The quality of care delivered to residents in long-term care in Australia: an indicator-based review of resident records (CareTrack Aged study).

BACKGROUND: This study estimated the prevalence of evidence-based care received by a population-based sample of Australian residents in long-term care (LTC) aged ≥ 65 years in 2021, measured by adherence to clinical practice guideline (CPG) recommendations. METHODS: Sixteen conditions/processes of care amendable to estimating evidence-based care at a population level were identified from prevalence data and CPGs. Candidate recommendations (n = 5609) were extracted from 139 CPGs which were converted to indicators. National experts in each condition rated the indicators via the RAND-UCLA Delphi process. For the 16 conditions, 236 evidence-based care indicators were ratified. A multi-stage sampling of LTC facilities and residents was undertaken. Trained aged-care nurses then undertook manual structured record reviews of care delivered between 1 March and 31 May 2021 (our record review period) to assess adherence with the indicators. RESULTS: Care received by 294 residents with 27,585 care encounters in 25 LTC facilities was evaluated. Residents received care for one to thirteen separate clinical conditions/processes of care (median = 10, mean = 9.7). Adherence to evidence-based care indicators was estimated at 53.2% (95% CI: 48.6, 57.7) ranging from a high of 81.3% (95% CI: 75.6, 86.3) for Bladder and Bowel to a low of 12.2% (95% CI: 1.6, 36.8) for Depression. Six conditions (skin integrity, end-of-life care, infection, sleep, medication, and depression) had less than 50% adherence with indicators. CONCLUSIONS: This is the first study of adherence to evidence-based care for people in LTC using multiple conditions and a standardised method. Vulnerable older people are not receiving evidence-based care for many physical problems, nor care to support their mental health nor for end-of-life care. The six conditions in which adherence with indicators was less than 50% could be the focus of improvement efforts.

Pharmacists as patient advocates: A series of case studies illustrating the impacts of a regular pharmacist service in residential aged care (nursing homes).

Background: Medicine-related problems are common in older people living in residential aged care facilities (RACFs). Recognising the significant medicine-related problems, the Australian government has announced a $345 million funding package to employ on-site pharmacists in RACFs starting in 2023. The new on-site pharmacists are to provide a range of clinical services to reduce medicine-related adverse events, promote quality use of medicines, and improve clinical governance and education. Underpinning these services, the authors argue that pharmacists play the critical role as resident advocates. Objective: This study aims to demonstrate how pharmacists can enhance their advocacy responsibility within and beyond the clinical environment to not only reduce medicine-related adverse events but also improve residents' overall health and quality of life. Methods: This study uses a case series methodology to demonstrate pharmacists' diverse roles in advocating for residents and their families. The case studies were based on participants enrolled in the Reducing Medicine-Induced Deterioration and Adverse Reactions (ReMInDAR) trial, a randomised controlled trial testing the effects of a regular pharmacist service across the Australian RACFs. Results: Pharmacists' advocacy ranged from persistence in follow-up with a resident's general practitioner (GP) to ensure the GP was aware that a patient was experiencing bleeding and bruising while on an anticoagulant, to advocating for a new bed for a resident with peripheral oedema who had been sleeping in his chair due to fear of falling out of his current bed. Conclusions: Our trial focussed on pharmacists serving as the residents' advocate to improve their overall health and quality of life, rather than just addressing a list of medicine-related problems. The pharmacist model used in the ReMInDAR trial supports pharmacists to work to their full scope of practice, helps guide the Australian government's new on-site pharmacist program, and serves as an exemplar pharmacist in aged care model internationally.

Prevalence and Preventability of Adverse Medicine Events in a Sample of Australian Aged-Care Residents: A Secondary Analysis of Data from the ReMInDAR Trial.

BACKGROUND: Aged care residents are vulnerable to the harmful effects of medicines; however, data on the prevalence and preventability of adverse medicine events in aged care residents are scarce. AIM: To determine the prevalence and preventability of adverse medicine events in Australian aged care residents. METHODS: A secondary analysis of data from the Reducing Medicine-Induced Deterioration and Adverse Reactions (ReMInDAR) trial was conducted. Potential adverse medicine events were identified and independently screened by two research pharmacists to produce a short-list of potential adverse medicine events. An expert clinical panel reviewed each potential adverse medicine to determine the likelihood that the event was medicine related (based on the Naranjo Probability Scale criteria). The clinical panel assessed preventability of medicine-related events using Schumock-Thornton criteria. RESULTS: There were 583 adverse events due to medicines, involving 154 residents (62% of the 248 study participants). There was a median of three medication-related adverse events (interquartile range [IQR] 1-5) per resident over the 12-month follow-up period. The most common medication-related adverse events were falls (56%), bleeding (18%) and bruising (9%). There were 482 (83%) medication-related adverse events that were preventable, most commonly falls (66% of preventable adverse medicine events), bleeding (12%) and dizziness (8%). Of the 248 residents, 133 (54% of the cohort) had at least one preventable adverse medicine event, with a median of 2 (IQR 1-4) preventable adverse medicine events per resident. CONCLUSION: In total, 62% of aged care residents in our study had an adverse medicine event and 54% had a preventable adverse medicine event in a 12-month period.

Using wrist-worn accelerometers to identify the impact of medicines with anticholinergic or sedative properties on sedentary time: A 12-month prospective analysis.

INTRODUCTION: Studies have shown that use of medicines with sedative or anticholinergic properties is associated with a decline in physical function; however, the effects have not been quantified, and it is not known how and which specific physical movements are affected. This prospective study quantified the impact of a change in sedative or anticholinergic load over time on 24-hour activity composition. METHODS: This study used data collected from a randomised trial assessing an ongoing pharmacist service in residential aged care. The 24-hour activity composition of sleep, sedentary behaviour, light-intensity physical activity, and moderate to vigorous physical activity was derived from 24-hour accelerometry bands. Mixed effect linear models were used to regress the multivariate outcome of 24-hour activity composition on medication load at baseline and at 12 months. A fixed effect interaction between trial stage and medication load was included to test for differing sedative or anticholinergic load effects at the two trial stages. RESULTS: Data for 183 and 85 participants were available at baseline and 12 months respectively. There was a statistically significant interaction between medication load and time point on the multivariate outcome of 24-hour activity composition (sedative F = 7.2, p < 0.001 and anticholinergic F = 3.2, p = 0.02). A sedative load increase from 2 to 4 over the 12-month period was associated with an average increase in daily sedentary behaviour by an estimated 24 min. CONCLUSION: As sedative or anticholinergic load increased, there was an increase in sedentary time. Our findings suggest wearable accelerometry bands are a possible tool for monitoring the effects on physical function of sedative and anticholinergic medicines. TRIAL REGISTRATION: The ReMInDAR trial was registered on the Australian and New Zealand Trials Registry ACTRN12618000766213.

Exploring what matters to residents of Australian aged care facilities with the Happy Life Index: comparison of qualitative responses between pre- and mid-Covid-19 pandemic time points.

PURPOSE: This study analysed data from a national survey of people living in Australian Residential Aged Care Facilities (RACFs) reporting on what is the best thing about where they live and suggestions for improvement. Data from prior to the Covid-19 pandemic were compared with data during the Covid-19 pandemic. METHODS: Qualitative data from the Happy Life Index Survey were analysed using summative content analysis to code the responses in the data sets and then organise them into categories. Once categorised, the pre-Covid-19 and mid-Covid-19 data sets were compared using descriptive statistics. RESULTS: A total of 4745 residents, from over 100 RACFs, provided 8512 open-text responses to at least one of the two survey questions. Pre-Covid-19 responses were compared with mid-Covid-19 responses and those trending towards relevance (5-10% change) were identified. There were both positive and negative relevant percent changes for staff number, food (general comments), and friendliness. A trending positive percentage change was observed for staff quality and the internal environment. There was a trending negative relevant percentage change for lifestyle activities, staff generally, level of contentedness, the general environment, general choice, and general views about the service. CONCLUSION: People living in RACFs notice the changes in staffing levels and visitors during restrictions imposed during infectious outbreaks. During these times, they appreciate the quality of the staff attending to their needs and the quality of their food. Further exploration is needed of the value of lifestyle activities and strategies to promote feelings of contentedness and general wellbeing during times of restriction.

Risk factors predictive of adverse drug events and drug-related falls in aged care residents: secondary analysis from the ReMInDAR trial.

BACKGROUND: Residents of aged-care facilities have high rates of adverse drug events. This study aimed to identify risk factors for adverse drug events in aged-care residents. METHOD: This was a secondary study using data from a multicentre randomised controlled trial. Data from 224 residents for whom there was 6 months of baseline information were analysed. We assessed the risk of adverse drug events and falls (post hoc) in the subsequent 6 months. Adverse events were identified via a key word search of the resident care record and adjudicated by a multidisciplinary panel using a modified version of the Naranjo criteria. Covariates identified through univariable logistic regression, including age, sex, medicines, physical activity, cognition (Montreal Cognitive Assessment), previous adverse events and health service use were included in multivariable models. RESULTS: Overall, 224 residents were included, with a mean age of 86 years; 70% were female. 107 (48%) residents had an adverse drug event during the 6-month follow-up. Falls and bleeding were experienced by 73 (33%) and 28 (13%) residents, respectively. Age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01-1.10), weight (OR 1.02, 95% CI 1.002-1.04), previous fall (OR 2.58, 95% CI 1.34-4.98) and sedative or hypnotic medicine use (OR 1.98, 95% CI 1.52-2.60) were associated with increased risk of adverse drug events. Increased cognition (OR 0.89, 95% CI 0.83-0.95) was protective. Risk factors for falls were previous fall (OR 3.27, 95% CI 1.68-6.35) and sedative or hypnotic medicines (OR 3.05, 95% CI 1.14-8.16). Increased cognition (OR 0.88, 95% CI 0.83-0.95) was protective. CONCLUSION: Our results suggest residents with a previous fall, reduced cognition, and prescription of sedative or hypnotic medicines were at higher risk of adverse drug events and should be considered for proactive prevention.

Frailty trajectory over one year among residential aged care (nursing home) residents.

Objectives: Large population-based studies examining frailty trajectory found a linear increase in frailty over time. The pattern in which frailty changes over time for an individual person is less well-described. We examined the frailty trajectory of older adults living in aged-care in Australia. Materials and methods: This secondary study used data from a randomised controlled trial involving 39 aged-care facilities in Australia. The trial intervention was an on-going pharmacist-led intervention occurring every 8 weeks over 12 months aimed at preventing medicine-induced deterioration and adverse reactions. Frailty was assessed using the Frailty Index. Participants were categorised as non-frail, pre-frail and frail. Individual frailty trajectory over 12 months was visualised using the alluvial plot. Case notes were examined to explore reasons for any rapid transitions in frailty status. Results: A total of 248 participants was included. At baseline, 40.3% were non-frail and 59.7% were pre-frail. The proportion of participants who were non-frail and pre-frail decreased over time; 15.7% were frail at 6 months and 23.4% were frail at 12 months. Overall, twenty different combinations of frailty transitions were identified over 12 months. Retrospective analysis of case notes suggest that death or transition from non-frail to frail was often preceded by hospitalisation, falls, medication change or clinically significant deterioration in grip strength or cognition. Conclusion: The degree of frailty increased over time, but there were variations in the individual trajectories. Regular monitoring of events that precede changes in frailty status is needed to identify strategies to prevent further deterioration in residents' conditions.

Medicine-related problems: A recurrent issue among residents living in nursing homes.

Aim: To examine the incidence and nature of medicine-related problems over time experienced by nursing home residents. Method: We analyzed records collected in the Reducing Medicine-Induced Deterioration and Adverse Events (ReMInDAR) trial. The trial pharmacists provided services to reduce medicine-induced deterioration and adverse reactions for residents every 8-weeks over a year. The problems identified by the pharmacists were documented in reports and subsequently classified independently by research pharmacists using the D.O.C.U.M.E.N.T system. The number and type of problems at each service and time to develop a new problem post first session were assessed. All analyses were performed using R software (Version 4.1.1). Results: The cohort was 115 nursing home residents who received 575 services. In the 12-months, a total of 673 medicine-related problems or symptom reports were identified in 112 residents. Most residents (75%) experienced a new medicine-related problem by the fourth month post the first assessment. After the first session, the proportion of residents with a new medicine-related problem or symptom report declined at each repeated pharmacy session (59% at visit 2 vs. 28% at visit 6, p < 0.01). Conclusion: Residents living in nursing homes frequently experience medicine-related problems. Our results suggest clinical pharmacist services performed every 4-months may have the potential to reduce the medicine-related problems in nursing homes.

Effect of an ongoing pharmacist service to reduce medicine-induced deterioration and adverse reactions in aged-care facilities (nursing homes): a multicentre, randomised controlled trial (the ReMInDAR trial).

OBJECTIVE: To assess the effectiveness of a pharmacist-led intervention using validated tools to reduce medicine-induced deterioration and adverse reactions. DESIGN AND SETTING: Multicenter, open-label parallel randomised controlled trial involving 39 Australian aged-care facilities. PARTICIPANTS: Residents on ≥4 medicines or ≥1 anticholinergic or sedative medicine. INTERVENTION: Pharmacist-led intervention using validated tools to detect signs and symptoms of medicine-induced deterioration which occurred every 8 weeks over 12 months. COMPARATOR: Usual care (Residential Medication Management Review) provided by accredited pharmacists. OUTCOMES: Primary outcome was change in Frailty Index at 12 months. Secondary outcomes included changes in cognition, 24-hour movement behaviour by accelerometry, grip strength, weight, adverse events and quality of life. RESULTS: 248 persons (median age 87 years) completed the study; 120 in the interventionand, 128 in control arms. In total 575 pharmacist, sessions were undertaken in the intervention arm. There was no statistically significant difference for change in frailty between groups (mean difference: 0.009, 95% CI: -0.028, 0.009, P = 0.320). A significant difference for cognition was observed, with a mean difference of 1.36 point change at 12 months (95% CI: 0.01, 2.72, P = 0.048). Changes in 24-hour movement behaviour, grip strength, adverse events and quality of life were not significantly different between groups. Point estimates favoured the intervention arm at 12 months for frailty, 24-hour movement behaviour and grip strength. CONCLUSIONS: The use of validated tools by pharmacists to detect signs of medicine-induced deterioration is a model of practice that requires further research, with promising results from this trial, particularly with regards to improved cognition.

Reducing medicine-induced deterioration and adverse reactions (ReMInDAR) trial: study protocol for a randomised controlled trial in residential aged-care facilities assessing frailty as the primary outcome.

INTRODUCTION: Many medicines have adverse effects which are difficult to detect and frequently go unrecognised. Pharmacist monitoring of changes in signs and symptoms of these adverse effects, which we describe as medicine-induced deterioration, may reduce the risk of developing frailty. The aim of this trial is to determine the effectiveness of a 12-month pharmacist service compared with usual care in reducing medicine-induced deterioration, frailty and adverse reactions in older people living in aged-care facilities in Australia. METHODS AND ANALYSIS: The reducing medicine-induced deterioration and adverse reactions trial is a multicentre, open-label randomised controlled trial. Participants will be recruited from 39 facilities in South Australia and Tasmania. Residents will be included if they are using four or more medicines at the time of recruitment, or taking more than one medicine with anticholinergic or sedative properties. The intervention group will receive a pharmacist assessment which occurs every 8 weeks. The pharmacists will liaise with the participants' general practitioners when medicine-induced deterioration is evident or adverse events are considered serious. The primary outcome is a reduction in medicine-induced deterioration from baseline to 6 and 12 months, as measured by change in frailty index. The secondary outcomes are changes in cognition scores, 24-hour movement behaviour, grip strength, weight, percentage robust, pre-frail and frail classification, rate of adverse medicine events, health-related quality of life and health resource use. The statistical analysis will use mixed-models adjusted for baseline to account for repeated outcome measures. A health economic evaluation will be conducted following trial completion using data collected during the trial. ETHICS AND DISSEMINATION: Ethics approvals have been obtained from the Human Research Ethics Committee of University of South Australia (ID:0000036440) and University of Tasmania (ID:H0017022). A copy of the final report will be provided to the Australian Government Department of Health. TRIAL REGISTRATION NUMBER: Australian and New Zealand Trials Registry ACTRN12618000766213.

Direct health and residential care costs of people living with dementia in Australian residential aged care.

OBJECTIVES: This analysis estimates the whole-of-system direct costs for people living with dementia in residential care by using a broad health and social care provision perspective and compares it to people without dementia living in residential care. METHODS: Data were collected from 541 individuals living permanently in 17 care facilities across Australia. The annual cost of health and residential care was determined by using individual resource use data and reported by the dementia status of the individuals. RESULTS: The average annual whole-of-system cost for people living with dementia in residential care was approximately AU$88 000 (US$ 67 100) per person in 2016. The cost of residential care constituted 93% of the total costs. The direct health care costs were comprised mainly of hospital admissions (48%), pharmaceuticals (31%) and out-of-hospital attendances (15%). While total costs were not significantly different between those with and without dementia, the cost of residential care was significantly higher and the cost of health care was significantly lower for people living with dementia. CONCLUSION: This study provides the first estimate of the whole-of-system costs of providing health and residential care for people living with dementia in residential aged care in Australia using individual level health and social care data. This predominantly bottom-up cost estimate indicates the high cost associated with caring for people with dementia living permanently in residential care, which is underestimated when limited cost perspectives or top-down, population costing approaches are taken.

Differences in hydroxylation and binding of Notch and HIF-1alpha demonstrate substrate selectivity for factor inhibiting HIF-1 (FIH-1).

FIH-1, factor inhibiting hypoxia-inducible factor-1 (HIF-1), regulates oxygen sensing by hydroxylating an asparagine within HIF-alpha. It also hydroxylates asparagines in many proteins containing ankyrin repeats, including Notch1-3, p105 and I?B?. Relative binding affinity and hydroxylation rate are crucial determinants of substrate selection and modification. We determined the contributions of substrate sequence composition and length and of oxygen concentration to the FIH-1-binding and/or hydroxylation of Notch1-4 and compared them with those for HIF-1alpha. We also demonstrated hydroxylation of two asparagines in Notch2 and 3, corresponding to Sites 1 and 2 of Notch1, by mass spectrometry for the first time. Our data demonstrate that substrate length has a much greater influence on FIH-1-dependent hydroxylation of Notch than of HIF-1alpha, predominantly through binding affinity rather than maximal reaction velocity. The K(m) value of FIH-1 for Notch1, < 0.2 microM, is at least 250-fold lower than that of 50 microM for HIF-1alpha. Site 1 of Notch1-3 appeared the preferred site of FIH-1 hydroxylation in these substrates. Interestingly, binding of Notch4 to FIH-1 was observed with an affinity almost 10-fold lower than for Notch1-3, but no hydroxylation was detected. Importantly, we demonstrate that the K(m) of FIH-1 for oxygen at the preferred Site 1 of Notch1-3, 10-19 microM, is an order of magnitude lower than that for Site 2 or HIF-1alpha. Hence, at least during in vitro hydroxylation, Notch is likely to become efficiently hydroxylated by FIH-1 even under relatively severe hypoxic conditions, where HIF-1alpha hydroxylation would be reduced.

Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway.

Accumulation of HIF-1alpha during normoxic conditions at high cell density has previously been shown to occur and can be used to stabilize HIF-1alpha protein in the absence of a specific anaerobic chamber. However, the impact and origin of this pool of HIF-1alpha, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1alpha stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1alpha stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1alpha accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70(S6K) phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O(2) levels, only slightly impacts upon the mTOR pathway under low cell density conditions. Thus, activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway whereas HIF-1alpha activation obtained in high confluency is totally dependent on mTOR pathway as rapamycin totally impaired (i) HIF-1alpha stabilization and (ii) mRNA levels of CA9 and BNIP3, two HIF-target genes.

Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways.

Cells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1alpha (HIF-1alpha) becomes stabilized and directly activates transcription of downstream genes. In addition to this "canonical" response, certain aspects of the pathway require integration with Notch signaling, i.e., HIF-1alpha can interact with the Notch intracellular domain (ICD) to augment the Notch downstream response. In this work, we demonstrate an additional level of complexity in this cross-talk: factor-inhibiting HIF-1 (FIH-1) regulates not only HIF activity, but also the Notch signaling output and, in addition, plays a role in how Notch signaling modulates the hypoxic response. We show that FIH-1 hydroxylates Notch ICD at two residues (N(1945) and N(2012)) that are critical for the function of Notch ICD as a transactivator within cells and during neurogenesis and myogenesis in vivo. FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation. In its modulation of the hypoxic response, Notch ICD enhances recruitment of HIF-1alpha to its target promoters and derepresses HIF-1alpha function. Addition of FIH-1, which has a higher affinity for Notch ICD than for HIF-1alpha, abrogates the derepression, suggesting that Notch ICD sequesters FIH-1 away from HIF-1alpha. In conclusion, the data reveal posttranslational modification of the activated form of the Notch receptor and an intricate mode of cross-coupling between the Notch and hypoxia signaling pathways.

ARDent about acetylation and deacetylation in hypoxia signalling.

Given the key role that the alpha subunit of the alphabeta heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) has in tumourigenesis, and in particular in angiogenesis, a full understanding of its regulation is crucial to the development of cancer therapeutics. Posttranslational acetylation and deacetylation of this subunit by an acetyltransferase called Arrest-defective-1 (ARD1) and by different histone deacetylases (HDACs), respectively, has been suggested as a mechanism. However, conflicting data bring into question the foundations of this mechanism and at present it is not clear what the precise role of these proteins is with respect to HIF. Nonetheless, the observation that small-molecule inhibitors of HDACs have anti-angiogenic activity suggests that acetylation and deacetylation of HIF or HIF modifiers represents a potential target in cancer therapy.

Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1alpha and is not induced by hypoxia or HIF.

The hypoxia-inducible factor (HIF) is a key player in a transcriptional pathway that controls the hypoxic response of mammalian cells. Post-translational modification of the alpha subunit of HIF determines its half-life and activity. Among the multiple reported modifications, acetylation, by an acetyltransferase termed arrest-defective-1 protein (ARD1), has been reported to decrease HIF-1alpha stability and therefore impact on hypoxic gene expression. In contrast, we report that both overexpression and silencing of ARD1 had no impact on the stability of HIF-1alpha or -2alpha and that cells silenced for ARD1 maintained hypoxic nuclear localization of HIF-1alpha. In addition, we show that the ARD1 mRNA and protein levels are not regulated by hypoxia in several human tumor cell lines, including cervical adenocarcinoma HeLa cells, fibrosarcoma HT1080 cells, adenovirus-transformed human kidney HEK293 cells, and human breast cancer MCF-7 cells. Using two model systems ((a) wild-type and HIF-1alpha-null mouse embryo fibroblasts and (b) HeLa cells silenced for HIF-1alpha or -2alpha by RNA interference), we demonstrate that the level of expression of the ARD1 protein is independent of HIF-1alpha and -2alpha. We also demonstrate that ARD1 is a stable, predominantly cytoplasmic protein expressed in a broad range of tissues, tumor cell lines, and endothelial cells. Taken together, our findings demonstrate that ARD1 has limited, if any, impact on the HIF signaling pathway.

HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs.

The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O2 concentrations.

The subtle side to hypoxia inducible factor (HIFalpha) regulation.

The transcription factor hypoxia inducible factor alpha-subunit (HIFalpha) is pivotal in the cellular response to the stress of hypoxia. Post-translational modification of HIFalpha by hydroxylase enzymes has recently been identified as a key "oxygen sensing" mechanism within the cell. The absence of the substrate oxygen prevents the hydroxylases from modifying HIFalpha during hypoxia and allows dramatic up-regulation of both HIFalpha protein stability and transcriptional activation capability. In addition to this oxygen-dependent response, increased HIFalpha protein levels and/or enhanced transcriptional activity during normoxic conditions can be stimulated by various receptor-mediated factors such as growth-factors and cytokines (insulin, insulin-like growth factor 1 or 2, endothelial growth factor, tumour necrosis factor alpha, angiotensin-2). Oncogenes are also capable of HIFalpha activation. This induction is generally less intense than that stimulated by hypoxia and although not fully elucidated, appears to occur via hypoxia-independent, receptor-mediated signal pathways involving either phosphatidyl-inositol-3-kinase/Akt or mitogen activated protein kinase (MAPK) pathways, depending on the cell-type. Activation of Akt increases HIFalpha protein synthesis in the cell and results in increased HIFalpha protein and transcriptional activity. MAPK also activates HIFalpha protein synthesis and additionally may potentiate HIF1alpha transcriptional activity via a separate mechanism that does not necessarily require protein stabilization. Here we review the mechanisms and function of receptor-mediated signals in the multifaceted regulation of HIFalpha.