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- Ghaderi, A, et al.
(författare)
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A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:10
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Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.
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- Harber-Aschan, Lisa, 1987-, et al.
(författare)
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Cardiometabolic risk profiles in a Sri Lankan twin and singleton sample
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionPrevention of cardiovascular disease and diabetes is a priority in low- and middle-income countries, especially in South Asia where these are leading causes of morbidity and mortality. The metabolic syndrome is a tool to identify cardiometabolic risk, but the validity of the metabolic syndrome as a clinical construct is debated. This study tested the existence of the metabolic syndrome, explored alternative cardiometabolic risk characterisations, and examined genetic and environmental factors in a South Asian population sample.MethodsData came from the Colombo Twin and Singleton follow-up Study, which recruited twins and singletons in Colombo, Sri Lanka, in 2012–2015 (n = 3476). Latent class analysis tested the clustering of metabolic syndrome indicators (waist circumference, high-density lipoprotein cholesterol, triglycerides, blood pressure, fasting plasma glucose, medications, and diabetes). Regression analyses tested cross-sectional associations between the identified latent cardiometabolic classes and sociodemographic covariates and health behaviours. Structural equation modelling estimated genetic and environmental contributions to cardiometabolic risk profiles. All analyses were stratified by sex (n = 1509 men, n = 1967 women).ResultsThree classes were identified in men: 1) “Healthy” (52.3%), 2) “Central obesity, high triglycerides, high fasting plasma glucose” (40.2%), and 3) “Central obesity, high triglycerides, diabetes” (7.6%). Four classes were identified in women: 1) “Healthy” (53.2%), 2) “Very high central obesity, low high-density lipoprotein cholesterol, raised fasting plasma glucose” (32.8%), 3) “Very high central obesity, diabetes” (7.2%) and 4) “Central obesity, hypertension, raised fasting plasma glucose” (6.8%). Older age in men and women, and high socioeconomic status in men, was associated with cardiometabolic risk classes, compared to the “Healthy” classes. In men, individual differences in cardiometabolic class membership were due to environmental effects. In women, genetic differences predicted class membership.ConclusionThe findings did not support the metabolic syndrome construct. Instead, distinct clinical profiles were identified for men and women, suggesting different aetiological pathways.
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- Rhead, Rebecca, et al.
(författare)
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Ethnic inequalities among NHS staff in England : workplace experiences during the COVID-19 pandemic
- 2024
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Ingår i: Occupational and Environmental Medicine. - 1351-0711 .- 1470-7926. ; 81:3, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study aims to determine how workplace experiences of National Health Service (NHS) staff varied by ethnicity during the COVID-19 pandemic and how these experiences are associated with mental and physical health at the time of the study.Methods An online Inequalities Survey was conducted by the Tackling Inequalities and Discrimination Experiences in Health Services study in collaboration with NHS CHECK. This Inequalities Survey collected measures relating to workplace experiences (such as personal protective equipment (PPE), risk assessments, redeployments and discrimination) as well as mental health (Patient Health Questionnaire (PHQ-9), Generalised Anxiety Disorder 7 (GAD-7)), and physical health (PHQ-15) from NHS staff working in the 18 trusts participating with the NHS CHECK study between February and October 2021 (N=4622).Results Regression analysis of this cross-sectional data revealed that staff from black and mixed/other ethnic groups had greater odds of experiencing workplace harassment (adjusted OR (AOR) 2.43 (95% CI 1.56 to 3.78) and 2.38 (95% CI 1.12 to 5.07), respectively) and discrimination (AOR 4.36 (95% CI 2.73 to 6.96) and 3.94 (95% CI 1.67 to 9.33), respectively) compared with white British staff. Staff from black ethnic groups also had greater odds than white British staff of reporting PPE unavailability (AOR 2.16 (95% CI 1.16 to 4.00)). Such workplace experiences were associated with negative physical and mental health outcomes, though this association varied by ethnicity. Conversely, understanding employment rights around redeployment, being informed about and having the ability to inform redeployment decisions were associated with lower odds of poor physical and mental health.Conclusions Structural changes to the way staff from ethnically minoritised groups are supported, and how their complaints are addressed by leaders within the NHS are urgently required.
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- Stagg, Anne L., et al.
(författare)
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Risk factors for the progression to multimorbidity among UK urban working-age adults. A community cohort study
- 2023
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Ingår i: PLOS ONE. - 1932-6203. ; 18:9
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe progression of long-term conditions (LTCs) from zero-to-one (initiation), and from one-to-many (progression)are common trajectories that impact a person’s quality of life including their ability to work. This study aimed to explore the demographic, socioeconomic, psychosocial, and health-related determinants of LTC initiation and progression, with a focus on work participation.MethodsData from 622 working-age adults who had completed two waves (baseline and follow-up) of the South-East London Community Health survey were analysed. Chi square tests and multinomial logistic regression were used to describe the associations between self-reported demographic, socioeconomic, psychosocial, and health-related variables, and the progression of LTCs.ResultsSmall social networks, an increased number of stressful life events, low self-rated health, functional impairment, and increased somatic symptom severity were all associated with both the progression from zero-to-one LTC and from one LTC to multimorbidity (two or more LTCs). Renting accommodation (RRR 1.73 [95% CI 1.03–2.90]), smoking (RRR 1.91 [95% CI 1.16–3.14]) and being overweight (RRR 1.88 [95% CL 1.12–3.16]) were unique risk factors of developing initial LTCs, whereas low income (RRR 2.53 [95% CI 1.11–5.80]), working part-time (RRR 2.82 ([95% CL 1.12–7.10]), being unemployed (RRR 4.83 [95% CI 1.69–13.84]), and making an early work exit (RRR 16.86 [95% CI 3.99–71.30]) all increased the risk of progressing from one LTC to multimorbidity compared to being employed full-time. At follow-up, depression was the most prevalent LTC in the unemployed group whereas musculoskeletal conditions were the most prevalent in those working.ConclusionsThe journey to multimorbidity is complex, with both common and unique risk factors. Non-full-time employment was associated with an increased risk of progression to multimorbidity. Future research should explore the risk and benefit pathways between employment and progression of LTCs. Interventions to prevent progression of LTCs should include mitigation of modifiable risk factors such as social isolation.
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