Safety and therapeutic efficacy of adoptive p53-specific T cell antigen receptor (TCR) gene transfer

Immunotherapy with T cells genetically modified by retroviral transfer of tumor-associated antigen (TAA)-specific T cell receptors (TCR) is a promising approach in targeting cancer. Therefore, using a universal TAA to target different tumor entities by only one therapeutic approach was the main criteria for our TAA-specific TCR. Here, an optimized (opt) αβ-chain p53(264-272)-specific and an opt single chain (sc) p53(264-272)-specific TCR were designed, to reduce mispairing reactions of endogenous and introduced TCR α and TCR β-chains, which might lead to off-target autoimmune reactions, similar to Graft-versus-host disease (GvHD). rnIn this study we evaluated the safety issues, which rise by the risk of p53TCR gene transfer-associated on/off-target toxicities as well as the anti-tumor response in vivo in a syngeneic HLA-A*0201 transgenic mouse model. We could successfully demonstrate that opt sc p53-specific TCR-redirected T cells prevent TCR mispairing-mediated lethal off-target autoimmunity in contrast to the parental opt αβ-chain p53-specific TCR. Since the sc p53-specific TCR proofed to be safe, all further studies were performed using sc p53-specific TCR redirected T cells only. Infusion of p53-specific TCR-redirected T cells in Human p53 knock-in (Hupki) mice after lymphodepletion-preconditioning regimen with either sublethal body irradiation (5Gy) or chemotherapy (fludarabine and cyclophosphamide) in combination with vaccination (anti-CD40, CpG1668 and p53(257-282) peptide) did not result in a depletion of hematopoietic cells. Moreover, adoptive transfer of high numbers of p53-specific TCR-redirected T cells in combination with Interleukin 2 (IL-2) also did not lead to toxic on-target reactions. The absence of host tissue damage was confirmed by histology and flow cytometry analysis. Furthermore, p53-specific TCR-redirected T cells were able to lyse p53+A2.1+ tumor cells in vitro. However, in vivo studies revealed the potent suppressive effect of the tumor microenvironment (TME) mediated by tumor-infiltrating myeloid-derived suppressor cells (MDSC). Accordingly, we could improve an insufficient anti-tumor response in vivo after injection of the sc p53-specific TCR-redirected T cells by additional depletion of immunosuppressive cells of the myeloid lineage.rnTogether, these data suggest that the optimized sc p53(264-272)-specific TCR may represent a safe and efficient approach for TCR-based gene therapy. However, combinations of immunotherapeutic strategies are needed to enhance the efficacy of adoptive cell therapy (ACT)-mediated anti-tumor responses.

Nanoparticular iron complex drugs for parenteral administration - physicochemical characterization, biological distribution and pharmacological safety

Iron deficiency is the most common deficiency disease worldwide with many patients who require intravenous iron. Within the last years new kind of parenteral iron complexes as well as generic preparations entered the market. There is a high demand for methods clarifying benefit to risk profiles of old and new iron complexes. It is also necessary to disclose interchangeability between originator and intended copies to avoid severe anaphylactic and anaphylactoid side reaction and assure equivalence of therapeutic effect.rnrnThe investigations presented in this work include physicochemical characterization of nine different parenteral iron containing non-biological complex drugs. rnWe developed an in-vitro assay, which allows the quantification of labile iron in the different complexes and thus it is a useful tool to estimate the pharmaclogical safety regarding iron related adverse drug events. This assay additionally allowed the estimation of complex stability by evaluation of degradation kinetics at the applied conditions.rnrnAn in-ovo study was performed to additionally compare different complexes in respect to body distribution. This in combination with complex stability information allowed the risk estimation of potential local acute and chronic reactions to iron overload.rnrnInformation obtained by the combination of the methods within this work are helpful to estimate the safety and efficacy profile of different iron containing non-biological complex drugs. rnrnPhysicochemical differences between the complexes were demonstrated in respect to size of the inorganic fraction, size and size distribution of the complete particles, structure of the inorganic iron fraction, morphology of the complexes and charge of the complexes. And furthermore significant differences in the biological behavior of different complexes were demonstrated. rnrnThe combination of complex stability and biodistribution as well as the combination of structure, size and stability represent helpful tools for the physicochemical characterization of iron containing non-biological complex drugs and for the estimation of pharmacological safety. This work thus represents an up to date summary of some relevant methods for the characterization of intravenous iron complex drugs in respect to pharmaceutical quality, pharmacological safety and aspects of efficacy. rnrnProspectively, it is worthwhile that the methods within this work will contribute to the development and/or characterization of iron containing nanoparticular formulations with beneficial efficacy and safety profiles.rn

Fire safety engineering: Confronto tra approccio prescrittivo e prestazionale applicato ad una attivita alberghiera

La complessa materia della prevenzione incendi può essere approcciata secondo due strategie sostanzialmente differenti. Da una parte, l’approccio di tipo deterministico, imperante in Italia, si concretizza nell’emanazione di norme estremamente prescrittive e nel ricorso da parte del progettista a strumenti di calcolo molto semplici. Il pregio maggiore di tale approccio risiede senza dubbio alcuno nella sua estrema semplicità, nella garanzia di una certa omogeneità di applicazione e nella possibilità di erogare in tempi ragionevoli una formazione uniforme ed accettabile ai controllori. Mentre il limite più evidente consiste nella rigidità, talora eccessiva, delle prescrizioni normative e nelle procedure di calcolo da adottare. Dall’altra, un approccio di tipo ingegneristico (Fire Safety Engineering), seguito per lo più nei paesi anglosassoni, si basa sulla predizione della dinamica evolutiva dell’incendio tramite l’applicazione di idonei modelli di calcolo fisicamente basati (physically sound). Punto di forza di questa seconda strategia è la sua estrema flessibilità, che consente la simulazione d’incendi di complessità anche molto elevata. Per contro i limiti più evidenti di tale approccio risiedono nella problematica validazione sperimentale dei modelli in argomento, data la natura distruttiva delle prove che andrebbero condotte, nella spinta preparazione richiesta ai professionisti ed ancor più ai controllori, dato il proliferare negli anni di modelli anche molto diversi tra loro, ed, infine, nel caso di raffinati modelli di campo, in un onere computazionale non sempre sostenibile con i PC di comune diffusione. Allo stato attuale in Italia il ricorso alla Fire Safety Engineering è di fatto circoscritto alle applicazioni per le quali non esiste una specifica norma prescrittiva, su tutte la valutazione del rischio in attività a rischio di incidente rilevante e la Fire Investigation; talora essa è impiegata anche per la valutazione della sicurezza equivalente in occasione di richiesta di deroga a norme prescrittive.

"The White Road" di Neil Gaiman: una proposta di traduzione

L'obiettivo del presente elaborato è di fornire una proposta di traduzione dall'inglese all'italiano del poema "The White Road" di Neil Gaiman, pubblicato in Ruby Slippers, Golden Tears (1995) e in Smoke and Mirrors (1998). L'elaborato è articolato in: una breve presentazione dell’autore, con accento sui temi ricorrenti presenti nelle sue opere; una descrizione del testo scelto, sia in termini di struttura che di contenuti e riferimenti culturali; la proposta di traduzione con testo originale a fronte; un’analisi dei problemi traduttivi riscontrati con le relative soluzioni adottate.

Modellazione avanzata di un incendio in uno stabilimento industriale secondo i principi della fire safety engineering

Lo sviluppo di un incendio all’interno di depositi di liquidi infiammabili costituisce uno scenario particolarmente critico a causa della rilevanza delle conseguenze che ne possono scaturire. L’incendio causato dalla formazione di grandi pozze sviluppatesi a seguito di forature dei contenitori e il rapido coinvolgimento di tutto lo stoccaggio rappresentano uno scenario di incendio tipico di queste realtà. Si ha quindi la necessità di adottare provvedimenti atti a garantire specifici obiettivi di sicurezza tramite l’introduzione di misure antincendio. La prevenzione incendi, sino al 2007, era basata esclusivamente su norme di tipo prescrittivo, in base alle quali si definivano le misure di sicurezza secondo un criterio qualitativo. Successivamente l’ingegneria antincendio si è sempre più caratterizzata da approcci basati su analisi di tipo prestazionale, in grado di dimostrare il raggiungimento dell’obiettivo di sicurezza sulla base del comportamento reale d’incendio ottenuto mediante un’accurata simulazione del fuoco che ragionevolmente può prodursi nell'attività. La modellazione degli incendi è divenuta possibile grazie allo sviluppo di codici di fluidodinamica computazionale (CFD), in grado di descrivere accuratamente l’evoluzione delle fiamme. Il presente studio si inserisce proprio nell’ambito della modellazione CFD degli incendi, eseguita mediante il software Fire Dynamics Simulator (FDS). L’obiettivo dell’elaborato è studiare l’azione dell’impianto di spegnimento a schiuma sullo sviluppo di un incendio di pozza in un deposito di liquidi infiammabili, in termini di riduzione della potenza termica rilasciata dal fuoco, al fine di determinare le temperature massime raggiunte, in corrispondenza delle quali valutare il comportamento di resistenza strutturale degli edifici. Il presente lavoro è articolato in 6 capitoli. Dopo il Capitolo 1, avente carattere introduttivo, vengono richiamati nel Capitolo 2 i principali concetti della chimica e fisica degli incendi. Nel Capitolo 3 vengono esaminate le normative intese ad unificare l’approccio ingegneristico alla sicurezza antincendio. Il Capitolo 4 fornisce una dettagliata descrizione del software di calcolo, FDS - Fire Dynamics Simulator, adoperato per la modellazione dell’incendio. Nel Capitolo 5 si procede alla progettazione prestazionale che conduce alla determinazione della curva naturale d'incendio in presenza degli impianti di spegnimento automatici. Infine nel Capitolo 6 si riportano le considerazioni conclusive.

Mortality from road traffic accidents in Switzerland: longitudinal and spatial analyses

Road traffic accidents (RTA) are an important cause of premature death. We examined socio-demographic and geographical determinants of RTA mortality in Switzerland by linking 2000 census data to RTA mortality records 2000-2005 (ICD-10 codes V00-V99). Data from 5.5 million residents aged 18-94 years, 1744 study areas, and 1620 RTA deaths were analyzed, including 978 deaths (60.4%) in motor vehicle occupants, 254 (15.7%) in motorcyclists, 107 (6.6%) in cyclists, and 259 (16.0%) in pedestrians. Weibull survival models and Bayesian methods were used to calculate hazard ratios (HR), and standardized mortality ratios (SMR) across study areas. Adjusted HR comparing women with men ranged from 0.04 (95% CI 0.02-0.07) in motorcyclists to 0.43 (95% CI 0.32-0.56) in pedestrians. There was a u-shaped relationship with age in motor vehicle occupants and motorcyclists. In cyclists and pedestrians, mortality increased after age 55 years. Mortality was higher in individuals with primary education (HR 1.53; 95% CI 1.29-1.81), and higher in single (HR 1.24; 95% CI 1.05-1.46), widowed (HR 1.31; 95% CI 1.05-1.65) and divorced individuals (HR 1.62; 95% CI 1.33-1.97), compared to persons with tertiary education or married persons. The association with education was particularly strong for pedestrians (HR 1.87; 95% CI 1.20-2.91). RTA mortality increased with decreasing population density of study areas for motor vehicle occupants (test for trend p<0.0001) and motorcyclists (p=0.0021) but not for cyclists (p=0.39) or pedestrians (p=0.29). SMR standardized for socio-demographic and geographical variables ranged from 82 to 190. Prevention efforts should aim to reduce inequities across socio-demographic and educational groups, and across geographical areas, with interventions targeted at high-risk groups and areas, and different traffic users, including pedestrians.

Chemotherapy patients' perceptions of drug administration safety

To explore chemotherapy patients' experiences of drug administration safety and to investigate the relationship between perceptions of risk and harm from error, staff safety practices, and patients' engagement in error prevention strategies.

Am I (un)safe here? Chemotherapy patients' perspectives towards engaging in their safety

To assess chemotherapy patients' perceptions of safety and their attitudes towards participating in error-prevention strategies.

Estimating Willingness to Pay for River Amenities and Safety Measures Associated with Shale Gas Extraction

This paper utilizes a Contingent Valuation Method survey of a random sample of residents to estimate that households are willing to pay an average of $12.00 per month for public projects designed to improve river access and $10.46 per month for additional safety measures that would eliminate risks to local watersheds from drilling for natural gas from underground shale formations. These estimates can be compared to the costs of providing each of these two amenities to help foster the formation of efficient policy decisions.

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Design Network meta-analysis. Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

Measles vaccination in HIV-infected children: systematic review and meta-analysis of safety and immunogenicity

Background. Measles control may be more challenging in regions with a high prevalence of HIV infection. HIV-infected children are likely to derive particular benefit from measles vaccines because of an increased risk of severe illness. However, HIV infection can impair vaccine effectiveness and may increase the risk of serious adverse events after receipt of live vaccines. We conducted a systematic review to assess the safety and immunogenicity of measles vaccine in HIV-infected children. Methods. The authors searched 8 databases through 12 February 2009 and reference lists. Study selection and data extraction were conducted in duplicate. Meta-analysis was conducted when appropriate. Results. Thirty-nine studies published from 1987 through 2008 were included. In 19 studies with information about measles vaccine safety, more than half reported no serious adverse events. Among HIV-infected children, 59% (95% confidence intervals [CI], 46–71%) were seropositive after receiving standard-titer measles vaccine at 6 months (1 study), comparable to the proportion of seropositive HIV-infected children vaccinated at 9 (8 studies) and 12 months (10 studies). Among HIV-exposed but uninfected and HIV-unexposed children, the proportion of seropositive children increased with increasing age at vaccination. Fewer HIV-infected children were protected after vaccination at 12 months than HIV-exposed but uninfected children (relative risk, 0.61; 95% CI, .50–.73). Conclusions. Measles vaccines appear to be safe in HIV-infected children, but the evidence is limited. When the burden of measles is high, measles vaccination at 6 months of age is likely to benefit children of HIV-infected women, regardless of the child's HIV infection status.

'New perspectives on well-known issues': patients' experiences and perceptions of safety in Swiss hospitals

Patients' reports of safety-related events and perceptions of safety can be a valuable source for hospitals. Patients of eight acute care hospitals in Switzerland were surveyed for safety-related events and concerns for safety. In workshops with hospitals areas for improvement were analyzed and priorities for change identified. To evaluate the benefit of the approach, semi-structured interviews were conducted with hospital risk managers. 3,983 patients returned the survey (55% response rate). 21.4% reported at least one definite safety event, and the mean number of 'definite' incidents per patient was 0.31 (95% CI=0.29 to 0.34). 3.2% were very concerned and 14.7% were somewhat concerned about medical errors and safety. Having experienced a safety-related event, younger age, length of stay, poor health and a poor education increased the probability of reporting concerns. With some exceptions, results confirmed the hospitals' a priori expectations regarding the strengths and weaknesses of their institutions. Risk managers emphasized the usability of results for their work and the special value of referring to the patient's perspective at their home institutions. A considerable fraction of patients subjectively experiences safety-related events and is concerned about safety. Patient-generated data introduced a new quality into the discussion of safety issues within hospitals, and some expected that patients' experiences and concerns could affect patient volumes. Though the study is limited by the short time horizon and the lack of follow-up, the results suggest that the described approach is feasible and can serve as a supplemental tool for risk identification and management.

Patients' and healthcare workers' perceptions of a patient safety advisory

To assess patients' and healthcare workers' (hcw) attitudes and experiences with a patient safety advisory, to investigate predictors for patients' safety-related behaviors and determinants for staff support for the advisory.