In this paper I argue that nursing research is losing its way. There are a number of ways in which this is happening; for example, people are spending much more time writing about methodology than getting on with the research itself and the reporting of discovery. Here, I address the extent to which we are debilitating the research enterprise through what passes as ‘ethics’ and ‘governance’ . I will refer to examples from nursing and related research to illustrate the gradual development of greater concern for the well-being of research participants and the prevention of harm. I will go on to illustrate how, in comparison to the search for knowledge in the wider world, the health professions (and in the UK nurses in particular) are making research more difficult to execute than it needs to be. In the development of defensive rules and procedures we have somehow forgotten exactly from what harms we are protecting our patients, students and staff . For those looking for a theoretical background to my views, they are, in essence, consequential, and I hope to show that with a harms and benefits approach we could bring much common sense to the critical appraisal of previous research and the approval and conduct of nursing research now and in the future.
The Care Programme Approach (CPA) for patients in contact with the specialist mental health services represents a significant change in care delivery for both patients and clinicians involved with mental health services. This study explores the attitudes and experiences of one group of patients on the CPA living in an outer London borough. One hundred and three patients were asked for their views and opinions; there was a response rate of 50%. The main findings of the study indicated that patients found the CPA process difficult to understand, and that there was an over-emphasis on administering the system. There was evidence to suggest that patients were unfamiliar with their treatment programmes, and that they lacked knowledge regarding their care. The study concluded that further research to examine patient attitudes to the CPA would be beneficial, since it was not possible to make precise conclusions based on the data available here.
A new research framework is described in this paper, termed 'the narrative thread'. It is a development of the case study, but argues that the paradigm of physical boundaries that has been used to define the case, can be shifted so that it is the phenomenon itself that defines the case, not where the case takes place. In addition, this framework has a number of attractive attributes, in that it is highly flexible, supports an inductive then a deductive approach, and gives formal guidance for both the incorporation of knowledge gained in literature reviews and the generation of theory.
The topic of young people drinking, and its related problems, continues to foster concern and controversy. This review highlights some of the main psychological, social and behavioural evidence related to the formation of children's attitudes to alcohol, the acquisition of drinking habits by young people and factors associated with patterns of alcohol consumption and its consequences. Some of the implications of this evidence are highlighted, and recommendations are suggested to curb levels of heavy/inappropriate drinking among youth. Many children are hostile to alcohol consumption by adults. The onset of adolescence generally reverses such negative attitudes and drinking is widely viewed by teenagers and young adults in a positive light as a symbol of being adult and sociable. Many young people drink to intoxication as part of the process of learning how to drink. Recent studies show that rates of heavy drinking, intoxication and negative consequences among teenagers vary considerably in different countries. Teenagers in north west Europe (including Denmark, Finland, Iceland, Ireland and the UK) report the highest rates, while those in the Mediterranean area report much lower ones. It is concluded that a sensible approach by parents should involve teaching their children to drink in moderation at home and that parents should set boundaries to control and protect their children from harm associated with periodic heavy drinking. School-based alcohol education has generally produced disappointing results and it is suggested that harm minimisation policies should be devised that are relevant to young people.
This paper explores a range of research methodology issues, all based in the social sciences, which emerged from an in-depth study of school nursing that was carried out in East Norfolk during 1996. The full report of the research itself (DeBell and Everett, 1997) presents the findings of that work. The paper here, in contrast, uses that research exercise as an opportunity to explore questions about research methodology and to suggest the philosophical roots of the methodological approaches used in this particular research. Such questions are usually only of secondary interest to the key findings in published work. Here, the findings are implied while the methodological issues are moved to the foreground. The underlying intention behind the paper is to reflect on some of the philosophical roots of the methodological approaches used in nursing research. In particular, the intention is to offer this specific research project as a subject for debate and discussion about research methodology itself. How do researchers design a project to answer a research question? What are the implications for research outcome, if any, of selecting one set of approaches rather than another? And, particularly, does nursing research need to establish its capability for philosophical reflection?
O objetivo desta nota técnica é apresentar duas propostas que visam aprimorar o desempenho do setor de distribuição no sentido de promover o aumento da eficiência em dois aspectos importantes, a eficiência do custo operacional e a qualidade na continuidade do fornecimento ao usuário.
Esta nota técnica tem por objetivo fazer uma síntese do quadro produtivo do setor agropecuário brasileiro nos últimos quinze anos, assim como apresentar indicadores de produtividade e sustentabilidade. O agronegócio1 é representativo no produto interno bruto do país, na dinâmica do comércio internacional, bem como na geração de empregos na economia (Fishlow e Vieira Filho, 2020).
Alicia Beeghly-Fadiel, Johnathan Cooks, Dajah Chase
et al.
Abstract BACKGROUND: A key clinical challenge in ovarian cancer is identifying new strategies to treat patients who do not respond to poly ADP-ribose polymerase (PARP) inhibitor (PARPi) therapy. We previously linked the nuclear orphan receptor NR4A1/TR3 to pro-growth and pro-survival effects in ovarian cancer cells. However, it is unknown whether inhibiting NR4A1 function has therapeutic effects alone or in combination with PARPi in vitro. Moreover, the prognostic value of NR4A1 expression in patient tumors remains ill-defined, as two prior reports had contradictory findings for associations with ovarian cancer survival. OBJECTIVE: We undertook this study to test the therapeutic potential of inhibiting NR4A1 in ovarian cancer cells, and to clarify the prognostic value of NR4A1 expression in patient tumors. METHODS: In a panel of established ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3), we inhibited NR4A1 using the chemical antagonist, 1,1-Bis(3'-indolyl)-1-(p-hydroxyphenyl) methane (C-DIM) and siRNA targeting NR4A1 (siNR4A1). Effects of C-DIM on cell growth, alone and in combination with the PARPi, olaparib and rucaparib, were assessed in sulforhodamine B (SRB) in vitro assays. Markers of apoptosis (cleaved PARP, cleaved caspase-3) and proliferation (Ki67, PCNA, p21) were measured by western blot or immunohistochemistry (IHC). In ovarian tumors, NR4A1 was measured by IHC in 203 clinically annotated formalin-fixed paraffin-embedded (FFPE) tissue samples from the Vanderbilt University Medical Center (VUMC) Tissue Repository for Ovarian Cancer (TROC). Staining intensity (1: weak; 2: moderate; 3: strong) and percent of positive nuclei (0-100) were multiplied to yield an H score for NR4A1 expression. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by Hazards Ratios (HR) and 95% Confidence Intervals (CI) from proportional hazards regression. RESULTS: In ovarian cancer cell lines, C-DIM induced concentration-dependent decreases in cell growth and markers of proliferation, and stimulated apoptosis. These effects were mimicked in cells transfected with siNR4A1 compared to a non-targeting siRNA-transfected control. In combination with PARPi, C-DIM induced synergistic growth inhibition and apoptosis in vitro. In tumors, NR4A1 expression lower than the median (H score <153.6) was more common among later stage, higher grade, serous tumors with suboptimal cytoreduction or platinum resistant disease. Higher NR4A1 expression was associated with better OS (HR: 0.52, 95% CI: 0.37–0.74) in unadjusted analyses. However, after adjustment for important prognostic covariates, including age, stage, grade, and histologic subtype, higher NR4A1 was associated with significantly shorter PFS (HR: 2.35, 95% CI: 1.29–4.28). CONCLUSIONS: Our current results reconcile the discrepancy between prior NR4A1 reports, as associations differed due to confounding by clinical covariates. Shorter survival among cases with higher NR4A1 expression is supported by experimental evidence showing reduced ovarian cancer cell growth and increased apoptosis following NR4A1 inhibition, both alone and when combined with a PARPi. Together, our findings support further development of NR4A1 inhibition as a novel therapeutic approach that could improve response to PARPi therapy among ovarian cancer patients with chemoresistant disease. Citation Format: Alicia Beeghly-Fadiel, Johnathan Cooks, Dajah Chase, Marta Crispens, Dineo Khabele, and Andrew J Wilson. PROGNOSTIC SIGNIFICANCE OF NR4A1/TR3 EXPRESSION IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-088.
Abstract Talazoparib, a potent PARP inhibitor (PARPi), induces synthetic lethality in BRCA-deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARPi's. We sought to formulate Talazoparib in a nanoparticle delivery system such that the drug could be administered intraperitoneally, localizing the entire dose at the disease site, to increase therapeutic efficacy and minimize toxicity. NanoTalazoparib was formulated and characterized and found to have a mean diameter of 70 nm and a neutral surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine tubal and human HGSOC cell lines and dose response compared to the first clinically approved PARPi, Olaparib. Dose response data indicated all cell lines were more sensitive to Talazoparib and NanoTalazoparib than Olaparib and all lines showed the same sensitivity to nanoformulations as free drugs. The human cell lines had various BRCA mutations and deletions, as well as a homologous recombination proficient (HRP) line, however, the HRP line was more sensitive to treatment than some HRD lines. Therapeutic efficacy was tested in vivo in a murine cancer model that mimics disseminated peritoneal disease. NanoTalazoparib 3X weekly for 8 weeks did not shrink tumors but resulted in tumor growth inhibition of 64% while an equivalent dose of oral Talazoparib only resulted in 34% growth inhibition. NanoTalazoparib suppressed the average volume of ascites at the study endpoint by 3.45 times more than oral Talazoparib. H&E staining of the tissues indicated no significant toxicity to the organs of the mononuclear phagocyte system. These results indicate that NanoTalazoparib can be used to localize PARPi therapy to the peritoneal cavity for disseminated late stage ovarian cancer treatment. Our data suggests that NanoTalazoparib could be utilized to delay the formation of tumor ascites for women with HR-deficient disease. While NanoTalazoparib did not effectively treat the disseminated disease at this dose, it may have clinical utility, either in combination with other therapies or as a maintenance therapy. Preclinical data indicates PARP inhibitors potentiate damage when combined with other cytotoxic treatments, however, in the clinic this has resulted in enhanced toxicity, forcing dose reduction and delay. The IP administration of NanoTalazoparib may provide a route to bypass some of the toxicities that have plagued combination treatments. Supported in part by Rivkin Foundation and CDMRP Ovarian Cancer Research Program Citation Format: Paige Baldwin, Anders Ohman, Jamie Medina, Daniela Dinulescu, Srinivas Sridhar. NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-087.
Abstract Due to peritoneal metastasis and frequent recurrence, ovarian cancer has the highest mortality among gynecological cancers. Epithelial to mesenchymal transition (EMT) contributes to ovarian tumor metastasis. In this study, we report for the first time that metal regulatory transcription factor 1 (MTF1) was upregulated in ovarian cancer, and its high expression was associated with poor patient survival and disease relapse. Knockout of MTF1 using lentiviral CRISPR/Cas9 nickase vector-mediated gene editing inhibited EMT by upregulating epithelial cell markers E-cadherin and cytokeratin 7, and downregulating mesenchymal markers Snai2 and β-catenin in ovarian cancer SKOV3 and OVCAR3 cells. Loss of MTF1 reduced cell proliferation, migration, and invasion in both SKOV3 and OVCAR3 cells. Knockout of MTF1 upregulated the expression of the KLF4 transcription factor, and attenuated two cellular survival pathways, ERK1/2 and AKT. Our studies demonstrated that MTF1 plays an oncogenic role and contributes to ovarian tumor metastasis by promoting EMT. MTF1 may be a novel biomarker for early diagnosis as well as a drug target for clinical therapy. Citation Format: Guannan Zhao, Lawrence M Pfeffer Junming Yue. KNOCKOUT OF MTF1 RESULTS IN THE INHIBITION OF EMT IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-120.