Protease-activated receptor 2: a promising therapeutic target for women's cancers.

Cancers affecting women, such as breast, uterine, ovarian, endometrial and cervical cancers, have become increasingly prevalent. The growing incidence and death rates associated with these cancers warrant the development of innovative and alternative approaches to current treatments. This article investigates the association of women's cancers with a molecular target known as protease-activated receptor 2 (PAR2), a G-protein coupled receptor that is expressed on the surface of cancer cells. Expression levels of the PAR2 gene were curated from publicly available databases and were found to be significantly overexpressed in tissues from patients with breast, uterine, ovarian, endometrial or cervical cancer compared to normal tissues. PAR2 overexpression has been previously linked to tumor progression and, in some cases, tumor growth. Activation of PAR2 by either endogenous proteases or synthetic agonists triggers certain downstream intracellular signaling pathways that have been associated with tumor progression, cell migration and invasion, angiogenesis and apoptosis of cancer cells. While recent advances have led to the identification of several PAR2 antagonists, none has yet been developed for human use. Additionally, PAR2 inhibition has been shown also to increase the efficacy of chemotherapeutic drugs, allowing them to be potentially used at less toxic doses in combination therapies for cancer. The present work briefly summarizes the current status of PAR2 as a potential therapeutic target for treating women's cancers. Significance Statement This article highlights potential roles for PAR2 in cancers affecting women. Overexpression of the PAR2 gene in women's cancers is associated with various oncogenic processes such as tumor progression, cell migration and invasion, ultimately contributing to poorer patient prognoses. Given the increasing incidence of women's cancers, there is an urgent need to develop novel therapeutic drugs and PAR2 represents a promising target for developing new treatments.

Protease-activated receptor 2 attenuates doxorubicin-induced apoptosis in colon cancer cells.

Drug resistance represents a major problem in cancer treatment. Doxorubicin (adriamycin) is an injectable DNA intercalating drug that halts cancer cell growth by inhibiting topoisomerase 2, but its long-term effectiveness is compromised by onset of resistance. This study demonstrates that expression of the PAR2 gene in human colon adenocarcinoma tissue samples was the highest among 32 different cancer types (n = 10,989), and higher in colon adenocarcinoma tissues (n = 331) than normal colon tissues (n = 308), revealing an association between PAR2 expression and human colon cancer. HT29 cells are a human colorectal adenocarcinoma cell line that is sensitive to the chemotherapeutic drug doxorubicin and also expresses PAR2. We find that PAR2 activation in HT29 cells, either by an endogenous protease agonist (trypsin) or an exogenous peptide agonist (2f-LIGRL-NH2), significantly reduces doxorubicin-induced cell death, reactive oxygen species production, caspase 3/7 activity and cleavage of caspase-8 and caspase-3. Moreover, PAR2-mediated MEK1/2-ERK1/2 pathway induced by 2f-LIGRL-NH2 leads to upregulated anti-apoptotic MCL-1 and Bcl-xL proteins that promote cellular survival. These findings suggest that activation of PAR2 compromises efficacy of doxorubicin in colon cancer. Further support for this conclusion came from experiments with human colon cancer HT29 cells, either with the PAR2 gene deleted or in the presence of a pharmacological antagonist of PAR2, which showed full restoration of all doxorubicin-mediated effects. Together, these findings reveal a strong link between PAR2 activation and signalling in human colon cancer cells and increased survival against doxorubicin-induced cell death. They support PAR2 antagonism as a possible new strategy for enhancing doxorubicin therapy.

Evidencing the Impact of Web-Based Coproduction With Youth on Mental Health Research: Qualitative Findings From the MindKind Study.

BACKGROUND: Public involvement in research is a growing phenomenon as well as a condition of research funding, and it is often referred to as coproduction. Coproduction involves stakeholder contributions at every stage of research, but different processes exist. However, the impact of coproduction on research is not well understood. Web-based young people's advisory groups (YPAGs) were established as part of the MindKind study at 3 sites (India, South Africa, and the United Kingdom) to coproduce the wider research study. Each group site, led by a professional youth advisor, conducted all youth coproduction activities collaboratively with other research staff. OBJECTIVE: This study aimed to evaluate the impact of youth coproduction in the MindKind study. METHODS: To measure the impact of web-based youth coproduction on all stakeholders, the following methods were used: analysis of project documents, capturing the views of stakeholders using the Most Significant Change technique, and impact frameworks to assess the impact of youth coproduction on specific stakeholder outcomes. Data were analyzed in collaboration with researchers, advisors, and YPAG members to explore the impact of youth coproduction on research. RESULTS: The impact was recorded on 5 levels. First, at the paradigmatic level, a novel method of conducting research allowed for a widely diverse group of YPAG representations, influencing study priorities, conceptualization, and design. Second, at the infrastructural level, the YPAG and youth advisors meaningfully contributed to the dissemination of materials; infrastructural constraints of undertaking coproduction were also identified. Third, at the organizational level, coproduction necessitated implementing new communication practices, such as a web-based shared platform. This meant that materials were easily accessible to the whole team and communication streams remained consistent. Fourth, at the group level, authentic relationships developed between the YPAG members, advisors, and the rest of the team, facilitated by regular web-based contact. Finally, at the individual level, participants reported enhanced insights into mental well-being and appreciation for the opportunity to engage in research. CONCLUSIONS: This study revealed several factors that shape the creation of web-based coproduction, with clear positive outcomes for advisors, YPAG members, researchers, and other project staff. However, several challenges of coproduced research were also encountered in multiple contexts and amid pressing timelines. For systematic reporting of the impact of youth coproduction, we propose that monitoring, evaluation, and learning systems be designed and implemented early.

Young people's data governance preferences for their mental health data: MindKind Study findings from India, South Africa, and the United Kingdom.

Mobile devices offer a scalable opportunity to collect longitudinal data that facilitate advances in mental health treatment to address the burden of mental health conditions in young people. Sharing these data with the research community is critical to gaining maximal value from rich data of this nature. However, the highly personal nature of the data necessitates understanding the conditions under which young people are willing to share them. To answer this question, we developed the MindKind Study, a multinational, mixed methods study that solicits young people's preferences for how their data are governed and quantifies potential participants' willingness to join under different conditions. We employed a community-based participatory approach, involving young people as stakeholders and co-researchers. At sites in India, South Africa, and the UK, we enrolled 3575 participants ages 16-24 in the mobile app-mediated quantitative study and 143 participants in the public deliberation-based qualitative study. We found that while youth participants have strong preferences for data governance, these preferences did not translate into (un)willingness to join the smartphone-based study. Participants grappled with the risks and benefits of participation as well as their desire that the "right people" access their data. Throughout the study, we recognized young people's commitment to finding solutions and co-producing research architectures to allow for more open sharing of mental health data to accelerate and derive maximal benefit from research.

Stimulation of GABA Receptors in the Lateral Septum Rapidly Elicits Food Intake and Mediates Natural Feeding.

The increasing prevalence of obesity and eating disorders makes identifying neural substrates controlling eating and regulating body weight a priority. Recent studies have highlighted the role of the lateral septum (LS) in eating control mechanisms. The current study explored the roles of gamma-aminobutyric acid (GABA) receptors within the LS in the control of food intake. Experiments with a rat model (n ≥ 11/group) showed that LS microinjection of the GABAA receptor agonist, muscimol, and the GABAB receptor agonist, baclofen hydrochloride (baclofen), elicited intense, dose-dependent feeding. In contrast, LS pretreatment with the GABAA receptor antagonist, picrotoxin, markedly reduced the muscimol-elicited feeding, and pretreatment injections with the GABAB receptor antagonist, 2-hydroxysaclofen (2-OH saclofen), reduced the baclofen evoked response. Next, we showed that picrotoxin injection at the beginning of the dark phase of the light-dark cycle-when rats show a burst of spontaneous eating-reduced naturally occurring feeding, whereas 2-OH saclofen was ineffective. These results indicate that the activation of LS GABAA and GABAB receptors strongly stimulates feeding and suggests potential roles in feeding control neurocircuitry. In particular, our evidence indicates that endogenous LS GABA and GABAA receptors may be involved in mediating naturally occurring nocturnal feeding.