Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Regulatory T lymphocytes (Treg) infiltrate human glioblastoma (GBM); are involved in tumor progression and correlate with tumor grade. Transient elimination of Tregs using CD25 depleting antibodies (PC61) has been found to mediate GBM regression in preclinical models of brain tumors. Clinical trials that combine Treg depletion with tumor vaccination are underway to determine whether transient Treg depletion can enhance anti-tumor immune responses and improve long term survival in cancer patients.Using a syngeneic intracrabial glioblastoma (GBM) mouse model we show that systemic depletion of Tregs 15 days after tumor implantation using PC61 resulted in a decrease in Tregs present in tumors, draining lymph nodes and spleen and improved long-term survival (50% of mice survived >150 days). No improvement in survival was observed when Tregs were depleted 24 days after tumor implantation, suggesting that tumor burden is an important factor for determining efficacy of Treg depletion in clinical trials. In a T cell dependent model of brain tumor regression elicited by intratumoral delivery of adenoviral vectors (Ad) expressing Fms-like Tyrosine Kinase 3 ligand (Flt3L) and Herpes Simplex Type 1-Thymidine Kinase (TK) with ganciclovir (GCV), we demonstrate that administration of PC61 24 days after tumor implantation (7 days after treatment) inhibited T cell dependent tumor regression and long term survival. Further, depletion with PC61 completely inhibited clonal expansion of tumor antigen-specific T lymphocytes in response to the treatment.Our data demonstrate for the first time, that although Treg depletion inhibits the progression/eliminates GBM tumors, its efficacy is dependent on tumor burden. We conclude that this approach will be useful in a setting of minimal residual disease. Further, we also demonstrate that Treg depletion, using PC61 in combination with immunotherapy, inhibits clonal expansion of tumor antigen-specific T cells, suggesting that new, more specific targets to block Tregs will be necessary when used in combination with therapies that activate anti-tumor immunity

Primary caregivers, healthcare workers, teachers and community leaders' perceptions and experiences of their involvement, practice and challenges of disclosure of HIV status to children living with HIV in Malawi: A qualitative study

Background: The World Health Organisation has recommended that healthcare workers, teachers and community leaders work with parents to support children living with HIV. The aim of this study was to assess the perceptions and experiences of primary caregivers and other care providers such as healthcare workers, teachers, and community leaders regarding their involvement, practice and challenges of HIV disclosure to children aged between 6 and 12 years living with HIV in Malawi. Methods: Twelve focus group discussions and 19 one-on-one interviews involving a total of 106 participants were conducted in all three administrative regions of Malawi. The interviews and focus group discussions explored perceptions and experiences regarding involvement, practice and challenges of disclosure of HIV status to children. Data were analysed using thematic analysis. Results: Primary caregivers, healthcare workers, teachers, and community leaders all reported that the disclosure of HIV status to children was not well coordinated because each of the groups of participants was working in isolation instead of working as a team. A "working together" model emerged from the data analysis where participants expressed the need for them to work as a team in order to promote safe and effective HIV status disclosure through talking about HIV, sharing responsibility and open communication. Participants reported that by working together, the team members would ensure that the prevalence of HIV disclosure to young children increases and that there would be a reduction in any negative impact of disclosure. Conclusion: Global resources are required to better support children living with HIV and their families. Healthcare workers and teachers would benefit greatly from training in working together with families living with HIV and, specifically, training in the disclosure process. Resources, in the form of books and other educational materials, would help them explain HIV and its effective management to children and families

Do social networks affect the use of residential aged care among older Australians?

Background: Older people's social networks with family and friends can affect residential aged care use. It remains unclear if there are differences in the effects of specific (with children, other relatives, friends and confidants) and total social networks upon use of low-level residential care and nursing homes. Methods: Data were drawn from the Australian Longitudinal Study of Ageing. Six waves of data from 1477 people aged ≥ 70 collected over nine years of follow-up were used. Multinomial logistic regressions of the effects of specific and total social networks on residential care use were carried out. Propensity scores were used in the analyses to adjust for differences in participant's health, demographic and lifestyle characteristics with respect to social networks. Results Higher scores for confidant networks were protective against nursing home use (odds ratio [OR] upper versus lower tertile of confidant networks = 0.50; 95%CI 0.33–0.75). Similarly, a significant effect of upper versus lower total network tertile on nursing home use was observed (OR = 0.62; 95%CI 0.43–0.90). Evidence of an effect of children networks on nursing home use was equivocal. Nursing home use was not predicted by other relatives or friends social networks. Use of lower-level residential care was unrelated to social networks of any type. Social networks of any type did not have a significant effect upon low-level residential care use. Discussion: Better confidant and total social networks predict nursing home use in a large cohort of older Australians. Policy needs to reflect the importance of these particular relationships in considering where older people want to live in the later years of life.Lynne C Giles, Gary FV Glonek, Mary A Luszcz and Gary R Andrew

Lab4CE: a Remote Laboratory for Computer Education

International audienceRemote practical activities have been demonstrated to be efficient when learners come to acquire inquiry skills. In computer science education, virtualization technologies are gaining popularity as this technological advance enables instructors to implement realistic practical learning activities, and learners to engage in authentic and problem-based learning. However, virtualization solutions have not been designed especially for education and do not address any pedagogical concern. Since several large-scale studies showed that instructional supports during practical activities are almost as important as technical features, this article investigates the following research question: how the scaffolding around the lab increases students’ engagement in remote practical learning of computer science? To answer this question, we introduce the Lab4CE environment, a remote laboratory for computer education which adopts a distributed, modular and flexible architecture to integrate a set of scaffolding tools and services intended for instructors and learners. An exploratory study conducted with 139 undergraduate students enrolled in the first year of a computer science degree suggests a positive effect of the framework on learners’ engagement when they come to practice system administration, and reveals a significant positive correlation between students’ activity within the system and students’ learning achievement