Interventions to manage occluded central venous access devices: An umbrella review.

The main objective of this umbrella review is to synthesise available evidence from systematic reviews on the effectiveness of interventions for the management of occlusions in central venous access devices. CVADS have been extensively utilised among the critically ill since the 1950s however have also been linked to an increase in catheter complications. CVAD occlusion can occur in 14%-36% of patients within 1-2 years of catheter placement and is a longstanding complication. Umbrella methodology was applied to review five healthcare databases. Databases were searched for publications from 2009 and 2022 and electronic keywords searches were conducted. The authors searched for reviews that reported on any intervention to prevent, maintain or manage patency of the central venous access devices within an acute care setting. Of the 278 articles identified from the initial search a total of 11 articles were identified. This umbrella review concluded that education enhances patient outcomes and decreases occlusion rates. Further studies are required to explore occlusion reduction strategies in relation to flushing and locking.

Scoping review of systematic reviews of nursing interventions in a neonatal intensive care unit or special care nursery.

AIM(S): To identify, synthesise and map systematic reviews of the effectiveness of nursing interventions undertaken in a neonatal intensive care unit or special care nursery. DESIGN: This scoping review was conducted according to the JBI scoping review framework. METHODS: Review included systematic reviews that evaluated any nurse-initiated interventions that were undertaken in an NICU or SCN setting. Studies that reported one or more positive outcomes related to the nursing interventions were only considered for this review. Each outcome for nursing interventions was rated a 'certainty (quality) of evidence' according to the Grading of Recommendations, Assessment, Development and Evaluations criteria. DATA SOURCES: Systematic reviews were sourced from the Cochrane Database of Systematic Reviews and Joanna Briggs Institute Evidence Synthesis for reviews published until February 2023. RESULTS: A total of 428 articles were identified; following screening, 81 reviews underwent full-text screening, and 34 articles met the inclusion criteria and were included in this review. Multiple nursing interventions reporting positive outcomes were identified and were grouped into seven categories. Respiratory 7/34 (20%) and Nutrition 8/34 (23%) outcomes were the most reported categories. Developmental care was the next most reported category 5/34 (15%) followed by Thermoregulation, 5/34 (15%) Jaundice 4/34 (12%), Pain 4/34 (12%) and Infection 1/34 (3%). CONCLUSIONS: This review has identified nursing interventions that have a direct positive impact on neonatal outcomes. However, further applied research is needed to transfer this empirical knowledge into clinical practice. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Implementing up-to-date evidence on effective nursing interventions has the potential to significantly improving neonatal outcomes. PATIENT OR PUBLIC CONTRIBUTION: No patient or public involvement in this scoping review.

Oral care measures for preventing nursing home-acquired pneumonia.

BACKGROUND: Pneumonia in residents of nursing homes can be termed nursing home-acquired pneumonia (NHAP). NHAP is one of the most common infections identified in nursing home residents and has the highest mortality of any infection in this population. NHAP is associated with poor oral hygiene and may be caused by aspiration of oropharyngeal flora into the lung. Oral care measures to remove or disrupt oral plaque might reduce the risk of NHAP. This is the first update of a review published in 2018. OBJECTIVES: To assess effects of oral care measures for preventing nursing home-acquired pneumonia in residents of nursing homes and other long-term care facilities. SEARCH METHODS: An information specialist searched CENTRAL, MEDLINE, Embase, one other database and three trials registers up to 12 May 2022. We also used additional search methods to identify published, unpublished and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated the effects of oral care measures (brushing, swabbing, denture cleaning mouthrinse, or combination) in residents of any age in nursing homes and other long-term care facilities. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed search results, extracted data, and assessed risk of bias in the included studies. We contacted study authors for additional information. We pooled data from studies with similar interventions and outcomes. We reported risk ratios (RRs) for dichotomous outcomes, mean differences (MDs) for continuous outcomes, and hazard ratios (HRs) or incidence rate ratio (IRR) for time-to-event outcomes, using random-effects models. MAIN RESULTS: We included six RCTs (6244 participants), all of which were at high risk of bias. Three studies were carried out in Japan, two in the USA, and one in France. The studies evaluated one comparison: professional oral care versus usual oral care. We did not include the results from one study (834 participants) because it had been stopped at interim analysis.  Consistent results from five studies, with 5018 participants, provided insufficient evidence of a difference between professional oral care and usual (simple, self-administered) oral care in the incidence of pneumonia. Three studies reported HRs, one reported IRRs, and one reported RRs. Due to the variation in study design and follow-up duration, we decided not to pool the data. We downgraded the certainty of the evidence for this outcome by two levels to low: one level for study limitations (high risk of performance bias), and one level for imprecision. There was low-certainty evidence from meta-analysis of two individually randomised studies that professional oral care may reduce the risk of pneumonia-associated mortality compared with usual oral care at 24 months' follow-up (RR 0.43, 95% CI 0.25 to 0.76, 454 participants). Another study (2513 participants) reported insufficient evidence of a difference for this outcome at 18 months' follow-up. Three studies measured all-cause mortality and identified insufficient evidence of a difference between professional and usual oral care at 12 to 30 months' follow-up. Only one study (834 participants) measured the adverse effects of the interventions. The study identified no serious events and 64 non-serious events, the most common of which were oral cavity disturbances (not defined) and dental staining. No studies evaluated oral care versus no oral care. AUTHORS' CONCLUSIONS: Although low-certainty evidence suggests that professional oral care may reduce mortality compared to usual care when measured at 24 months, the effect of professional oral care on preventing NHAP remains largely unclear. Low-certainty evidence was inconclusive about the effects of this intervention on incidence and number of first episodes of NHAP. Due to differences in study design, effect measures, follow-up duration, and composition of the interventions, we cannot determine the optimal oral care protocol from current evidence.  Future trials will require larger samples, robust methods that ensure low risk of bias, and more practicable interventions for nursing home residents.

Educating the educators: Implementing cultural safety in the nursing and midwifery curriculum.

BACKGROUND: The Australian Nursing and Midwifery Accreditation Council mandates the teaching of cultural safety in Bachelor of Nursing and Midwifery programs in Australia. However nursing and midwifery academics may lack the awareness and knowledge required to share and develop cultural safety practices with their students. Specific cultural safety professional development for academics may be needed. OBJECTIVES: This research explores how nursing and midwifery academics at an Australian university understand cultural safety and whether they are equipped to embed it in the curriculum. It also examines whether professional development workshops can support academics to prepare for cultural safety. METHODS: An intervention involving three cultural safety professional development workshops was offered to nursing academics at an Australian university. The authors used qualitative surveys to consider whether the workshops deepened participants' understanding of cultural safety and developed the self-reflection required to embed cultural safety in teaching. RESULTS: The workshops contributed to participants' improved understandings of culture, colonisation, white privilege and the need for self-reflection, but not all participants developed a working knowledge of cultural safety practice. CONCLUSION: Professional development workshops can assist nursing and midwifery academics to develop their knowledge of cultural safety, but detailed, contextual understanding is likely to need more than three sessions. Academics' motivations to include cultural safety in their teaching may be linked to their desire for patient-driven and equitable services and a desire to meet accreditation requirements.

Assessing the Content and Readability of Robotic and Laparoscopic Sacrocolpopexy Information Online.

IMPORTANCE: Apical pelvic organ prolapse is a common condition that affects women. Currently, sacrocolpopexy is considered the criterion standard surgical treatment, with an increasing preference for minimally invasive techniques. OBJECTIVE: In this study, the content and readability of select internet pages describing robotic and laparoscopic sacrocolpopexy were evaluated. STUDY DESIGN: Using an online key word planner, the phrases "robotic sacrocolpopexy" and "laparoscopic sacrocolpopexy" were determined to be the most popular search terms. These terms were systematically browsed in incognito mode in 3 of the most popular web search engines: Google, Yahoo, and Bing. Links that were nontext primary, duplicate, irrelevant, and non-English were excluded. The Flesch-Kincaid Grade Level and Flesch-Kincaid Reading Ease indices were used to assess readability. RESULTS: The average readability of all sites was 12.9, requiring at least a 12th-grade reading level, which is significantly higher than the recommended American Medical Association/National Institutes of Health (AMA/NIH) level of sixth-grade or below. One hundred percent of all analyzed sites were above this recommended sixth-grade reading level. There was no significant difference between mean grade level or reading ease score from the type of web source (P = 0.32 and 0.34, respectively), approach of surgery (P = 0.91, 0.70), or specialty (P = 0.48, 0.36). CONCLUSIONS: Almost all websites require at least a high school education to properly comprehend, regardless of source or specialty. It is important that health care providers be aware of available information, so they may direct patients to specific resources that are personally validated or provide in-office materials at an appropriate reading level.

Medication errors by nursing students on clinical practice: An integrative review.

BACKGROUND: Medication errors are a serious concern and often due to multiple factors. The largest workforce in healthcare are nurses. Nurses play a major role in medication management especially in medication administration. To become proficient in safe medication administration undergraduate nurses, need to be provided with adequate training in clinical settings. Aim This integrative review aims to identify literature that reports medication errors including prevalence, types, causes and barriers of reporting whilst nursing students are on clinical placement. METHODS: A review was conducted of five electronic databases to identify original empirical research published between 2007 and 2021. An integrative review method using Strengthening the Report of Observational Studies in Epidemiology guidelines was used to direct this review. FINDINGS: The initial search yielded 1574 articles. A total of six full text articles met the eligibility criteria were reviewed. The prevalence of medication errors made by nursing students on clinical placement was 6-1.1%. Causes were due to student, education and environmental factors. Types of errors medication calculations, incorrect name of patient, wrong medication and omission of medication administration. DISCUSSION: This review confirms previous studies with 10-5% of all errors by nurses are medication errors in hospitals. Strategies to improve medication administration are increasing staffing, communication, education and supervision of students. CONCLUSION: Medication administration is a multifactorial process that involves medication skills. Closer supervision, improved education on technology and consistency is required in number of rights of medication administration.

Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

Would Surgeons Opt for Polypropylene Mesh if They Hypothetically Had Stress Urinary Incontinence or Pelvic Organ Prolapse?

INTRODUCTION: Mesh is routinely used to treat stress urinary incontinence (SUI) and pelvic organ prolapse (POP). However, its use remains controversial. The FDA (U.S. Food and Drug Administration) ultimately deemed mesh use for SUI and transabdominal POP repair acceptable, while cautioning against transvaginal mesh for POP repair. The objective of this study was to evaluate personal opinions regarding mesh use among clinicians who routinely treat POP and SUI if they themselves were to hypothetically have either condition. METHODS: A nonvalidated survey was sent to the Society of Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction (SUFU) members, and American Urogynecologic Society (AUGS) members. The questionnaire asked participants if they were to hypothetically have SUI/POP which treatment they would elect. RESULTS: A total of 141 participants completed the survey (20% response rate). A significant proportion preferred synthetic mid urethral slings (MUS) for SUI (69%, p <0.001). Surgeon volume was significantly associated with MUS preference for SUI in both univariate and multivariate analyses (OR 3.21 and 3.67, p <0.003). A significant proportion of providers preferred transabdominal repair or native tissue repair for POP (27% and 34% respectively, p <0.001). Private practice was significantly associated with transvaginal mesh preference for POP in univariate analysis but not multivariate analysis (OR 3.45, p <0.04). CONCLUSIONS: The use of mesh for SUI and POP has been controversial, leading to the FDA, SUFU and AUGS statements on synthetic mesh use. Our study found that the majority of SUFU and AUGS members who regularly perform these surgeries prefer MUS for SUI. Preferences regarding POP treatments varied.

Association of Physical Function With Driving Space and Crashes Among Older Adults.

BACKGROUND AND OBJECTIVES: Balancing both driver mobility and safety is important for the well-being of older adults. However, research on the association of physical function with these 2 driving outcomes has yielded inconsistent findings. This study examined whether physical functioning of older drivers, as measured by the Short Physical Performance Battery (SPPB), is associated with either driving space or crash involvement. METHODS: Using cross-sectional data of active drivers aged 65-79 years from the AAA Longitudinal Research on Aging Drivers (LongROAD) study (n = 2,990), we used multivariate log-binomial and logistic regressions to estimate the associations of the SPPB with either self-reported restricted driving space in the prior 3 months or any crashes in the past year. Interaction with gender was assessed using likelihood ratio tests. RESULTS: After adjustment, older drivers with higher SPPB scores (higher physical functioning) had lower prevalence of restricted driving space (8-10 vs. 0-7, prevalence ratio [PR] = 0.88, 95% confidence interval [CI]: 0.78-0.99; 11-12 vs. 0-7, PR = 0.78, 95% CI: 0.61-0.99). Fair (8-10), but not good (11-12), scores were significantly associated with reduced crash involvement (8-10 vs. 0-7, odds ratio [OR] = 0.71, 95% CI: 0.60-0.84). Gender was not a significant effect modifier. DISCUSSION AND IMPLICATIONS: This study provides evidence that higher physical functioning is associated with better driving mobility and safety and that the SPPB may be useful for identifying at-risk drivers. Further research is needed to understand physical functioning's longitudinal effects and the SPPB's role in older driver intervention programs.

Locating "gold standard" evidence for simulation as a substitute for clinical practice in prelicensure health professional education: A systematic review.

AIMS AND OBJECTIVES: To extract, examine and report the highest available levels of evidence from healthcare disciplines in the use of simulation-based education as substitution for clinical placement in prelicensure programmes. BACKGROUND: Simulation is widely employed across prelicensure health professional education to create safe, realistic clinical learning experiences for students. Whether simulation can be employed to substitute for actual clinical placement, and if so, in what proportion, replacement ratio and duration, is unclear. METHODS: A systematic review and quality appraisal of primary studies related to prelicensure students in all health disciplines, guided by the PRISMA checklist. RESULTS: Ten primary studies were included, representing 2,370 students from three health disciplines in four countries. Nine studies were experimental and quasi-experimental and methodological quality was assessed as moderate to high with good to very good inter-rater agreement. Direct substitution of simulation for clinical practice ranged from 5% to 50%. With one exception, replacement ratios were 1:1 and duration of replacement ranged from 21 hr-2 years. Levels of evaluation included measures of reaction, knowledge and behaviour transfer; no negative outcomes were reported. We appraised practicalities for design of substitution, design limitations and knowledge transfer to accreditation standards for prelicensure programmes. CONCLUSIONS: This review synthesised highest levels and quality of available evidence for substitution of simulation for clinical placement in health professional education. Included studies were heterogenous in simulation interventions (proportion, ratio and duration) and in the evaluation of outcomes. Future studies should incorporate standardised simulation curricula, widen the health professions represented and strengthen experimental designs. RELEVANCE TO CLINICAL PRACTICE: Current evidence for clinical educational preparation does not appear to be translated into programme accreditation standards governing clinical practice experience for prelicensure programmes in relevant jurisdictions. Overall, a stronger evidence base is necessary to inform future curricula and policy development, to strengthen clinical practice in health.

The ATP-binding cassette transporter ABCF1 is a hepatic oncofetal protein that promotes chemoresistance, EMT and cancer stemness in hepatocellular carcinoma.

ATP-binding cassette (ABC) transporters mediate multidrug resistance and cancer stem cell properties in various model systems. Yet, their biological significance in cancers, especially in hepatocellular carcinoma (HCC), remains unclear. In this study, we investigated the function of ABCF1 in HCC and explored its potential as a therapeutic target. ABCF1 was highly expressed in fetal mouse livers but not in normal adult livers. ABCF1 expression was upregulated in HCCs. These results demonstrate that ABCF1 functions as a hepatic oncofetal protein. We further demonstrated elevated ABCF1 expression in HCC cells upon acquiring chemoresistance. Suppression of ABCF1 by siRNA sensitized both parental cells and chemoresistant cells to chemotherapeutic agents. Reversely, ABCF1 overexpression promoted chemoresistance and drug efflux. In addition, overexpression of ABCF1 enhanced migration, spheroid and colony formation and epithelial-mesenchymal transition (EMT) induction. RNA sequencing analysis revealed EMT inducers HIF1α/IL8 and Sox4 as potential mediators for the oncogenic effect of ABCF1 in HCC progression. Together, this study illustrates that ABCF1 is a novel potential therapeutic target for HCC treatment.

Oral care measures for preventing nursing home-acquired pneumonia.

BACKGROUND: Pneumonia occurring in residents of long-term care facilities and nursing homes can be termed 'nursing home-acquired pneumonia' (NHAP). NHAP is the leading cause of mortality among residents. NHAP may be caused by aspiration of oropharyngeal flora into the lung, and by failure of the individual's defence mechanisms to eliminate the aspirated bacteria. Oral care measures to remove or disrupt oral plaque might be effective in reducing the risk of NHAP. OBJECTIVES: To assess effects of oral care measures for preventing nursing home-acquired pneumonia in residents of nursing homes and other long-term care facilities. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 15 November 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 10), MEDLINE Ovid (1946 to 15 November 2017), and Embase Ovid (1980 to 15 November 2017) and Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1937 to 15 November 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. We also searched the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, and the Sciencepaper Online to 20 November 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated the effects of oral care measures (brushing, swabbing, denture cleaning mouthrinse, or combination) in residents of any age in nursing homes and other long-term care facilities. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed search results, extracted data, and assessed risk of bias in the included studies. We contacted study authors for additional information. We pooled data from studies with similar interventions and outcomes. We reported risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, and hazard ratio (HR) for time-to-event outcomes, using random-effects models. MAIN RESULTS: We included four RCTs (3905 participants), all of which were at high risk of bias. The studies all evaluated one comparison: professional oral care versus usual oral care. We did not pool the results from one study (N = 834 participants), which was stopped at interim analysis due to lack of a clear difference between groups.We were unable to determine whether professional oral care resulted in a lower incidence rate of NHAP compared with usual oral care over an 18-month period (hazard ratio 0.65, 95% CI 0.29 to 1.46; one study, 2513 participants analysed; low-quality evidence).We were also unable to determine whether professional oral care resulted in a lower number of first episodes of pneumonia compared with usual care over a 24-month period (RR 0.61, 95% CI 0.37 to 1.01; one study, 366 participants analysed; low-quality evidence).There was low-quality evidence from two studies that professional oral care may reduce the risk of pneumonia-associated mortality compared with usual oral care at 24-month follow-up (RR 0.41, 95% CI 0.24 to 0.72, 507 participants analysed).We were uncertain whether or not professional oral care may reduce all-cause mortality compared to usual care, when measured at 24-month follow-up (RR 0.55, 95% CI 0.27 to 1.15; one study, 141 participants analysed; very low-quality evidence).Only one study (834 participants randomised) measured adverse effects of the interventions. The study identified no serious events and 64 non-serious events, the most common of which were oral cavity disturbances (not defined) and dental staining.No studies evaluated oral care versus no oral care. AUTHORS' CONCLUSIONS: Although low-quality evidence suggests that professional oral care could reduce mortality due to pneumonia in nursing home residents when compared to usual care, this finding must be considered with caution. Evidence for other outcomes is inconclusive. We found no high-quality evidence to determine which oral care measures are most effective for reducing nursing home-acquired pneumonia. Further trials are needed to draw reliable conclusions.

Granulin-epithelin precursor interacts with 78-kDa glucose-regulated protein in hepatocellular carcinoma.

BACKGROUND: Granulin-epithelin precursor (GEP) is a secretory growth factor, which has been demonstrated to control cancer growth, invasion, drug resistance and immune escape. Our previous studies and others also demonstrated its potential in targeted therapy. Comprehensive characterization of GEP partner on cancer cells are warranted. We have previously shown that GEP interacted with heparan sulfate on the surface of liver cancer cells and the interaction is crucial for GEP-mediated signaling transduction. This study aims to characterize GEP protein partner at the cell membrane with the co-immunoprecipitation and mass spectrometry approach. METHODS: The membrane fraction from liver cancer model Hep3B was used for capturing binding partner with the specific monoclonal antibody against GEP. The precipitated proteins were analyzed by mass spectrometry. After identifying the GEP binding partner, this specific interaction was validated in additional liver cancer cell line HepG2 by co-immunoprecipitation using GRP78 and GEP antibodies, respectively, as the bait. GRP78 transcript levels in hepatocellular carcinoma (HCC) clinical samples (n = 77 pairs) were examined by real-time quantitative RT-PCR. GEP and GRP78 protein expressions were investigated by immunohistochemistry on paraffin sections. RESULTS: We identified the GEP-binding protein as 78-kDa glucose-regulated protein (GRP78, also named heat shock 70-kDa protein 5, HSPA5). This interaction was validated in independent HCC cell lines. Increased GRP78 mRNA levels were demonstrated in liver cancer tissues compared with the paralleled liver tissues (t-test, P = 0.002). GRP78 and GEP transcript levels were significantly correlated (Spearman's correlation, P = 0.001), and the proteins were also detectable in the cytoplasm of liver cancer cells by immunohistochemical staining. CONCLUSIONS: GRP78 and GEP are interacting protein partners in liver cancer cells and may play a role in GEP-mediated cancer progression in HCC.

Comprehensive characterization of the patient-derived xenograft and the paralleled primary hepatocellular carcinoma cell line.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with high mortality and morbidity worldwide. The limited clinically relevant model has impeded the development of effective HCC treatment strategy. Patient-derived xenograft (PDX) models retain most of the characteristics of original tumors and were shown to be highly predictive for clinical outcomes. Notably, primary cell line models allow in-depth molecular characterization and high-throughput analysis. Combined usage of the two models would provide an excellent tool for systematic study of therapeutic strategies. Here, we comprehensively characterized the novel PDX and the paralleled primary HCC cell line model. METHODS: Tumor tissues were collected from HCC surgical specimens. HCC cells were sorted for in vivo PDX and in vitro cell line establishment by the expression of hepatic cancer stem cell marker to enhance cell viability and the rate of success on subsequent culture. The PDX and its matching primary cell line were authenticated and characterized in vitro and in vivo. RESULTS: Among the successful cases for generating PDXs and primary cells, HCC40 is capable for both PDX and primary cell line establishment, which were then further characterized. The novel HCC40-PDX and HCC40-CL exhibited consistent phenotypic characteristics as the original tumor in terms of HBV protein and AFP expressions. In common with HCC40-PDX, HCC40-CL was tumorigenic in immunocompromised mice. The migration ability in vitro and metastatic properties in vivo echoed the clinical feature of venous infiltration. Genetic profiling by short tandem repeat analysis and p53 mutation pattern consolidated that both the HCC40-PDX and HCC40-CL models were derived from the HCC40 clinical specimen. CONCLUSIONS: The paralleled establishment of PDX and primary cell line would serve as useful models in comprehensive studies for HCC pathogenesis and therapeutics development for personalized treatment.

Exploring factors affecting registered nurses' pursuit of postgraduate education in Australia.

The aim of this study was to explore the factors influencing registered nurses' pursuit of postgraduate education in specialty nursing practice in Australia. Despite the increased requirement for postgraduate education for advanced practice, little has been reported on the contributory factors involved in the decision to undertake further education. The Nurses' Attitudes Towards Postgraduate Education instrument was administered to 1632 registered nurses from the Nurses and Midwives e-Cohort Study across Australia, with a response rate of 35.9% (n = 568). Data reduction techniques using principal component analysis with varimax rotation were used. The analysis identified a three-factor solution for 14 items, accounting for 52.5% of the variance of the scale: "facilitators," "professional recognition," and "inhibiting factors." Facilitators of postgraduate education accounted for 28.5% of the variance, including: (i) improves knowledge; (ii) increases nurses' confidence in clinical decision-making; (iii) enhances nurses' careers; (iv) improves critical thinking; (v) improves nurses' clinical skill; and (vi) increased job satisfaction. This new instrument has potential clinical and research applications to support registered nurses' pursuit of postgraduate education.

Hepatic cancer stem cell marker granulin-epithelin precursor and ß-catenin expression associate with recurrence in hepatocellular carcinoma.

Granulin-epithelin precursor (GEP) has been demonstrated to confer enhanced cancer stem-like cell properties in hepatocellular carcinoma (HCC) cell line models in our previous studies. Here, we aimed to examine the GEP-expressing cells in relation to the stem cell related molecules and stem-like cell properties in the prospective HCC clinical cohort. GEP protein levels were significantly higher in HCCs than the paralleled non-tumor liver tissues, and associated with venous infiltration. GEPhigh cells isolated from clinical HCC samples exhibited higher levels of stem cell marker CD133, pluripotency-associated signaling molecules ß-catenin, Oct4, SOX2, Nanog, and chemodrug transporter ABCB5. In addition, GEPhigh cells possessed preferential ability to form colonies and spheroids, and enhanced in vivo tumor-initiating ability while their xenografts were able to be serially subpassaged into secondary mouse recipients. Expression levels of GEP and pluripotency-associated genes were further examined in the retrospective HCC cohort and demonstrated significant correlation of GEP with ß-catenin. Notably, HCC patients with high GEP and ß-catenin levels demonstrated poor recurrence-free survival. In summary, GEP-positive HCC cells directly isolated from clinical specimens showed ß-catenin elevation and cancer stem-like cell properties.

Restoration of natural killer activity in hepatocellular carcinoma by treatment with antibody against granulin-epithelin precursor.

Impairment of natural killer (NK) cell activity is an important mechanism of tumor immunoevasion. We have previously shown that expression of granulin-epithelin precursor (GEP) in hepatocellular carcinoma (HCC) cells rendered the cells resistant to NK cell immunosurveillance. Here, we examined whether targeting GEP could rescue NK activity in HCC patients. The current study demonstrated that quantities and activities of NK cells were significantly lower in HCC patients compared with healthy individuals, and were negatively correlated with GEP levels in HCC cells. NK cells demonstrated enhanced expression of the stimulatory receptors natural-killer group 2, member D (NKG2D) and CD69, increased secretion of IFN-γ and perforin, and cytotoxicity against HCC cells upon GEP suppression. Opposite phenotypes of NK cells were observed when GEP was overexpressed in HCC cells. Importantly, GEP blockage by monoclonal antibody A23 restored NK activity in HCC patients and sensitized HCC cells to NK cytotoxicity. Furthermore, A23 induced NK-mediated antibody-dependent cell-mediated cytotoxicity against HCC. In summary, the activity of NK cells in HCC was impaired by GEP expression, which could be rescued by GEP antibody. This study provides new insight for treatments targeting GEP to boost NK activity in HCC patients.

Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity.

Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin-epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain-related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n = 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P = 0.089) expression was observed when compared with those in nontumor (n = 80) and normal livers (n = 10). Serum GEP (P = 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n = 80) than in healthy individuals (n = 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P = 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy.

Establishment and characterization of a novel primary hepatocellular carcinoma cell line with metastatic ability in vivo.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive and heterogeneous disease. HCC cell lines established from different patients would be useful in elucidating the molecular pathogenesis. However, success of HCC primary culture establishment remains at low rate. We aim to establish and characterize HCC primary culture and the derived cell line. METHODS: Fresh tumor tissues were collected from 30 HCC patients. Culture conditions were optimized for the attachment and growth of the isolated hepatocytes. Granulin-epithelin precursor (GEP), a growth factor reported to associate with cancer stem cell properties, was examined by flow cytometry to elucidate its role on primary culture establishment. The primary cell line was characterized in detail. RESULTS: Cells isolated from 16 out of 30 HCC cases (53%) had viability more than 70% and were subject to subsequent in vitro culture. 7 out of 16 cases (44%) could give rise to cells that were able to attach and grow in culture. GEP expression levels significantly correlated with the viability of isolated hepatocytes and success rate of subsequent primary culture establishment. Cells from HCC patient 21 grew and expanded rapidly in vitro and was selected to be further characterized. The line, designated HCC21, derived from a Hong Kong Chinese female patient with HCC at Stage II. The cells exhibited typical epithelial morphology and expressed albumin, AFP and HBV antigens. The cell line was authenticated by short tandem repeat analysis. Comparative genome hybridization analysis revealed chromosomal loss at 1p35-p36, 1q44, 2q11.2-q24.3, 2q37, 4q12-q13.3, 4q21.21-q35.2, 8p12-p23, 15q11.2-q14, 15q24-q26, 16p12.1-p13.3, 16q, 17p, 22q and gain at 1q21-q43 in both HCC21 cells and the original clinical tumor specimen. Sequence analysis revealed p53 gene mutation. Subcutaneous injection of HCC21 cells into immunodeficient mice showed that the cells were able to form tumors at the primary injection sites and metastatic tumors in the peritoneal cavity. CONCLUSIONS: The newly established cell line could serve as useful in vitro and in vivo models for studying primary HCC that possess metastasis ability.

Altered regulation of DNA ligase IV activity by aberrant promoter DNA methylation and gene amplification in colorectal cancer.

Colorectal cancer (CRC) presents as a very heterogeneous disease which cannot sufficiently be characterized with the currently known genetic and epigenetic markers. To identify new markers for CRC we scrutinized the methylation status of 231 DNA repair-related genes by methyl-CpG immunoprecipitation followed by global methylation profiling on a CpG island microarray, as altered expression of these genes could drive genomic and chromosomal instability observed in these tumors. We show for the first time hypermethylation of MMP9, DNMT3A and LIG4 in CRC which was confirmed in two CRC patient groups with different ethnicity. DNA ligase IV (LIG4) showed strong differential promoter methylation (up to 60%) which coincided with downregulation of mRNA in 51% of cases. This functional association of LIG4 methylation and gene expression was supported by LIG4 re-expression in 5-aza-2'-deoxycytidine-treated colon cancer cell lines, and reduced ligase IV amounts and end-joining activity in extracts of tumors with hypermethylation. Methylation of LIG4 was not associated with other genetic and epigenetic markers of CRC in our study. As LIG4 is located on chromosome 13 which is frequently amplified in CRC, two loci were tested for gene amplification in a subset of 47 cases. Comparison of amplification, methylation and expression data revealed that, in 30% of samples, the LIG4 gene was amplified and methylated, but expression was not changed. In conclusion, hypermethylation of the LIG4 promoter is a new mechanism to control ligase IV expression. It may represent a new epigenetic marker for CRC independent of known markers.