Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5′-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5′-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5′-monophosphate, which is further transformed to the active 5′-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan’s research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents

I Contributi della Video-Analisi per la Ricerca nei Servizi per la Prima Infanzia

This paper presents a review of the literature on the use of video-analysis in Early Childhood Education and Care (ECEC) contexts. The purpose of conducting such review emerged from the needs of exploring possibilities and limitations of video-analysis as a research mediational tool in ECEC services, especially in a European context. Constituting an integral task of a larger study funded by the Erasmus + grant program, and titled Transition Children and Kindergarten, this review considers English language studies and studies written in the language of the project partner countries (i.e. Italy, Poland, and Belgium/Flanders). The narrative synthesis of the studies considered develops around three emerging areas in which video-analysis in ECEC has been used already, namely: (1) teachers/parents/community’s reflection, consciousness and empowerment; (2) diversity and inclusion; (3) interaction children-educator. The paper ends with a final conclusion on the relevance of video-analysis for ECEC practitioners’ professional development and collaborative growth.Questo articolo presenta una rassegna della letteratura sull’uso della video analisi per la ricerca educativa nei servizi per l’infanzia. In particolare, la revisione della letteratura qui illustrata esplorale possibilità e i limiti come strumento di mediazione per la ricerca e la formazione di educatori e insegnanti che entro tali servizi operano. Condotta nell’ambito di uno studio europeo intitolato Transition Children and Kindergarten (TRACKs), la rassegna considera sia gli studi pubblicati in lingua inglese sia quelli pubblicati nella lingua dei paesi partner del progetto (Italia, Polonia, Belgio/ Regione Fiamminga). La sintesi narrativa degli studi considerati si sviluppa attorno a tre aree emergenti in cui è già stata utilizzata la video analisi nei servizi per l’infanzia, vale a dire: (1) riflessione, coscientizzazione ed empowerment di educatori e insegnanti, genitori, comunità; (2) diversità e inclusione; (3) interazioni tra adulti e bambini. Il documento si conclude con una riflessione rispetto all'utilizzo della video-analisi come strumento per favorire lo sviluppo professionale e la crescita collaborativa dei professionisti nei servizi ECEC

Fluorinated nucleosides as an important class of anticancer and antiviral agents

Fluorine-containing nucleoside analogs (NAs) represent a significant class of the US FDA-approved chemotherapeutics widely used in the clinic. The incorporation of fluorine into drug-like agents modulates lipophilic, electronic and steric parameters, thus influencing pharmacodynamic and pharmacokinetic properties of drugs. Fluorine can block oxidative metabolism of drugs and the formation of undesired metabolites by changing H-bonding interactions. In this review, we focus our attention on chemical fluorination reagents and methods used in the NAs field, including positron emission tomography radiochemistry. We briefly discuss both the cellular biology and clinical properties of FDA-approved and fluorine-containing nucleoside/nucleotide analogs in development as well as common resistance mechanisms associated with their use. Finally, we emphasize pronucleotide strategies used to improve therapeutic outcome of NAs in the clinic. </jats:p

Cerebral palsy and obstetric-neonatological interventions

Cerebral palsy is a disease that puts a great mental burden on caregivers and generates very high social costs. Children withCP require many years of rehabilitation and medical care. The etiology of the disease is undoubtedly multifactorial, and thepathogenesis is associated with focal damage to the central nervous system. One can find descriptions of well-documentedinterventions in the literature that reduce the risk of CP in certain groups of pregnant and neonatal patients, and interventionsthat have a potentially protective effect. In this review, we have analyzed the available literature in terms of prenataland postnatal interventions that may have an impact on reducing the incidence of this condition in children

Symmetrical diamidates as a class of phosphate prodrugs to deliver the 5'-monophosphate form of anticancer nucleoside analogues

We herein report on the application of phosphorodiamidate technology to both pyrimidine and purine nucleosides with anticancer activity. Sixteen symmetrical phosphorodiamidates esterified with natural amino acids such as L‐alanine and glycine were synthesized. All the compounds were evaluated for their cytotoxic activity in a wide panel of solid and leukemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate‐type prodrugs

Interleukin-6 and C-reactive protein, successful aging, and mortality : the PolSenior study

BACKGROUND: In the elderly, chronic low-grade inflammation (inflammaging) is a risk factor for the development of aging-related diseases and frailty. Using data from several thousand Eastern Europeans aged 65 years and older, we investigated whether the serum levels of two proinflammatory factors, interleukin-6 (IL-6) and C-reactive protein (CRP), were associated with physical and cognitive performance, and could predict mortality in successfully aging elderly. RESULTS: IL-6 and CRP levels systematically increased in an age-dependent manner in the entire study group (IL-6: n = 3496 individuals, p < 0.001 and CRP: n = 3632, p = 0.003), and in the subgroup of successfully aging individuals who had never been diagnosed with cardiovascular disease, myocardial infarction, stroke, type 2 diabetes, or cancer, and had a Mini Mental State Examination (MMSE) score ≥24 and a Katz Activities of Daily Living (ADL) score ≥5 (IL-6: n = 1258, p < 0.001 and CRP: n = 1312, p < 0.001). In the subgroup of individuals suffering from aging-related diseases/disability, only IL-6 increased with age (IL-6: n = 2238, p < 0.001 and CRP: n = 2320, p = 0.249). IL-6 and CRP levels were lower in successfully aging individuals than in the remaining study participants (both p < 0.001). Higher IL-6 and CRP levels were associated with poorer physical performance (lower ADL score) and poorer cognitive performance (lower MMSE score) (both p < 0.001). This association remained significant after adjusting for age, gender, BMI, lipids, estimated glomerular filtration rate, and smoking status. Longer survival was associated with lower concentrations of IL-6 and CRP not only in individuals with aging-related diseases/disability (HR = 1.063 per each pg/mL, 95 % CI: 1.052-1.074, p < 0.001 and HR = 1.020 per each mg/L, 95 % CI: 1.015-1.025, p < 0.001, respectively) but also in the successfully aging subgroup (HR = 1.163 per each pg/mL, 95 % CI: 1.128-1.199, p < 0.001 and HR = 1.074 per each mg/L, 95 % CI: 1.047-1.100, p < 0.001, respectively). These associations remained significant after adjusting for age, gender, BMI, lipids and smoking status. The Kaplan-Meier survival curves showed similar results (all p < 0.001). CONCLUSIONS: Both IL-6 and CRP levels were good predictors of physical and cognitive performance and the risk of mortality in both the entire elderly population and in successfully aging individuals

Participants’ perspectives of the advanced ovarian cancer biomarker study VALTIVE1: a qualitative study

Objectives: VALTIVE1 is a multi-centre, single-arm, non-interventional biomarker study for patients with advanced ovarian cancer. Plasma samples (Tie2 concentration) are collected to detect vascular control in tumours during standard treatment with chemotherapy and bevacizumab. This qualitative study embedded in VALTIVE1 aimed to assess the acceptability and feasibility of a potential VALTIVE2 trial. It explored the participants’ perceptions of the study and treatments and how they might feel if bevacizumab were discontinued based on the results from the biomarker test. Design: This qualitative study used semi-structured telephone interviews, which were analysed using deductive and inductive thematic analysis. Settings: Cancer treatment sites in the UK. Participants: Participants recruited to VALTIVE1 were invited to take part in qualitative interviews. 11 female participants took part from four clinical sites. Results: Participants reported that they experienced side effects attributed to bevacizumab, including stiffness, pain, fatigue, nose bleeds and muscle aches. Participants felt that combining chemotherapy and bevacizumab may have increased the severity of the side effects they experienced. Most participants felt that it was acceptable, if not preferable, to be allocated to a group in a future VALTIVE2 study where bevacizumab may be discontinued according to the results from the biomarker test. A clear preference of participants was to be informed of the biomarker test results, health status and treatment side effects. Conclusion: A future trial should consider ensuring all participants have access to test results, as participants indicated a preference to know whether bevacizumab was working and to discontinue bevacizumab if it had not prevented tumour growth based on the biomarker results. Comprehensive and ongoing information and support regarding treatment side effects should be provided to all participants throughout their cancer pathways and trials. Trial registration number: NCT04523116

Application of ProTide technology to Gemcitabine: A successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development

Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents