HMGA1 Induces Intestinal Polyposis in Transgenic Mice and Drives Tumor Progression and Stem Cell Properties in Colon Cancer Cells

Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES) cells to facilitate an epithelial-mesenchymal transition (EMT), invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood.To determine how HMGA1 functions in metastatic colon cancer, we manipulated HMGA1 expression in transgenic mice and colon cancer cells. We discovered that HMGA1 drives proliferative changes, aberrant crypt formation, and intestinal polyposis in transgenic mice. In colon cancer cell lines from poorly differentiated, metastatic tumors, knock-down of HMGA1 blocks anchorage-independent cell growth, migration, invasion, xenograft tumorigenesis and three-dimensional colonosphere formation. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the knock-down cells. Knock-down of HMGA1 also inhibits metastatic progression to the liver in vivo. In metastatic colon cancer cells, HMGA1 induces expression of Twist1, a gene involved in embryogenesis, EMT, and tumor progression, while HMGA1 represses E-cadherin, a gene that is down-regulated during EMT and metastatic progression. In addition, HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa.Our findings demonstrate for the first time that HMGA1 drives proliferative changes and polyp formation in the intestines of transgenic mice and induces metastatic progression and stem-like properties in colon cancer cells. These findings indicate that HMGA1 is a key regulator, both in metastatic progression and in the maintenance of a stem-like state. Our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in metastatic, poorly differentiated colon cancer

Implementation of the "FASTHUG" concept decreases the incidence of ventilator-associated pneumonia in a surgical intensive care unit

<p>Abstract</p> <p>Background</p> <p>Ventilator-associated pneumonia (VAP) is a leading cause of morbidity and mortality in critically ill patients. The Institute for Healthcare Improvement 100,000 Lives Campaign made VAP a target of prevention and performance improvement. Additionally, the Joint Commission on Accreditation of Health Organizations' 2007 Disease Specific National Patient Safety Goals included the reduction of healthcare-associated infections. We report implementation of a performance improvement project that dramatically reduced our VAP rate that had exceeded the 90^thpercentile nationally.</p> <p>Methods</p> <p>From 1 January 2004 to 31 December 2005 a performance improvement project was undertaken to decrease our critical care unit VAP rate. In year one (2004) procedural interventions were highlighted: aggressive oral care, early extubation, management of soiled or malfunctioning respiratory equipment, hand washing surveillance, and maximal sterile barrier precautions. In year two (2005) an evaluative concept called FASTHUG (daily evaluation of patients' feeding, analgesia, sedation, thromboembolic prophylaxis, elevation of the head of the bed, ulcer prophylaxis, and glucose control) was implemented. To determine the long-term effectiveness of such an intervention a historical control period (2003) and the procedural intervention period of 2004, i.e., the pre-FASTHUG period (months 1–24) were compared with an extended post-FASTHUG period (months 25–54).</p> <p>Results</p> <p>The 2003 surgical intensive care VAP rate of 19.3/1000 ventilator-days served as a historical control. Procedural interventions in 2004 were not effective in reducing VAP, p = 0.62. However, implementation of FASTHUG in 2005, directed by a critical care team, resulted in a rate of 7.3/1000 ventilator-days, p ≤ .01. The median pneumonia rate was lower after implementation of FASTHUG when compared to the historical control year (p = .028) and the first year after the procedural interventions (p = .041) using follow-up pairwise comparisons. The pre-FASTHUG period (2003–2004, months 1–24) when compared with an extended post-FASTHUG period (2005–2007, 25–54 months) also demonstrated a significant decrease in the VAP rate, p = .0004. This reduction in the post-FASTHUG period occurred despite a rising Severity of Illness index in critically ill patients, p = .001.</p> <p>Conclusion</p> <p>Implementation of the FASTHUG concept, in the daily evaluation of mechanically ventilated patients, significantly decreased our surgical intensive care unit VAP rate.</p

Applying the quality improvement collaborative method to process redesign: a multiple case study

<p>Abstract</p> <p>Background</p> <p>Despite the widespread use of quality improvement collaboratives (QICs), evidence underlying this method is limited. A QIC is a method for testing and implementing evidence-based changes quickly across organisations. To extend the knowledge about conditions under which QICs can be used, we explored in this study the applicability of the QIC method for process redesign.</p> <p>Methods</p> <p>We evaluated a Dutch process redesign collaborative of seventeen project teams using a multiple case study design. The goals of this collaborative were to reduce the time between the first visit to the outpatient's clinic and the start of treatment and to reduce the in-hospital length of stay by 30% for involved patient groups. Data were gathered using qualitative methods, such as document analysis, questionnaires, semi-structured interviews and participation in collaborative meetings.</p> <p>Results</p> <p>Application of the QIC method to process redesign proved to be difficult. First, project teams did not use the provided standard change ideas, because of their need for customised solutions that fitted with context-specific causes of waiting times and delays. Second, project teams were not capable of testing change ideas within short time frames due to: the need for tailoring changes ideas and the complexity of aligning interests of involved departments; small volumes of involved patient groups; and inadequate information and communication technology (ICT) support. Third, project teams did not experience peer stimulus because they saw few similarities between their projects, rarely shared experiences, and did not demonstrate competitive behaviour. Besides, a number of project teams reported that organisational and external change agent support was limited.</p> <p>Conclusions</p> <p>This study showed that the perceived need for tailoring standard change ideas to local contexts and the complexity of aligning interests of involved departments hampered the use of the QIC method for process redesign. We cannot determine whether the QIC method would have been appropriate for process redesign. Peer stimulus was non-optimal as a result of the selection process for participation of project teams by the external change agent. In conclusion, project teams felt that necessary preconditions for successful use of the QIC method were lacking.</p

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Although the <it>high mobility group A1 </it>(<it>HMGA1</it>) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. <it>HMGA1 </it>functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, <it>HMGA1 </it>is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from <it>HMGA1a </it>transgenic mice at different stages in tumorigenesis.</p> <p>Results</p> <p>RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.</p> <p>Conclusions</p> <p>We found that <it>HMGA1 </it>induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. <it>HMGA1 </it>also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into <it>HMGA1 </it>function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant <it>HMGA1 </it>expression.</p

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of$500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs$150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82$144 per year, in 52% at $264, and in 87$114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health

Multicenter Evaluation of a Novel Surveillance Paradigm for Complications of Mechanical Ventilation

Ventilator-associated pneumonia (VAP) surveillance is time consuming, subjective, inaccurate, and inconsistently predicts outcomes. Shifting surveillance from pneumonia in particular to complications in general might circumvent the VAP definition's subjectivity and inaccuracy, facilitate electronic assessment, make interfacility comparisons more meaningful, and encourage broader prevention strategies. We therefore evaluated a novel surveillance paradigm for ventilator-associated complications (VAC) defined by sustained increases in patients' ventilator settings after a period of stable or decreasing support.We assessed 600 mechanically ventilated medical and surgical patients from three hospitals. Each hospital contributed 100 randomly selected patients ventilated 2-7 days and 100 patients ventilated >7 days. All patients were independently assessed for VAP and for VAC. We compared incidence-density, duration of mechanical ventilation, intensive care and hospital lengths of stay, hospital mortality, and time required for surveillance for VAP and for VAC. A subset of patients with VAP and VAC were independently reviewed by a physician to determine possible etiology.Of 597 evaluable patients, 9.3% had VAP (8.8 per 1,000 ventilator days) and 23% had VAC (21.2 per 1,000 ventilator days). Compared to matched controls, both VAP and VAC prolonged days to extubation (5.8, 95% CI 4.2-8.0 and 6.0, 95% CI 5.1-7.1 respectively), days to intensive care discharge (5.7, 95% CI 4.2-7.7 and 5.0, 95% CI 4.1-5.9), and days to hospital discharge (4.7, 95% CI 2.6-7.5 and 3.0, 95% CI 2.1-4.0). VAC was associated with increased mortality (OR 2.0, 95% CI 1.3-3.2) but VAP was not (OR 1.1, 95% CI 0.5-2.4). VAC assessment was faster (mean 1.8 versus 39 minutes per patient). Both VAP and VAC events were predominantly attributable to pneumonia, pulmonary edema, ARDS, and atelectasis.Screening ventilator settings for VAC captures a similar set of complications to traditional VAP surveillance but is faster, more objective, and a superior predictor of outcomes

Cost-effectiveness of ward-based pharmacy care in surgical patients: protocol of the SUREPILL (Surgery & Pharmacy In Liaison) study

<p>Abstract</p> <p>Background</p> <p>Preventable adverse drug events (pADEs) are widely known to be a health care issue for hospitalized patients. Surgical patients are especially at risk, but prevention of pADEs in this population is not demonstrated before. Ward-based pharmacy interventions seem effective in reducing pADEs in medical patients. The cost-effectiveness of these preventive efforts still needs to be assessed in a comparative study of high methodological standard and also in the surgical population. For these aims the SUREPILL (Surgery & Pharmacy in Liaison) study is initiated.</p> <p>Methods/Design</p> <p>A multi-centre controlled trial, with randomisation at ward-level and preceding baseline assessments is designed. Patients admitted to the surgical study wards for elective surgery with an expected length of stay of more than 48 hours will be included. Patients admitted to the intervention ward, will receive ward-based pharmacy care from the clinical pharmacy team, i.e. pharmacy practitioners and hospital pharmacists. This ward-based pharmacy intervention includes medication reconciliation in consultation with the patient at admission, daily medication review with face-to-face contact with the ward doctor, and patient counselling at discharge. Patients admitted in the control ward, will receive standard pharmaceutical care.</p> <p>The primary clinical outcome measure is the number of pADEs per 100 elective admissions. These pADEs will be measured by systematic patient record evaluation using a trigger tool. Patient records positive for a trigger will be evaluated on causality, severity and preventability by an independent expert panel. In addition, an economic evaluation will be performed from a societal perspective with the costs per preventable ADE as the primary economic outcome. Other outcomes of this study are: severity of pADEs, number of patients with pADEs per total number of admissions, direct (non-)medical costs and indirect non-medical costs, extra costs per prevented ADE, number and type of pharmacy interventions, length of hospital stay, complications registered in a national complication registration system for surgery, number of readmissions within three months after initial admission (follow-up), quality of life and number of non-institutionalized days during follow-up.</p> <p>Discussion</p> <p>This study will assess the cost-effectiveness of ward-based pharmacy care on preventable adverse drug events in surgical patients from a societal perspective, using a comparative study design.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2258">NTR2258</a></p

A review of significant events analysed in general practice: implications for the quality and safety of patient care

<p>Abstract</p> <p>Background</p> <p>Significant event analysis (SEA) is promoted as a team-based approach to enhancing patient safety through reflective learning. Evidence of SEA participation is required for appraisal and contractual purposes in UK general practice. A voluntary educational model in the west of Scotland enables general practitioners (GPs) and doctors-in-training to submit SEA reports for feedback from trained peers. We reviewed reports to identify the range of safety issues analysed, learning needs raised and actions taken by GP teams.</p> <p>Method</p> <p>Content analysis of SEA reports submitted in an 18 month period between 2005 and 2007.</p> <p>Results</p> <p>191 SEA reports were reviewed. 48 described patient harm (25.1%). A further 109 reports (57.1%) outlined circumstances that had the potential to cause patient harm. Individual 'error' was cited as the most common reason for event occurrence (32.5%). Learning opportunities were identified in 182 reports (95.3%) but were often non-specific professional issues not shared with the wider practice team. 154 SEA reports (80.1%) described actions taken to improve practice systems or professional behaviour. However, non-medical staff were less likely to be involved in the changes resulting from event analyses describing patient harm (p < 0.05)</p> <p>Conclusion</p> <p>The study provides some evidence of the potential of SEA to improve healthcare quality and safety. If applied rigorously, GP teams and doctors in training can use the technique to investigate and learn from a wide variety of quality issues including those resulting in patient harm. This leads to reported change but it is unclear if such improvement is sustained.</p