use a FlexKnot parameterization to model the full signal component
in a free-form manner, not assuming any particular shape or functional form.
This method uses Bayesian model selection to find the simplest signal that can
explain the data. We test our methods on both, synthetic data and publicly
available EDGES low-band data. We find that the Gaussian Process can clearly
capture the foreground-orthogonal signal component of both data sets. The
FlexKnot method correctly recovers the full shape of the input signal used in
the synthetic data and yields a multi-modal distribution of different signal
shapes that can explain the EDGES observations.Comment: 18 pages, 17 figures, accepted for publication in MNRA
Strontium substituted hydroxyapatite with β-lactam integrin agonists to enhance mesenchymal cells adhesion and to promote bone regeneration
Multi-functionalization of calcium phosphates to get delivery systems of therapeutic agents is gaining increasing relevance for the development of functional biomaterials aimed to solve problems related to disorders of the muscolo-skeletal system. In this regard, we functionalized Strontium substituted hydroxyapatite (SrHA) with some β-lactam integrin agonists to develop materials with enhanced properties in promoting cell adhesion and activation of intracellular signaling as well as in counteracting abnormal bone resorption. For this purpose, we selected two monocyclic β-lactams on the basis of their activities towards specific integrins on promoting cell adhesion and signalling. The amount of β-lactams loaded on SrHA could be modulated on changing the polarity of the loading solution, from 3.5â24 wt% for compound 1 and from 3.2â8.4 wt% for compound 2. Studies on the release of the β-lactams from the functionalized SrHA in aqueous medium showed an initial burst followed by a steady-release that ensures a small but constant amount of the compounds over time. The new composites were fully characterized. Co-culture of human primary mesenchymal stem cells (hMSC) and human primary osteoclast (OC) demonstrated that the presence of β-lactams on SrHA favors hMSC adhesion and viability, as well as differentiation towards osteoblastic lineage. Moreover, the β-lactams were found to enhance the inhibitory role of Strontium on osteoclast viability and differentiation
Higher protein intake is associated with improved muscle strength in elite senior athletes
OBJECTIVE:
The optimal protein intake for elderly individuals who exercise regularly has not yet been clearly defined. The aim of this study was to test the hypothesis that protein intake level is associated with muscle strength in elderly elite athletes.
METHODS:
We evaluated 50 elite senior athletes (38 men and 12 women) participating in the European Master Games 2011 in an observational cross-sectional study. Participants were divided into two groups-lower (LPI) or higher (HPI) protein intake-according to the median value of their ratio of urinary urea nitrogen to urinary creatinine (i.e., 8.8 g/L), as a marker of protein intake. A dietary interview confirmed differences in protein consumption between the LPI and HPI groups. We also evaluated body composition (bioimpedance), muscle strength, and hematochemical indices.
RESULTS:
LPI and HPI groups were homogeneous for age (72 [68-74] and 71 [68-74] y, respectively), fat-free mass index (18.4 [17-19.4] and 18.2 [17-19.1] kg/m2), body fat (18.3% [12.3-20.7%] and 16.6% [13.6-21.2%]), and glomerular filtration rate (57.7 [53.8-64.9] and 62.7 [56.1-69.3] mL/min/1.73 m2). The HPI group showed greater leg and trunk muscle strength (N) compared with the LPI group (left leg extension, 339 [238-369] versus 454 [273-561], respectively, P < 0.05; right leg extension, 319 [249-417] versus 432 [334-635], P 64 0.05; trunk extension, 435 [370-467] versus 464 [390-568], P 64 0.05).
CONCLUSIONS:
Higher protein intake in elite senior athletes is associated with a greater muscle strength
Higher risk for influenza-associated pulmonary aspergillosis (IAPA) in asthmatic patients: A Swiss multicenter cohort study on IAPA in critically ill influenza patients
Background: Influenza-associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with high morbidity and mortality.
Methods: We conducted a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/2018 and 2019/2020 influenza seasons. All adults with PCR-confirmed influenza infection and treatment on intensive-care unit (ICU) for >24 h were included. IAPA was diagnosed according to previously published clinical, radiological, and microbiological criteria. We assessed risk factors for IAPA and predictors for poor outcome, which was a composite of in-hospital mortality, ICU length of stay âĽ7 days, mechanical ventilation âĽ7 days, or extracorporeal membrane oxygenation.
Results: One hundred fifty-eight patients (median age 64 years, 45% females) with influenza were included, of which 17 (10.8%) had IAPA. Asthma was more common in IAPA patients (17% vs. 4% in non-IAPA, P = 0.05). Asthma (OR 12.0 [95% CI 2.1-67.2]) and days of mechanical ventilation (OR 1.1 [1.1-1.2]) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non-IAPA, P = 0.001) and vasoactive support (75% vs. 45%, P = 0.03) and had more complications including ARDS (53% vs. 26%, P = 0.04), respiratory bacterial infections (65% vs. 37%, P = 0.04), and higher ICU-mortality (35% vs. 16.4%, P = 0.05). IAPA (OR 28.8 [3.3-253.4]), influenza A (OR 3.3 [1.4-7.8]), and higher SAPS II score (OR 1.07 [1.05-1.10]) were independent predictors of poor outcome.
Interpretation: High clinical suspicion, early diagnostics, and therapy are indicated in IAPA because of high morbidity and mortality. Asthma is likely an underappreciated risk factor for IAPA.
Keywords: asthma; influenza; influenza-associated aspergillosis; intensive care medicine; invasive aspergillosis
Higher risk for influenza-associated pulmonary aspergillosis (IAPA) in asthmatic patients: A Swiss multicenter cohort study on IAPA in critically ill influenza patients.
BACKGROUND
Influenza-associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with high morbidity and mortality.
METHODS
We conducted a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/2018 and 2019/2020 influenza seasons. All adults with PCR-confirmed influenza infection and treatment on intensive-care unit (ICU) for >24âh were included. IAPA was diagnosed according to previously published clinical, radiological, and microbiological criteria. We assessed risk factors for IAPA and predictors for poor outcome, which was a composite of in-hospital mortality, ICU length of stay âĽ7âdays, mechanical ventilation âĽ7âdays, or extracorporeal membrane oxygenation.
RESULTS
One hundred fifty-eight patients (median age 64âyears, 45% females) with influenza were included, of which 17 (10.8%) had IAPA. Asthma was more common in IAPA patients (17% vs. 4% in non-IAPA, Pâ=â0.05). Asthma (OR 12.0 [95% CI 2.1-67.2]) and days of mechanical ventilation (OR 1.1 [1.1-1.2]) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non-IAPA, Pâ=â0.001) and vasoactive support (75% vs. 45%, Pâ=â0.03) and had more complications including ARDS (53% vs. 26%, Pâ=â0.04), respiratory bacterial infections (65% vs. 37%, Pâ=â0.04), and higher ICU-mortality (35% vs. 16.4%, Pâ=â0.05). IAPA (OR 28.8 [3.3-253.4]), influenza A (OR 3.3 [1.4-7.8]), and higher SAPS II score (OR 1.07 [1.05-1.10]) were independent predictors of poor outcome.
INTERPRETATION
High clinical suspicion, early diagnostics, and therapy are indicated in IAPA because of high morbidity and mortality. Asthma is likely an underappreciated risk factor for IAPA
The role of the WISE Consortium in the European DEDIPAC-KH project
WISE (Wellness, nutrItion, Sport and Exercise prevention) is a research consortium including five Italian research teams (University of Turin, University of Milan, University of Trieste, Universiy of Rome âForo Italicoâ, University of Bari), operating within the broader framework of the DEDIPAC-KH joint action (Determinants of Diet and Physical Activity Knowledge Hub). Research actions within the WISE consortium, funded by the Italian Ministry of Higher Education & Research, are in line with the main objective of the DEDIPAC-KH of developing an international and interdisciplinary network of researchers on dietary, physical activity and sedentary behaviours, related determinant research and policy interventions. More specifically, the WISE consortium research aimed to contribute to the following task (1.2.4 - Task Leader: Prof. Alan Donnelly): perform SLRs to identify state-of the art methods for physical activity and sedentary behaviour measurements. The focus of task 1.2.4 was to examine the methodological effectiveness (validity, reliability and sensitivity/responsiveness) of measures of physical activity and sedentary behaviours. The approach taken with this task was to examine the methodological effectiveness of measures of physical activity and sedentary behaviours in two populations; i) child/adolescence and ii) adults. Findings on methodological effectiveness of measures of physical activity and sedentary behaviours constitute the basis for a variety of publication and reports, and conference communications. The DEDIPAC-KH project created an unique opportunity for developing a comprehensive analysis on the determinants of diet and physical activity in Italy, and fostered successful collaboration with leading international groups. The findings of the WISE project created valuable information for the implementation of successful policies in Italy.This work was supported by MIUR
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