Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma.

Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.

Therapeutic Efficacy of a Bivalent Inhibitor of Prostate-Specific Membrane Antigen Labeled with 67Cu.

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is promising for prostate cancer. We previously reported a ligand, 64Cu-CuSarbisPSMA, featuring 2 lysine-ureido-glutamate groups. Here, we report the therapeutic potential of 67Cu-CuSarbisPSMA. Methods: Growth of PSMA-positive xenografts was evaluated after treatment with 67Cu-CuSarbisPSMA or 177Lu-LuPSMA imaging and therapy (I&T). Results: At 13 d after injection, tumor growth was similarly inhibited by the 2 tracers in a dose-dependent manner. Survival was comparable after single (30 MBq) or fractionated (2 × 15 MBq, 2 wk apart) administrations. Conclusion:67Cu-CuSarbisPSMA is efficacious in a PSMA-expressing model of prostate cancer.

Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre.

BACKGROUND: Detection of homozygous deletion of the p16 gene (CDKN2A) by fluorescence in situ hybridization (FISH) has been investigated as an ancillary technique in the diagnosis of malignant mesothelioma. METHOD: This retrospective study reviewed the results of all p16 FISH tests performed at a regional mesothelioma centre from February 2012 to November 2019 in cases of possible mesothelioma to examine the diagnostic utility of this test as well as patients characteristics and survival in p16 FISH positive mesothelioma versus p16 FISH negative mesothelioma. RESULTS: P16 FISH testing was requested in 216 pathological samples in the study period. The test failure rate was 4% (10/216). Median time from request to result was 10 days (IQR 7-13, range 1-30). The sensitivity, specificity, NPV and PPV were 60 %, 100 %, 39 % and 100 % respectively. There were no false positive results and this genetic aberration was only detected in cases of mesothelioma. The prevalence of p16 FISH positive mesothelioma was higher in cytological specimens compared to histological specimens (75 % vs 58 %, p = 0.03) and lower in women compared to men (33 % vs 66 %, p = 0.003). P16 FISH positive mesothelioma was associated with significantly worse survival (median overall survival 285 vs 339 days, p = 0.0018). This remained significant after adjusting for confounding variables (OR 4.4, 95 %CI 1.84-11.14, p = 0.001). CONCLUSIONS: In this study, 60 % of mesotheliomas harbour a homozygous deletion of CDKN2A and can be accurately, reliably and efficiently identified by p16 FISH testing. This test can be embedded within routine practice in mesothelioma pathways to enhance diagnostic accuracy.

Using creative co-design to develop a decision support tool for people with malignant pleural effusion.

BACKGROUND: Malignant pleural effusion (MPE) is a common, serious problem predominantly seen in metastatic lung and breast cancer and malignant pleural mesothelioma. Recurrence of malignant pleural effusion is common, and symptoms significantly impair people's daily lives. Numerous treatment options exist, yet choosing the most suitable depends on many factors and making decisions can be challenging in pressured, time-sensitive clinical environments. Clinicians identified a need to develop a decision support tool. This paper reports the process of co-producing an initial prototype tool. METHODS: Creative co-design methods were used. Three pleural teams from three disparate clinical sites in the UK were involved. To overcome the geographical distance between sites and the ill-health of service users, novel distributed methods of creative co-design were used. Local workshops were designed and structured, including video clips of activities. These were run on each site with clinicians, patients and carers. A joint national workshop was then conducted with representatives from all stakeholder groups to consider the findings and outputs from local meetings. The design team worked with participants to develop outputs, including patient timelines and personas. These were used as the basis to develop and test prototype ideas. RESULTS: Key messages from the workshops informed prototype development. These messages were as follows. Understanding and managing the pleural effusion was the priority for patients, not their overall cancer journey. Preferred methods for receiving information were varied but visual and graphic approaches were favoured. The main influences on people's decisions about their MPE treatment were personal aspects of their lives, for example, how active they are, what support they have at home. The findings informed the development of a first prototype/service visualisation (a video representing a web-based support tool) to help people identify personal priorities and to guide shared treatment decisions. CONCLUSION: The creative design methods and distributed model used in this project overcame many of the barriers to traditional co-production methods such as power, language and time. They allowed specialist pleural teams and service users to work together to create a patient-facing decision support tool owned by those who will use it and ready for implementation and evaluation.

Peptide Receptor Radionuclide Therapy with 67Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of 64Cu and 67Cu, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr3)-octreotate, called 64Cu-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of 67Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, 177Lu-LuDOTA-Tyr3-octreotate (177Lu-LuTATE). Methods: The antitumor efficacy of various doses of 67Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with 177Lu-LuTATE. Results: Seven days after a single administration of 67Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of 177Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both 67Cu-CuSarTATE and 177Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of 67Cu-CuSarTATE or 177Lu-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (67Cu-CuSarTATE: 47 vs. 36 d [P = 0.036]; 177Lu-LuTATE: 46 vs. 29 d [P = 0.040]). Conclusion: This study demonstrates that 67Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of 67Cu-CuSarTATE and 177Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of 67Cu-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer.

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.

An Evaluation of Trends in Patient and Public Awareness of IR.

PURPOSE: To evaluate patient and public awareness of interventional radiology (IR). MATERIALS AND METHODS: This single-center study prospectively administered voluntary paper surveys to 80 patients in an academic hospital radiology waiting room. Separate, Internet-based surveys were administered to the general public. Additionally, Internet metadata were used to evaluate relative search engine activity and IR-related news coverage compared with similar procedural specialties. RESULTS: 65% of radiology department outpatients had no prior knowledge of IR. Of the general population surveyed, 72% could not identify an interventional radiologist as a physician. Relative annual IR-related Google search volumes peaked in 2004 and were at their nadir in 2011. After normalizing for number of practicing physicians, IR was the subject of substantially fewer Google searches than similar specialties (15.9% of urology volumes, 27.9% of cardiology volumes, and 39.0% of vascular surgery volumes). Between 2006 and 2016, IR had a similar rate of annual increase in the volume of Internet news results as similar medical specialties, although the volumes reached by IR in 2016 were obtained by more established fields, such as cardiology, in 2011. CONCLUSIONS: These data provide metrics of current and historical awareness trends in IR, which demonstrate low patient and public awareness. The findings of this study may help guide future efforts to promote patient and public awareness of IR.

Click chemistry enables preclinical evaluation of targeted epigenetic therapies.

The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.

Advance care planning in a community setting.

AIM: To evaluate the effects of implementing an advance care planning process within pilot sites in North Ayrshire in 2010, focusing on people with palliative care needs. METHOD: Data were collected from participants in advance care planning training using a questionnaire. Semi-structured interviews were conducted and an audit of documentation was undertaken. RESULTS: Thirty nine questionnaires were returned, a response rate of 16%. Twenty four out of 25 (96%) participants rated the training as having improved their understanding of the advance care planning process. The general consensus in interviews was that advance care planning is a worthwhile process. Participants reported patients achieving their preferred place of end of life care and greater consultation regarding hospitalisation. CONCLUSION: Within the pilot sites, advance care planning training enhanced the ability of professionals to implement the advance care planning process and record the wishes of patients and residents.

Co-targeting deoxyribonucleic acid-dependent protein kinase and poly(adenosine diphosphate-ribose) polymerase-1 promotes accelerated senescence of irradiated cancer cells.

PURPOSE: To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells. METHODS AND MATERIALS: The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation. RESULTS: Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive ß-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent ß-galactosidase activity. CONCLUSION: Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.

Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells.

DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive ß-galactosidase staining, G(2)-M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade.

Differential (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models.

UNLABELLED: The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling. METHODS: Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting. RESULTS: Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 µM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively. CONCLUSION: While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.

In vivo activity of combined PI3K/mTOR and MEK inhibition in a Kras(G12D);Pten deletion mouse model of ovarian cancer.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras(G12D) activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% ± 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogen-activated protein kinase pathway downstream of Kras(G12D) expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.

Preclinical evaluation of nilotinib efficacy in an imatinib-resistant KIT-driven tumor model.

The novel KIT inhibitor nilotinib is currently being evaluated for its clinical utility in the treatment of gastrointestinal stromal tumor. However, the effects of nilotinib in cells expressing commonly occurring KIT mutations remain to be fully defined. The aim of this study was therefore to investigate the efficacy of nilotinib against cells expressing imatinib-sensitive or imatinib-resistant KIT mutations and to evaluate [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging as a biomarker of nilotinib response in vivo. Nilotinib inhibited the proliferation of imatinib-responsive V560G-KIT FDC-P1 and imatinib-resistant D816V-KIT FDC-P1 cells with a GI(50) of 4.9 and 630 nmol/L, respectively, whereas apoptosis studies revealed that nilotinib and imatinib were equipotent against the V560G cell line. In contrast, although 10 micromol/L nilotinib induced >50% apoptosis in the D816V cells at 16 hours, 10 micromol/L imatinib had no effect on cell survival at 24 hours. Syngeneic DBA2/J mice bearing FDC-P1-KIT tumors were evaluated for response to nilotinib by FDG-PET. V560G-KIT FDC-P1 tumor FDG uptake was significantly reduced compared with baseline levels following 2 days of nilotinib treatment. In contrast, no effect of nilotinib was observed on tumor growth or FDG-PET uptake into D816V tumors despite intratumoral drug levels reaching in excess of 10 micromol/L at 4 hours after dosing. Biomarker analysis revealed the inhibition of KIT phosphorylation in V560G but not D816V tumors. These findings show the in vivo activity of nilotinib in the treatment of tumors bearing V560G-KIT but not D816V-KIT and the utility of FDG-PET imaging to assess tumor response to this agent.

Epidemiology of basal-like breast cancer.

Risk factors for the newly identified "intrinsic" breast cancer subtypes (luminal A, luminal B, basal-like and human epidermal growth factor receptor 2-positive/estrogen receptor-negative) were determined in the Carolina Breast Cancer Study, a population-based, case-control study of African-American and white women. Immunohistochemical markers were used to subtype 1,424 cases of invasive and in situ breast cancer, and case subtypes were compared to 2,022 controls. Luminal A, the most common subtype, exhibited risk factors typically reported for breast cancer in previous studies, including inverse associations for increased parity and younger age at first full-term pregnancy. Basal-like cases exhibited several associations that were opposite to those observed for luminal A, including increased risk for parity and younger age at first term full-term pregnancy. Longer duration breastfeeding, increasing number of children breastfed, and increasing number of months breastfeeding per child were each associated with reduced risk of basal-like breast cancer, but not luminal A. Women with multiple live births who did not breastfeed and women who used medications to suppress lactation were at increased risk of basal-like, but not luminal A, breast cancer. Elevated waist-hip ratio was associated with increased risk of luminal A in postmenopausal women, and increased risk of basal-like breast cancer in pre- and postmenopausal women. The prevalence of basal-like breast cancer was highest among premenopausal African-American women, who also showed the highest prevalence of basal-like risk factors. Among younger African-American women, we estimate that up to 68% of basal-like breast cancer could be prevented by promoting breastfeeding and reducing abdominal adiposity.

Identification of a basal-like subtype of breast ductal carcinoma in situ.

Microarray profiling of invasive breast carcinomas has identified subtypes including luminal A, luminal B, HER2-overexpressing, and basal-like. The poor-prognosis, basal-like tumors have been immunohistochemically characterized as estrogen receptor (ER)-negative, HER2/neu-negative, and cytokeratin 5/6-positive and/or epidermal growth factor receptor (EGFR)-positive. The aim of this study was to determine the prevalence of basal-like ductal carcinoma in situ in a population-based series of cases using immunohistochemical surrogates. A total of 245 pure ductal carcinoma in situ cases from a population-based, case-control study were evaluated for histologic characteristics and immunostained for ER, HER2/neu, EGFR, cytokeratin 5/6, p53, and Ki-67. The subtypes were defined as: luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 positive (ER-, HER2+), and basal-like (ER-, HER2-, EGFR+, and/or cytokeratin 5/6+). The prevalence of breast cancer subtypes was basal-like (n = 19 [8%]); luminal A, n = 149 (61%); luminal B, n = 23 (9%); and HER2+/ER-, n = 38 (16%). Sixteen tumors (6%) were unclassified (negative for all 4 defining markers). The basal-like subtype was associated with unfavorable prognostic variables including high-grade nuclei (P < .0001), p53 overexpression (P < .0001), and elevated Ki-67 index (P < .0001). These studies demonstrate the presence of a basal-like in situ carcinoma, a potential precursor lesion to invasive basal-like carcinoma.

The influence of managed care on U.S. baccalaureate nursing education programs.

The transformation of health care into managed care has raised many issues and concerns for nurse educators. The milieu in which nurses currently practice reflects the restructuring shaped by managed care principles. The shift from acute care to expanded community services has changed the way health care is provided within hospital settings. The organization of nursing programs has been affected by this shift, and the ramifications of these external forces on curriculum structure have altered the way nursing students are educated. This article presents research demonstrating the changes in the structure of the curricula for baccalaureate nursing education in 2001, which were caused by health care reform in effect since 1994.

Cycling time trial performance during different phases of the menstrual cycle.

Submaximal exercise performance has not previously been assessed in the late follicular phase of the menstrual cycle, which is associated with a pre-ovulatory surge in oestrogen. Therefore, we compared cycling time trial performance during the early follicular (EF), late follicular (LF) and mid-luteal (ML) phase of the menstrual cycle in trained and untrained eumenorrhoeic women who cycled 30 and 15 km, respectively, in a non-fasted state. The women completed the three cycling time trials on a conventional racing bicycle mounted on an air-braked ergometer. We required resting oestrogen to increase by at least twofold above EF phase values in both the LF and ML phases and this resulted in a number of exclusions reducing the sample size of each group. No significant difference was noted in the finishing time between the different menstrual phases in trained (n=5) or untrained (n=8) group, albeit limited by sample size. However, analysis of the combined trained and untrained group data (n=13) revealed a trend for a faster finishing time (P=0.027) in the LF phase compared to the EF phase as 73% of the subjects showed improvements with an average of 5.2+/-2.9% (or 2.1+/-1.1 min) in the LF phase (for alpha=0.05 requires P<0.017). Combined group analysis yielded no difference between performance in the EF and ML phase or between the LF and ML phase. Thus, further research is encouraged to confirm the tendency for a faster time trial in the LF phase, which coincides with the pre-ovulatory surge in oestrogen.

The healthy Hawaii initiative: A social ecological approach promoting healthy communities.

PURPOSE: The tobacco settlement has provided the opportunity for the state of Hawaii to implement the Healthy Hawaii Initiative (HHI), targeting smoking, poor nutrition and physical inactivity. The purpose of this paper is to describe and document preliminary findings. METHODS: The social ecological model is translated into practice through school and community grants to create systems, environmental and policy changes, teacher training on health and physical education standards, continuing education for the medical community in behavioral health, and a public education campaign. A comprehensive evaluation provides ongoingfeedback for program improvement and progress on the effects of psychosocial mediators, behaviors, and long-term chronic diseases. RESULTS AND DISCUSSION: Preliminary process results presented here are promising. The components are thought to interact synergistically to bring about behavior changes statewide. The HHI is one example of how to implement a multilevel initiative to target the three major behavioral determinants of chronic disease (tobacco use, physical inactivity, and poor nutrition) and build healthier communities.

Organization and representation of patient safety data: current status and issues around generalizability and scalability.

Recent reports have identified medical errors as a significant cause of morbidity and mortality among patients. A variety of approaches have been implemented to identify errors and their causes. These approaches include retrospective reporting and investigation of errors and adverse events and prospective analyses for identifying hazardous situations. The above approaches, along with other sources, contribute to data that are used to analyze patient safety risks. A variety of data structures and terminologies have been created to represent the information contained in these sources of patient safety data. Whereas many representations may be well suited to the particular safety application for which they were developed, such application-specific and often organization-specific representations limit the sharability of patient safety data. The result is that aggregation and comparison of safety data across organizations, practice domains, and applications is difficult at best. A common reference data model and a broadly applicable terminology for patient safety data are needed to aggregate safety data at the regional and national level and conduct large-scale studies of patient safety risks and interventions.