Search

Oncolytic adenoviruses have been considered for use as anticancer therapy for decades, and numerous means of conferring tumor selectivity have been developed. As with any new therapy, the trip from the laboratory bench to the clinic has revealed a number of significant development hurdles. Viral therapies are subject to specific regulations and must meet a variety of well-defined criteria for purity, potency, stability, and product characterization prior to their use in the clinic. Published regulatory guidelines, although developed specifically for biotechnology-derived products, are applicable to the production of oncolytic adenoviruses and other cell-based products, and they should be consulted early during development. Most importantly, both the manufacturing process and the development of characterization and release assays should be science-driven, use the best available science and technology, and must consider the unique nature of the product: a living, and mutatable, virus. Potentially significant impacts on product quality and safety stem from the possibility of genetic instability related to over-engineering the viruses (as evidenced by their recombination and/or occasional reversion to wild-type virus during manufacturing). This report provides examples of some of the critical components affecting the development and production of clinical grade material and summarizes the significant progress made in recent years.Oncogene (2005) 24, 7792–7801. doi:10.1038/sj.onc.1209045 [ABSTRACT FROM AUTHOR]

Background: For a long time, surgery of insular gliomas was considered at high risk for postoperative cognitive deficits, but recent studies highlighted the feasibility of the surgical approach. The aims of our study were to investigate the presence of language impairment before and after surgery and the relationship between language impairment and tumor volume preoperatively and extent of resection (EOR) 3 months after surgery. Methods: Thirty-five patients with insular gliomas underwent an extensive language assessment before and few days after surgery, and after 3 months. Intraoperative neurophysiological monitoring (IOM) and brain mapping with direct electrical stimulation (DES) were used in all the cases; 8 patients underwent awake craniotomy. Statistical analysis was performed on the language tests administered. Results: Patients with pure left insular lesion showed language impairment before and after surgery. Overall, patients with a left lesion showed a drop of performance after surgery followed by a partial recovery. Moreover, when the tumor involved the insula and adjacent networks, we observed a more severe deficit. No correlations were found between tumor volume, EOR, and language impairment. Conclusions: Left insular lobe is an important hub in language networks; its involvement determines pre- and postsurgical deficits, together with the involvement of white matter connections. Tumor volume and EOR are not risk factors per se directly related to language functioning. Surgery of insular gliomas is possible with a pre- and intraoperative extensive study of the patient with IOM and awake surgery, and encouraged by the trend of cognitive recovery highlighted. [ABSTRACT FROM AUTHOR]

In this work, we describe the association of a novel homozygous VPS11 variant with adult‐onset generalized dystonia, providing a detailed clinical report and biological evidence of disease mechanism. Vps11 is a subunit of the homotypic fusion and protein sorting (HOPS) complex, which promotes the fusion of late endosomes and autophagosomes with the lysosome. Functional studies on mutated fibroblasts showed marked lysosomal and autophagic abnormalities, which improved after overexpression of the wild type Vps11 protein. In conclusion, a deleterious VPS11 variant, damaging the autophagic and lysosomal pathways, is the probable genetic cause of a novel form of generalized dystonia. ANN NEUROL 2021;89:834–839 [ABSTRACT FROM AUTHOR]

Background: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson's disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of "poor stimulation responders" among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered.Methods: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale <50 in medication on/stimulation on condition) treated with STN-DBS for at least 5 years underwent a crossover, double-blind, randomized evaluation of acute effects of stimulation. Physicians, caregivers, and patients were blinded to stimulation conditions. Poor stimulation responders (MDS-UPDRS part III change <10% between stimulation on/medication off and stimulation off/medication off) maintained the stimulation off/medication on condition for 1 month for open-label assessment.Results: Thirty-six patients were included. The acute effect of stimulation was significant (17% MDS-UPDRS part III), with 80% of patients classified as "good responders." Seven patients were classified as "poor stimulation responders," and the stimulation was switched off, but in 4 cases the stimulation was switched back "on" because of worsening of parkinsonism and dysphagia with a variable time delay (up to 10 days). No serious adverse effects occurred.Conclusions: The vast majority of late-stage PD patients (92%) show a meaningful response to STN-DBS. Effects of stimulation may take days to disappear after its discontinuation. We present a safe and effective decisional algorithm that could guide physicians and caregivers in making challenging therapeutic decisions in late-stage PD. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

A field study conducted with professional athletes (N = 420, 72.2% men, Mage = 25.14) examined the antecedents of stress linked to career termination. We hypothesized that stress linked to career termination may be affected by the type of passion (harmonious and obsessive) athletes develop for their sport activity, and that this passion may be affected by regulatory mode orientations (locomotion and assessment) and need for closure (NFC). The present findings confirm our hypotheses that locomotion positively predict stress linked to career termination through a partial mediation of harmonious passion, while assessment and NFC negatively predict stress through the mediation of obsessive passion. In conclusion, this study provides further information to existing intervention programs aimed at preventing the negative consequences related to athletes' career termination. [ABSTRACT FROM AUTHOR]

In this retrospective study, we evaluated both efficacy and effectiveness of safinamide 50 and 100 mg in the treatment of motor fluctuations and disabling dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD). Ninety-one PD patients were evaluated during the first year of commercialization of the drug, both prior to starting safinamide and at the last available follow-up. Evaluations were based on the Unified Parkinson's Disease Scale part III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS) walking and balance item 9 score, daily time spent in OFF and in ON with disabling dyskinesias (1 week diary), mean daily dose of levodopa (LD), dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I), monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD). Eight patients withdrew safinamide within the first month for minor side effects. At the follow-up evaluation, after a mean time with safinamide of 7.5 months ± 3.4, all patients showed a significant improvement of all the scale scores, except for HY, and of the daily dosages of the drugs and the LEDD. The same results were shown by PD patients treated with safinamide 50 mg and patients who started safinamide without switching from a previous MAOBI. PD patients with safinamide 100 mg and patients who started safinamide switching from a previous MAOBI significantly improved in time spent in OFF and LEDD. In conclusion, safinamide is safe and effective in improving motor complications in patients with idiopathic PD and can be considered a useful levodopa sparing strategy. [ABSTRACT FROM AUTHOR]

In double refereeing, agreement between referees is fundamental for the achievement of a flawless and smooth refereeing activity. Nonetheless, the agreeement can be affected by several external and internal factors, with a negative impact on the consistency of the refereeing and the fluidity of the game. The referee's Decision Threshold (DT) is the limit above which the evidence of a foul results in the call of an infraction by the referee. It represents the individual refereeing style, and it is one of the factors that can contribute to low agreement between the referees. We present an application of a new Bayesian procedure to estimate referee's DT in a typical refereeing task. To this end, 56 italian professional handball (FIGH) referees were asked to evaluate 96 potential foul plays, belonging to four different infraction types: 7-m throw, passive play, offensive foul, disciplinary sanctions. The proposed method provides information about: (i) referee's individual DT; (ii) the agreement between pairs of referees (i.e., one-to-one); (iii) the agreement between each referee and all the other referees (i.e., one-to-total); (iv) the agreement between each referee and a reference referee (i.e., one-to-expert); (v) the proportion of agreement between the referees and a reference referee for each potential foul play. Sport federations would profit by this procedure in different ways: by using the information about the DT to train referees, by detecting referees with a low agreement with their colleagues or with the reference referee, by focusing training on specific plays to improve the arbitration class internal consistency. • Agreement among referees is crucial for the quality of refereeing. • The definition of a foul play depends on a referee-specific decision threshold (DT). • Discrepancies between referees' DTs may lead to spurious agreements and disagreements. • We present a model quantifying agreement among referees, net of the influence of DTs. • This model improves the evaluation of refereeing consistency. [ABSTRACT FROM AUTHOR]

Photocatalytic thin films composed of titanium dioxide and poly(styrene sulfonate) with hierarchical porosity and high transparency were prepared by the layer-by-layer self-assembly method. The influence of preparation conditions on the structure and photocatalytic activity of the films was investigated. It was found there is no need to reach adsorption equilibrium during layer deposition. Using very short deposition times, films with better transparency and higher activity for methylene blue photo-oxidation were obtained. Diffusion limitations due to strong adsorption of dye molecules and ammonia to the polyelectrolyte were revealed. These results indicate that films could be devised to selectively degrade specific target molecules in a mixture. The films were deposited on a three-dimensional carbon substrate and successfully demonstrated in a photoelectrochemical water splitting experiment. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility, safety, and efficacy of vaccination with autologous tumor cells genetically modified with an adenoviral vector (Ad-GM) to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF), we conducted a phase I/II multicenter trial in patients with early and advanced stage non-small-cell lung cancer (NSCLC). Vaccines were generated from autologous tumor harvests. Intradermal injections were given every 2 weeks for a total of three to six vaccinations. Tumors were harvested from 83 patients, 20 with early-stage NSCLC and 63 with advanced- stage NSCLC; vaccines were successfully manufactured for 67 patients, and 43 patients were vaccinated. The most common toxicity was a local injection-site reaction (93%). Three of 33 advanced-stage patients, two with bronchioloalveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and >or=22 months). Longer survival was observed in patients receiving vaccines secreting GM-CSF at more than 40 ng/24 h per 10(6) cells (median survival = 17 months, 95% confidence interval [CI] = 6 to 23 months) than in patients receiving vaccines secreting less GM-CSF (median survival = 7 months, 95% CI = 4 to 10 months) (P =.028), suggesting a vaccine dose-related survival advantage. [ABSTRACT FROM AUTHOR]

Lentiviral vectors have demonstrated great potential as gene therapy vectors mediating efficient ex vivo and in vivo gene delivery and long-term transgene expression in both dividing and nondividing cells. However, for clinical studies it must be demonstrated that lentiviral vector preparations are safe and not contaminated by replication-competent recombinants related to the parental pathogenic virus. Here we describe a sensitive assay for the detection of replication-competent lentiviruses (RCL) in large-scale preparations of HIV-based lentiviral vectors. This RCL assay for lentiviral vectors is based on the principles used for retroviral vectors, using a highly permissive cell line, C8166-45, for RCL amplification and an appropriate positive control virus to establish the assay sensitivity. The assay is capable of detecting 1 RCL infectious unit in a background of 2.5 × 108 transducing units of vector in a single test culture. Statistically representative samples from large-scale lentiviral vector productions were assayed using multiple test cultures for each lot. Overall, a total of 1.4 × 1010 transducing units of vector from 10 independent 14-liter production lots were screened and no RCL was detected. We propose to implement this assay as a release testing for clinical-grade lentiviral vector preparations intended for gene therapy clinical trials. [Copyright &y& Elsevier]