Adjuvant oncolytic virotherapy for personalized anti-cancer vaccination.

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.

Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks.

The study of rare human syndromes characterized by radiosensitivity has been instrumental in identifying novel proteins and pathways involved in DNA damage responses to ionizing radiation. In the present study, a mutation in mitochondrial poly-A-polymerase (MTPAP), not previously recognized for its role in the DNA damage response, was identified by exome sequencing and subsequently associated with cellular radiosensitivity. Cell lines derived from two patients with the homozygous MTPAP missense mutation were radiosensitive, and this radiosensitivity could be abrogated by transfection of wild-type mtPAP cDNA into mtPAP-deficient cell lines. Further analysis of the cellular phenotype revealed delayed DNA repair, increased levels of DNA double-strand breaks, increased reactive oxygen species (ROS), and increased cell death after irradiation (IR). Pre-IR treatment of cells with the potent anti-oxidants, α-lipoic acid and n-acetylcysteine, was sufficient to abrogate the DNA repair and clonogenic survival defects. Our results firmly establish that mutation of the MTPAP gene results in a cellular phenotype of increased DNA damage, reduced repair kinetics, increased cell death by apoptosis, and reduced clonogenic survival after exposure to ionizing radiation, suggesting a pathogenesis that involves the disruption of ROS homeostasis.

Comparison of a 16- versus a 19-day interval between controlled internal drug release removal and prostaglandin F2α following a 14-day controlled internal drug release treatment and fixed-time artificial insemination in postpartum beef cows.

This experiment compared 2 long-term controlled internal drug release (CIDR)-based protocols to synchronize estrus before fixed-time artificial insemination (FTAI) in postpartum beef cows. Cows were assigned to treatments by age, BCS, and days postpartum. Cows assigned to the 14- to 19-d CIDR-PGF2α protocol (n = 196) received CIDR inserts (1.38 g progesterone [P4]) from d 0 to 14 and PGF2α (25 mg, i.m.) 19 d after CIDR removal on d 33. Cows assigned to the 14-to-16-d CIDR-PGF2α protocol (n = 195) received CIDR inserts from d 3 to 17 and PGF2α 16 d after CIDR removal on d 33. Cows were artificially inseminated on d 36, 72 h after PGF2α, with GnRH (100 µg, i.m.) at FTAI. Cows were exposed for natural service 14 d after FTAI for 75 d. Blood samples for P4 were collected at d -10 and 0 to determine pretreatment estrous cyclicity status and again at PGF2α. Blood samples for estradiol (E2) were collected at PGF2α and FTAI. HeatWatch estrus detection transmitters were used from CIDR removal until FTAI to determine onset of estrus after CIDR removal and PGF2α. Dominant follicle diameter was determined at PGF2α and FTAI. Pregnancy diagnosis was performed 70 d after FTAI and confirmed at d 140 of gestation. Estrous response after CIDR removal was similar between treatments. Cows in both treatments had similar size dominant follicles on d 33 at PGF2α and d 36 at FTAI. Progesterone at PGF2α was greater (P = 0.03) for 14-to-16-d compared to 14-to-19-d treated cows. Mean concentrations of E2 at PGF2α were similar between treatments but were greater (P = 0.01) at FTAI for 14-to-16-d compared to 14-to-19-d treated cows. Estrous response after PGF2α was greater (P < 0.01) for 14-to-19-d compared to 14-to-16-d treated cows (47.4 vs. 29.7%, respectively). Pregnancy rate resulting from FTAI was affected by the treatment × age group interaction (P = 0.08). Pregnancy rate after FTAI among cows ≥ 4 yr tended to be greater (P = 0.06) for 14-to-19-d compared to the 14-to-16-d treated cows, suggesting that the 14-to-19-d schedule works better for older age cows compared with the 14-to-16-d schedule. Final pregnancy rates were similar between the 2 treatments. In summary, these data indicate that a range in intervals from CIDR removal to PGF2α may be feasible when using long-term CIDR-based protocols in cows and raise questions that warrant further study regarding the benefits of extending this interval based on cow age.

Parent-managed behavioral treatment for preschool children with autism: some characteristics of UK programs.

Early intensive behavioral intervention for autism has attracted controversy since Lovaas (1987) reported that 47% of his experimental group attained normal functioning. We summarize child and program data from 75 children receiving EIBI in the UK. The majority of children (57%) started treatment later than in Lovaas (1987), and 16% did not exceed his minimum IQ criterion. Children experienced fewer hours of treatment (mean of 32 hours vs. 40 hours per week), and their programs received relatively infrequent supervision. 21% of programs received supervision from individuals currently accredited as competent to provide Lovaas's treatment. No child started early enough, and received 40 hours per week, and had accredited supervision. Due to these variations from his model, Lovaas (1987) findings are unlikely to be replicated for this sample of children.

Progress and outcomes for children with autism receiving parent-managed intensive interventions.

Parent-managed behavioral interventions for young children with autism are under-researched. We analyzed data from 66 children served by 25 different early intervention consultants. After a mean of 31.6 months of intervention IQ scores had not changed (N = 22). Vineland adaptive behavior scores had increased significantly by 8.9 points (N = 21). No children aged > 72 months attained normal functioning, i.e., IQ > 85 and unassisted mainstream school placement (N = 42). Progress for 60 children across 12 months was found for mental age (5.4 months), adaptive behavior (9.7 months), and language (5.1 months). The interventions did not reproduce results from clinic-based professionally directed programs. The effectiveness of the parent-managed intervention model as it has developed and the adequacy of professional services in that model are discussed.

Purification and bioassays of a diuretic and natriuretic fraction from garlic (Allium sativum).

The intravenous administration of a purified fraction (6 microg/kg) to anaesthesized dogs was followed by a significant biphasic diuretic and natriuretic response which reached a maximum at 180 min after injection. Chloride, but not potassium ions, followed the natriuretic profile. No changes were observed in arterial blood pressure or in the electrocardiogram. The purified garlic fraction also induced an inhibitory dose-dependent effect on kidney Na, K-ATPase.

Experimental functional analyses for challenging behavior: a study of validity and reliability.

The convergent validity of an experimental (analog) functional analysis was investigated by a comparison of three separate ways of interpreting the data derived from such an assessment: two previously published methods and the criterion Z method derived by the authors. Data from the experimental functional analysis of the challenging behavior(s) of 27 individuals with intellectual disabilities were analyzed to assess agreement between the three forms of interpretation. The test-retest reliability of all three methods over periods of 2 weeks, 1 month, and 3 months was also calculated. The results suggest that the methods of interpreting function from experimental assessments can give different results and that the test-retest reliability of the experimental functional analyses is poor. The implications of these findings are discussed in relation to clinical practice.

Behavioural effects of long-term multi-sensory stimulation.

OBJECTIVES: Regular access to a multi-sensory environment (MSE or Snoezelen room) was compared with a non-complex sensory environment for individuals with learning disabilities. We also tested the prediction that those individuals whose challenging behaviour was maintained by sensory consequences would benefit most from exposure to the MSE. DESIGN: The conditions were compared over 16-week periods using a double crossover design, and were matched for social contact and attention from the enabler. Participants were randomly assigned to orders of treatments. METHODS: Participants were 27 adults with severe/profound learning disabilities who exhibited challenging behaviour. Behaviour was assessed before and after each treatment phase using both direct observation and standardized assessments (the Functional Performance Record and the Problem Behaviour Inventory). The behavioural observations formed the basis of a functional analysis of each individual's challenging behaviour. RESULTS: Some participants became more calm and relaxed while in the MSE, however, the objective measures of behaviour outside the treatment settings revealed no difference between the MSE and control conditions. Challenging behaviour maintained by sensory consequences showed no greater responsivity to the MSE than to the control condition. CONCLUSIONS: The multi-sensory environment had no effects beyond those that could be ascribed to the social interaction between participant and enabler. Anecdotal evidence of favourable responses within the MSE itself could not be confirmed outside the environment.