| 1. |
- Kennedy, S. A., et al.
(författare)
-
Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D
- 2020
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Corsonello, Andrea, et al.
(författare)
-
The relevance of geriatric assessments on the association between chronic kidney disease stages and mortality among older people : A secondary analysis of a multicentre cohort study
- 2022
-
Ingår i: Age and Ageing. - : Oxford University Press. - 0002-0729 .- 1468-2834. ; 51:7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: age-adapted definition of chronic kidney disease (CKD) does not take individual risk factors into account. We aimed at investigating whether functional impairments influence CKD stage at which mortality increases among older people. Methods: our series consisted of 2,372 outpatients aged 75 years or more enrolled in a multicentre international prospective cohort study. The study outcome was 24-month mortality. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Geriatric assessments included handgrip strength, short physical performance battery (SPPB), cognitive impairment, dependency in basic activities of daily living (BADL) and risk of malnutrition. Analysis was carried out by Cox regression, before and after stratification by individual functional impairments. Survival trees including kidney function and functional impairments were also investigated, and their predictivity assessed by C-index. Results: overall, mortality was found to increase starting from eGFR = 30-44.9 ml/min/1.73 m2 (hazard ratio [HR] = 3.28, 95% confidence interval [CI] = 1.81-5.95) to ACR = 30-300 mg/g (HR = 1.96, 95%CI = 1.23-3.10). However, in survival trees, an increased risk of mortality was observed among patients with impaired handgrip and eGFR = 45-59.9 ml/min/1.73 m2, as well as patients with ACR < 30 mg/g and impaired handgrip and SPPB. Survival tree leaf node membership had greater predictive accuracy (C-index = 0.81, 95%CI = 0.78-0.84 for the eGFR survival tree and C-index = 0.77, 95%CI = 0.71-0.81 for the ACR survival tree) in comparison with that of individual measures of kidney function. Conclusions: physical performance helps to identify a proportion of patients at an increased risk of mortality despite a mild-moderate impairment in kidney function and improves predictive accuracy of individual measures of kidney function. © 2022 The Author(s). Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.
|
|
| 5. |
- Eikelboom, Willem S., et al.
(författare)
-
Effects of the DICE Method to Improve Timely Recognition and Treatment of Neuropsychiatric Symptoms in Early Alzheimer's Disease at the Memory Clinic : The BEAT-IT Study
- 2023
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 93:4, s. 1407-1423
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD) and are associated with negative outcomes. However, NPS are currently underrecognized at the memory clinic and non-pharmacological interventions are scarcely implemented. Objective: To evaluate the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) method™ to improve the care for NPS in AD at the memory clinic. Methods: We enrolled sixty community-dwelling people with mild cognitive impairment or AD dementia and NPS across six Dutch memory clinics with their caregivers. The first wave underwent care as usual (n = 36) and the second wave underwent the DICE method (n = 24). Outcomes were quality of life (QoL), caregiver burden, NPS severity, NPS-related distress, competence managing NPS, and psychotropic drug use. Reliable change index was calculated to identify responders to the intervention. A cost-effectiveness analysis was performed and semi-structured interviews with a subsample of the intervention group (n = 12). Results: The DICE method did not improve any outcomes over time compared to care as usual. Half of the participants of the intervention group (52%) were identified as responders and showed more NPS and NPS-related distress at baseline compared to non-responders. Interviews revealed substantial heterogeneity among participants regarding NPS-related distress, caregiver burden, and availability of social support. The intervention did not lead to significant gains in quality-adjusted life years and well-being years nor clear savings in health care and societal costs. Conclusion: The DICE method showed no benefits at group-level, but individuals with high levels of NPS and NPS-related distress may benefit from this intervention.
|
|
| 6. |
- Eikelboom, Willem S., et al.
(författare)
-
Evaluating the DICE method to improve early recognition and treatment of neuropsychiatric symptoms in early Alzheimer’s disease
- 2022
-
Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S8
-
Tidskriftsartikel (refereegranskat)abstract
- Background: While neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic. Method: A total of 60 community-dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table-1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL-AD) and caregivers (Carerqol-7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI-Q & BEHAVE-AD), NPS-related distress (NPI-Q), competence managing NPS (additional NPI-Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group-level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes. Result: We found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table-2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS-related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement. Conclusion: This Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group-level, but suggest that particular participants might benefit from this approach. Data will be re-analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS-related knowledge and management styles of participants.
|
|
| 7. |
|
|
| 8. |
- Artzi-Medvedik, Rada, et al.
(författare)
-
Impaired kidney function is associated with lower quality of life among community-dwelling older adults The screening for CKD among older people across Europe (SCOPE) study
- 2020
-
Ingår i: BMC Geriatrics. - : BMC. - 1471-2318 .- 1471-2318. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Background Quality of life (QoL) refers to the physical, psychological, social and medical aspects of life that are influenced by health status and function. The purpose of this study was to measure the self-perceived health status among the elderly population across Europe in different stages of Chronic Kidney Disease (CKD). Methods Our series consisted of 2255 community-dwelling older adults enrolled in the Screening for Chronic Kidney Disease (CKD) among Older People across Europe (SCOPE) study. All patients underwent a comprehensive geriatric assessment (CGA), including included demographics, clinical and physical assessment, number of medications taken, family arrangement, Geriatric Depression Scale (GDS), Cumulative Illness Rating Scale, History of falls, Lower urinary tract symptoms, and Short Physical Performance Battery (SPPB). Estimated glomerular filtration rate (eGFR) was calculated by Berlin Initiative Study (BIS) equation. Quality of life was assessed by Euro Qol questionnaire (Euro-Qol 5D) and EQ-Visual Analogue Scale (EQ-VAS). The association between CKD (eGFR < 60, < 45 ml or < 30 ml/min/1.73m(2)) and low EQoL-VAS was investigated by multivariable logistic regression models. Results CKD was found to be significantly associated with low EQoL-VAS in crude analysis (OR = 1.47, 95%CI = 1.16-1.85 for eGFR< 60; OR = 1.38, 95%CI = 1.08-1.77 for eGFR< 45; OR = 1.57, 95%CI = 1.01-2.44). Such association was no longer significant only when adjusting for SPPB (OR = 1.20, 95%CI = 0.93-1.56 for eGFR< 60; OR = 0.87, 95%CI = 0.64-1.18 for eGFR< 45; OR = 0.84, 95%CI = 0.50-1.42), CIRS and polypharmacy (OR = 1.16, 95%CI = 0.90-1.50 for eGFR< 60; OR = 0.86, 95%CI = 0.64-1.16 for eGFR< 45; OR = 1.11, 95%CI = 0.69-1.80) or diabetes, hypertension and chronic obstructive pulmonary disease (OR = 1.28, 95%CI = 0.99-1.64 for eGFR< 60; OR = 1.16, 95%CI = 0.88-1.52 for eGFR< 45; OR = 1.47, 95%CI = 0.92-2.34). The association between CKD and low EQoL-VAS was confirmed in all remaining multivariable models. Conclusions CKD may significantly affect QoL in community-dwelling older adults. Physical performance, polypharmacy, diabetes, hypertension and COPD may affect such association, which suggests that the impact of CKD on QoL is likely multifactorial and partly mediated by co-occurrent conditions/risk factors.
|
|
| 9. |
- Artzi-Medvedik, Rada, et al.
(författare)
-
Quality of Life and Kidney Function in Older Adults : Prospective Data of the SCOPE Study
- 2023
-
Ingår i: Journal of Clinical Medicine. - 2077-0383. ; 12:12
-
Tidskriftsartikel (refereegranskat)abstract
- A longitudinal alteration in health-related quality of life (HRQoL) over a two-year period and its association with early-stage chronic kidney disease (CKD) progression was investigated among 1748 older adults (>75 years). HRQoL was measured by the Euro-Quality of Life Visual Analog Scale (EQ-VAS) at baseline and at one and two years after recruitment. A full comprehensive geriatric assessment was performed, including sociodemographic and clinical characteristics, the Geriatric Depression Scale-Short Form (GDS-SF), Short Physical Performance Battery (SPPB), and estimated glomerular filtration rate (eGFR). The association between EQ-VAS decline and covariates was investigated by multivariable analyses. A total of 41% of the participants showed EQ-VAS decline, and 16.3% showed kidney function decline over the two-year follow-up period. Participants with EQ-VAS decline showed an increase in GDS-SF scores and a greater decline in SPPB scores. The logistic regression analyses showed no contribution of a decrease in kidney function on EQ-VAS decline in the early stages of CKD. However, older adults with a greater GDS-SF score were more likely to present EQ-VAS decline over time, whereas an increase in the SPPB scores was associated with less EQ-VAS decline. This finding should be considered in clinical practice and when HRQoL is used to evaluate health interventions among older adults.
|
|
| 10. |
- Britting, Sabine, et al.
(författare)
-
Kidney function and other factors and their association with falls updates The screening for CKD among older people across Europe (SCOPE) study
- 2020
-
Ingår i: BMC Geriatrics. - : BMC. - 1471-2318 .- 1471-2318. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Reduced kidney function has become a major public health concern, especially among older people, as Chronic Kidney Disease (CKD) is associated with increased risk of end stage renal disease and mortality. Falls are a serious negative health outcome in older persons with one third of people aged 65 years experiencing a fall per year and increasing fall rates with increasing age. The impact of CKD on falls in older community-dwelling persons is not well investigated. Additionally, lower urinary tract symptoms (LUTS) may also increase the risk of falls. Therefore, our aim was to investigate the impact of CKD and LUTS on falls as well as on injurious falls. Methods: The SCOPE study is an observational, multinational, multicenter, prospective cohort study involving communitydwelling older persons aged 75 years and more recruited from August 2016 to March 2018 in seven European countries. The main outcomes of the present study were any falls and any injurious falls during the 12 months before enrolment The cross-sectional association of estimated glomerular filtration rate (eGFR) and LUIS with study outcomes was investigated by logistic regression analysis adjusted for baseline characteristics of enrolled subjects. Results: Our series consisted of 2256 SCOPE participants (median age = 795 years, 55.7% female). Of them, 746 participants experienced a fall and 484 reported an injurious fall in the 12 months prior to baseline assessment CKD was not significantly associated with falls (OR = 0.95, 95%CI = 0.79-1.14 for eGFR< 60; OR = 1.02, 95%CI = 0.81-128 for eGFR< 45; OR = 1.08, 95%CI = 0.74-1.57 for eGFR< 30) or injurious falls (OR = 0.91, 95%CI = 0.67-124 for eGFR< 60; OR = 0.93, 95%CI = 0.63-137 for eGFR< 45; OR = 1.19, 95%CI = 0.62-2.29 for eGFR< 30). LUTS were found significantly associated with both falls (OR = 156, 95960 =129-1.89) and injurious falls (OR = 158, 95%0 =1.14-2.19), and such associations were confirmed in all multivariable models. Conclusions: Cross-sectional data suggest that CKD may not be associated with history of falls or injurious falls, whereas LUTS is significantly associated with the outcomes.
|
|
