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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Gyllensten, Ulf B., et al.
(författare)
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Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. The aim of our study was to broadly measure protein biomarkers to find tests for the early detection of ovarian cancer. We found that combinations of 4-7 protein biomarkers can provide highly accurate detection of early- and late-stage ovarian cancer compared to benign conditions. The performance of the tests was then validated in a second independent cohort. Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.
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- Kauppi, Wivica, 1970-, et al.
(författare)
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Lived experiences of being cared for by ambulance clinicians when experiencing breathlessness—A phenomenological study
- 2023
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Ingår i: Scandinavian Journal of Caring Sciences. - : John Wiley & Sons. - 0283-9318 .- 1471-6712.
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundBreathlessness is a serious and distressing symptom and a common reason why patients require prehospital care by ambulance clinicians. However, little is known about how patients experience this care when they are in a state of breathlessness. AimThe aim of this study is to describe the lived experiences of being cared for by ambulance clinicians when experiencing breathlessness. MethodsFourteen lifeworld interviews were conducted with patients who experienced breathlessness and were cared for by ambulance clinicians. The interviews were analysed using a qualitative phenomenological approach. FindingsThe essential meaning of being cared for by ambulance clinicians when experiencing breathlessness is described in two ways: existential humanising care, in which the experience is that of being embraced by a genuine presence or existential dehumanising care, in which feeling exposed to an objectifying presence is the main experience. This meaning has four constituents: surrendering to and trusting in the care that will come; being exposed to an objectifying presence is violating; being embraced by a genuine presence is relieving; and knowing is dwelling. ConclusionThe findings reveal that the ability of ambulance clinicians to provide existential humanising and trustful care, which is the foundation of professional judgement, was essential in how patients responded to and handled the overall situation when breathlessness.
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| 5. |
- Kauppi, Wivica, 1970-, et al.
(författare)
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Patients' lived experiences of breathlessness prior to prehospital care – A phenomenological study
- 2022
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Ingår i: Nursing Open. - : John Wiley & Sons, Ltd. - 2054-1058. ; 9:4, s. 2179-2189
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Aims and objectives The study aimed to describe how breathlessness is experienced by patients prior to prehospital care. Design A qualitative phenomenological design. Methods Lifeworld interviews were conducted with 14 participants. The analysis was carried out within the descriptive phenomenological framework. Results The essential meaning of the breathlessness phenomenon is described as an existential fear in terms of losing control over one?s body and dying, which involves a battle to try to regain control. This is further described by four constituents: being in an unknown body, striving to handle the situation, the ambiguity of having loved ones close and reaching the utmost border. Conclusions Patients describe a battling for survival. It is at the extreme limit of endurance that patients finally choose to call the emergency number. It is a challenge for the ambulance clinician (AC) to support these patients in the most optimal fashion.
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- Rajwa, Pawel, et al.
(författare)
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Research protocol for an observational health data analysis on the adverse events of systemic treatment in patients with metastatic hormone-sensitive prostate cancer : big data analytics using the PIONEER platform
- 2024
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Ingår i: European Urology Open Science. - : Elsevier. - 2666-1691 .- 2666-1683. ; 63, s. 81-88
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Tidskriftsartikel (refereegranskat)abstract
- Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.
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