Participant experiences in phase I pediatric oncology clinical trials

Indiana University-Purdue University Indianapolis (IUPUI)Phase I clinical trials (P1Ts) are the first step in testing new medical therapies in humans, and are essential for developing new and innovative therapies for children with cancer. P1Ts are ethically controversial as they are not intended to directly benefit participants, but are particularly controversial for children with cancer who are only able to participate when there is no known curative therapy for their cancer. Benefits of pediatric oncology P1T participation may include improved quality of life (QOL) and hope. Risks may include fostering unrealistic hope, burdening children with additional medical procedures and toxicities, and limiting the opportunity for palliation. The goal of this dissertation was to investigate the P1T participation experience for children with cancer and their parents by: (1) assessing what is currently known about the participation experience, (2) exploring ways to understand and assess treatment burden and QOL during participation, and (3) interviewing parents about the experience of having a child participate in a P1T. Following a review of the literature, two studies were conducted: a longitudinal pilot study of 13 parent and child dyads who enrolled in a pediatric oncology early phase clinical trial at the recruiting institution, and a phenomenological study of 11 parents of children with cancer who participated in pediatric oncology P1Ts. Key findings included a dearth of research on the experiences of children and parents in pediatric oncology P1Ts. Instead, existing research has focused on consent processes. The longitudinal pilot study provided some insight into experiences of children and parents during trial participation, including that there may be time points when parents’ and children’s perceptions of the child’s quality of life substantively differ. Interviews with parents confirmed some of the anticipated benefits and risks of participation in P1Ts, and highlighted parents’ sense of running out of time to find an effective treatment and needing to use time they have with their child well. Specific challenges in conducting this research were participant attrition due to disease progression and the need for multi-site research to obtain an adequate sample

Knowledge of the signs and symptoms and risk factors of lung cancer in Australia: Mixed methods study

© 2016 Crane et al. Background: Lung cancer is the leading cause of cancer death in Australia. There is potential that health promotion about the risks and warning signs of lung cancer could be used to reduce delays in symptom presentation when symptoms are first detected. This study investigated knowledge, attitudes and beliefs which might impact help-seeking behaviour and could provide insight into possible public health interventions in New South Wales (NSW). Methods: A convergent mixed method study design was used wherein data from 16 qualitative focus groups of residents (40+ years), purposefully recruited and stratified by smoking status, age and geography (metropolitan/regional), were compared with a CATI administered population-wide telephone survey (n = 1,000) using the Cancer Research UK cancer awareness measure (LungCAM). Qualitative findings were analysed thematically using NVIVO. Logistic regression analysis was used to investigate predictors of symptom knowledge in STATA. Findings were integrated using triangulation techniques. Results: Across focus groups, haemoptysis was the only symptom creating a sense of medical urgency. Life experiences evoked a 'wait and see' attitude to any health deterioration. Perceived risk was low amongst those at risk with current smokers preferring to deny their risk while former smokers were generally unaware of any ongoing risk. The quantitative sample consisted of females (62 %), 40-65 years (53 %), low SES (53 %), former (46 %) and current smokers (14 %). In quantitative findings, haemoptysis and dyspnoea were the most recognised symptoms across the sample population. Age (<65 years), sex (female) and high socio-economic status contributed to a higher recognition of symptoms. Smoking was recognised as a cause of lung cancer, yet ever-smokers were less likely to recognise the risk of lung cancer due to second-hand smoke (OR 0.7 95 % CI 0.5-0.9). Conclusion: While there was some recognition of risk factors and symptoms indicative of lung cancer, there was disparity across the sample population. The qualitative findings also suggest that knowledge may not lead to earlier presentation; a lack of urgency about symptoms considered trivial, and smoking-related barriers such as stigma may also contribute to time delays in presentation. Public health interventions may be required to increase awareness of risk and emphasise the importance of seeking medical attention for ongoing symptoms

Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection.

Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead