A novel cell line panel reveals non-genetic mediators of platinum resistance and phenotypic diversity in high grade serous ovarian cancer.

OBJECTIVES: Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model. METHODS: We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whole genome sequencing, RNASeq and creation of intraperitoneal models. RESULTS: Mutational signature analysis indicated that platinum-resistant cell lines evolved from a pre-existing ancestral clone but a unifying mutational cause for drug resistance was not identified. However, cisplatin-resistant and carboplatin-resistant cells evolved recurrent changes in gene expression that significantly overlapped with independent samples obtained from multiple patients with relapsed HGSC. Gene Ontology Biological Pathways (GOBP) related to the tumour microenvironment, particularly the extracellular matrix, were repeatedly enriched in cisplatin-resistant cells, carboplatin-resistant cells and also in human resistant/refractory samples. The majority of significantly over-represented GOBP however, evolved uniquely in either cisplatin- or carboplatin-resistant cell lines resulting in diverse intraperitoneal behaviours that reflect different clinical manifestations of relapsed human HGSC. CONCLUSIONS: Our clinically relevant and usable models reveal a key role for non-genetic factors in the evolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell-intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum-resistant HGSC.

Advance directives in skilled nursing facility residents transferred to emergency departments.

OBJECTIVE: Ten years have passed since Congress enacted the Patient Self-Determination Act to promote the use of advance directives (ADs). This study was performed to determine the frequency, type, demographic distribution, and utility of ADs that accompany residents of skilled nursing facilities (SNFs) transferred to emergency departments (EDs). METHODS: This was an observational, cross-sectional cohort of SNF residents, transferred to two urban, academic EDs. Chart review and physician interviews were conducted on consecutive patients arriving during 12-hour data collection shifts. RESULTS: Among 715 patients entered, 315 [44%, 95% confidence interval (95% CI) = 40% to 48%] had an AD. Advance directives were significantly more prevalent among white (50%) than African American (34%) or Hispanic (39%) patients (p < 0.001), and varied from 0% to 94% among SNFs. Of the 315 patients with ADs, do-not-resuscitate (DNR) orders were the most prevalent (65%, 95% CI = 58% to 69%). Although 75% (95% CI = 69% to 81%) of the DNR orders addressed cardiopulmonary resuscitation (CPR), only 12% (95% CI = 8% to 16%) addressed intubation. Among 39 patients who required intubation or CPR, 44% had ADs, 82% (95% CI = 57% to 96%) of which were deemed useful. CONCLUSIONS: Despite a decade of legislation promoting their use, ADs are lacking in most SNF residents transferred to EDs for evaluation and in most settings in which a clinical indication exists for intubation or CPR. Variation in their prevalence appears to be associated with both ethnicity and SNF origin. Although about three-fourths of DNR ADs addressed CPR, only about one in ten offered guidance regarding intubation. When available, ADs are used in most instances to guide emergency care.

Health promotion and senior women with limited incomes.

Health promotion is increasingly being recognized as making an important contribution to the well-being of Canada's seniors. Most research relating to this topic, however, has focused on middle-income senior men and women. An exploratory study using ethnographic methods was conducted to explore and describe the health promotion experience of senior women living on limited incomes. Interviews with a total of 11 urban senior women living on limited incomes were analyzed. A major finding of this study was that the women utilized a wide variety of "ways of living" that are presented in the model, Health Promotion as Self Nurturance. Health promotion was perceived to be influenced by living on a limited income by most participants; however, 3 of the participants believed that their health status and income level were unrelated. Findings are discussed and implications for community health nurses are offered.

Respite--a coping strategy for family caregivers.

The caregiver respite experience is seen as one way to moderate the negative consequences of caregiving. From an interpretivist research orientation, this study explored how 10 family caregivers of persons with dementia experienced respite. From a coping theoretical perspective, the caregiver respite experience is discussed as a process of "getting out" of the caregiver world, and is linked to avoidance strategies of emotion-focused coping. The following three phases within the coping dimension of the respite experience were found: caregivers recognizing their need to get out of the caregiver world, giving themselves permission to actually get out from it temporarily, and having the appropriate social support resources available to facilitate the getting out. The critical practice and research implications linked to caregivers' ability to acknowledge their need for respite are described.

Urinary excretion of aquaporin-2 in humans: a potential marker of collecting duct responsiveness to vasopressin.

The vasopressin-sensitive water channel (aquaporin 2; AQP-2) mediates water transport across the apical plasma membrane of the renal collecting ducts and is excreted in human urine. This study presents the hypothesis that measurements of the AQP-2 excretion rate might be used as a marker of collecting-duct responsiveness to vasopressin, and therefore could be useful in the clinical evaluation of various water-balance disorders. This study presents information about the development of an antibody to human AQP-2, and measures the urinary excretion of AQP-2 by quantitative Western analysis. A standard curve of band densities was generated by using known quantities of the modified immunizing peptide to derive the amount of AQP-2 contained in aliquots of urine. AQP-2 urinary excretion changed with short-term alterations in hydration status produced either by water loading (76% decrease, P < 0.01) or by 3% sodium chloride (760% increase, P < 0.01). Steady-state 24-h urinary excretion of AQP-2 was 43 +/- 10 nmol/24 h (or 28.5 +/- 6.9 pmol/mg creatinine), and 20 +/- 6 nmol/24 h (or 18.3 +/- 7.9 pmol/mg creatinine) in men and women, respectively. Therefore, urinary AQP-2 excretion can be quantified by using Western analysis, and may serve as a marker of collecting-duct responsiveness to vasopressin in different physiologic settings.

Health promotion in a scheduled cyclical format.

Many previously described health promotion programs focus on a limited number of issues, such as exercise, or direct their attention to multiple topics concurrently. In an effort to generate increased employee interest in important health concepts and to assure that appropriate emphasis is given to all relevant major health promotion topics, we have developed a four-year program, superimposed on our preexisting health maintenance/promotion structure. The first year of the program focuses on cardiovascular disease prevention; the second, on early cancer detection and prevention; the third, on psychologic and social issues; and the fourth, on other significant topics such as accidents, diabetes, pregnancy, and musculoskeletal disorders. Such an approach provides for a comprehensive program, maximizing the participation of available corporate and community resources, encourages employee participation by sequential attention to different issues, and affords the opportunity for directing attention to revisions and additions predicated by medical advances.