"Studio di nuove strategie sintetiche coinvolgenti eterocicli a piccolo anello."

Riassunto: Questo lavoro di Tesi sperimentale, prende in considerazione l’apertura di sistemi eterociclici a piccolo anello, come vinilaziridine e vinilepossidi, ad opera di nucleofili che permettono la formazione di nuovi legami carbonio-carbonio, in modo da ottenere composti polifunzionalizzati. Partendo dagli studi del gruppo di ricerca con cui ho lavorato, che riguardavano l’apertura di anelli tensionati, secondo una modalità di tipo SN2’, catalizzata da metalli di transizione, si è cercato di sviluppare una nuova metodologia che utilizzasse come nucleofili nitroderivati. Questi, sono una buona fonte di carbanioni, per l’elevata proprietà elettron-attrattrice del gruppo nitro, e risultano validi building block per la particolarità della loro chimica che ne permette utili trasformazioni in gruppi funzionali diversi. A questo proposito, utilizzando come riferimento l’unico esempio, riportato in letteratura, di nitrometilazione del 2-vinilossirano, effettuata da Deardorff (J. Org. Chem. 1996, 61, 3616-3622.), si è provato a sviluppare delle procedure che prevedessero l’uso di nitroderivati di varia reattività, con sistemi catalitici a base di diversi metalli di transizione. Il lavoro si è focalizzato soprattutto sull’utilizzo di complessi a base di palladio (0), sia generati in situ, da precursori quali Pd2(dba)3 , Pd(OAc)2 con PPh 3 o altri liganti fosfinici, sia preformati come Pd(PPh3)4 . Quest’ultimo si è rivelato il sistema più efficiente nell’addizione, che avviene in tempi brevi e in condizioni neutre. Questa reazione, forma un prodotto di addizione che non subisce decarbossilazione, come invece avviene in una reazione analoga condotta su alcol allilici, recentemente descritta in letteratura (Tunge, J. A., Angew. Chem. Int. Ed. 2010, 123, 1726-1729.). Probabilmente nel nostro caso il meccanismo di reazione, per l’ addizione riportata nello Schema 2, prevede la generazione di un complesso π-allile-palladio che porta all’apertura del anello eterociclico, generando una specie anionica che deprotona il nitrocomposto attivandolo all’ attacco regioselettivo in posizione γ. Con l’intento di verificare la generalità del metodo, è stato effettuato uno screening di nucleofili, utilizzando α-metilnitrochetoni, etilnitroacetati e nitroalcani disattivati, sui diversi substrati, portando all’ addizione selettiva e agli attesi prodotti di apertura 1,4 che possono essere trasformati in composti 1,5 polifunzionali. Una eccezione è rappresentata dagli ossa e aza-bicicli (3) che non mostrano alcun tipo di reattività. Inoltre, dall’idea di una catalisi metallica sostenibile ed economica, si sono analizzati metalli più abbondanti e comuni, come surrogati dei complessi a base di palladio. Il sistema costituito da CuCl / tBuOLi che genera la specie catalitica in situ, con la complessazione da parte di un ligante fosfinico ha fornito una certa attività con l’utilizzo di etilnitroacetato come nucleofilo, senza dare riscontri positivi con semplici nitroalcani. I complessi a base di ferro (II), come il TBAFe Bu4N[Fe(CO)3(NO)], e liganti fortemente σ-donatori, come i carbeni N-eterociclici, si sono invece rivelati inefficienti come evidenziato dalle analisi NMR, in cui si ritrovano i segnali relativi ai composti di partenza. La catalisi di questa addizione è stata analizzata anche ad opera di organocatalizzatori, quali i sali derivati della cinconidina. La nostra ipotesi è che questi possano svolgere un duplice ruolo, complessandosi con il substrato, tramite la formazione di legami ad idrogeno e attivando il nucleofilo per la presenza di un sito a carattere basico. Questi hanno però portato agli attesi prodotti di reazione solo con l’etilnitroacetato. Inoltre le reazioni sono avvenute utilizzando condizioni di reazioni drastiche, in cui si è rivelato necessario l’uso di basi forti, riscaldamento e lunghi tempi di reazion

Metabolomic approach to profile functional and metabolic changes in heart failure

Heart failure (HF) is characterized by a series of adaptive changes in energy metabolism. The use of metabolomics enables the parallel assessment of a wide range of metabolites. In this study, we appraised whether metabolic changes correlate with HF severity, assessed as an impairment of functional contractility, and attempted to interpret the role of metabolic changes in determining systolic dysfunction

Comparison of 'time to detection' values between BacT/ALERT VIRTUO and BacT/ALERT 3D instruments for clinical blood culture samples

Abstract Objectives The early detection of bacteraemia and fungemia is of paramount importance to guide antimicrobial therapy in septic patients. In this study the 'time to detection' (TTD) value for the new blood culture system BacT/ALERT VIRTUO (VIRTUO) was evaluated in 1462 positive clinical bottles and compared with the TTD for 1601 positive clinical bottles incubated in the BacT/ALERT 3D system (BTA-3D). Methods The most representative microorganisms isolated from bottles incubated in both blood culture systems were divided into eight categories (in order of frequency): coagulase-negative staphylococci (CoNS), Escherichia coli, Enterobacteriaceae (other than E. coli ), Staphylococcus aureus, Enterococcus spp , viridans group streptococci, Pseudomonas aeruginosa , and Candida spp . Results The comparison of TTD values for the two blood culture systems strongly indicated that growth of the first five groups listed above was detected earlier with VIRTUO than with BTA-3D ( p Conclusions The new VIRTUO blood culture system can reduce the TTD for more than 75% of isolated microorganisms

Plasma concentration of presepsin and its relationship to the diagnosis of infections in multiple trauma patients admitted to intensive care

Background and aims: Septic complications represent the pre- dominant cause of late death in poly-trauma patients. The necessi- ty to differentiate septic from non septic patients is more relevant at the early stage of the illness in order to improve the clinical out- come and to reduce the mortality. The identification of a sensitive and specific, clinically reliable, biomarker capable to early recog- nize incoming septic complications in trauma patients whose expression is not influenced by concomitant traumatic injuries, is still a challenge for the researchers in the field. patients (9 females and 39 males, mean age 47.6\ub119 years) with mul- tiple trauma was performed. The inclusion criterion was to suffer from acute trauma since no more than 24 hours and the exclusion cri- teria were the following: antibiotic treatment on admission and main- tained for more than 48 hours; on-going infection on admission not associated with trauma; treatment with immunosuppressors/ immunomodulants; age <18 years old. Presepsin was measured using an automated chemiluminescence analyser at 1, 3, 5 and 8 days post of hospitalization. The diagnosis of systemic inflammatory response syndrome (SIRS)/infection was established according to the criteria of the Surviving Sepsis Campaign. Materials and methods: A retrospective analysis on 48 adult Results and conclusions: In patients with SIRS, the mean pre- sepsin concentration was 917,08 (\ub169.042) ng/L vs 980,258 (\ub11951.32) ng/L in patients without SIRS (P=0.769). In the infected patients, the mean presepsin concentration was 1513.25 (\ub12296.54) ng/L vs 654.21 (\ub1511,068) ng/L (P<0.05) calculated among the non infected upon admission. The plasma presepsin concentration increased progressively during the first 8 days of hospitalization. Presepsin concentration in the infected patients was significantly higher than in non-infected patients. On the other hands no signifi- cant differences were found in the plasma level of presepsin among patients with and without SIRS. Any other clinical condition related to the trauma did not affect presepsin. Our data clearly suggest that presepsin may be considered an helpful diagnostic tool to early diagnose sepsis in trauma patients

Increased CNV-Region Deletions in Mild Cognitive Impairment (MCI) and Alzheimer\u27s Disease (AD) Subjects in the ADNI Sample

We investigated the genome-wide distribution of CNVs in the Alzheimer\u27s disease (AD) Neuroimaging Initia- tive (ADNI) sample (146 with AD, 313 with Mild Cognitive Impairment (MCI), and 181 controls). Comparison of single CNVs between cases (MCI and AD) and controls shows overrepresentation of large hetero- zygous deletions in cases (p-value b 0.0001). The analysis of CNV-Regions identifies 44 copy number variable loci of heterozygous deletions, with more CNV-Regions among affected than controls (p = 0.005). Seven of the 44 CNV-Regions are nominally significant for association with cognitive impairment. We validated and con- firmed our main findings with genome re-sequencing of selected patients and controls. The functional pathway analysis of the genes putatively affected by deletions of CNV-Regions reveals enrichment of genes implicated in axonal guidance, cell–cell adhesion, neuronal morphogenesis and differentiation. Our findings support the role of CNVs in AD, and suggest an association between large deletions and the development of cognitive impairment

Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

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COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death. Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon