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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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- Grövdal, Michael, et al.
(författare)
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Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy
- 2010
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 150:3, s. 293-302
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Tidskriftsartikel (refereegranskat)abstract
- This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.
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- Grövdal, Michael, et al.
(författare)
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Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:23, s. 7107-7112
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
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- Göthesson, Johanna, et al.
(författare)
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Children's and adolescent's narratives about pain and negative experiences in diabetes treatment
- 2023
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Ingår i: Journal for Specialists in Pediatric Nursing. - : John Wiley & Sons. - 1539-0136 .- 1744-6155. ; 28:1
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Tidskriftsartikel (refereegranskat)abstract
- Pain and fear associated with needle procedures have been found to be more common among children and adolescents treated for type 1 diabetes (T1D) than among others in their age group. Furthermore, high glycated haemoglobin (HbA1c) values are associated with needle-related fear.Aim: To describe negative experiences of needle procedures in childhood diabetes treatment from children's and adolescents' own perspectives. Methods: Short written narratives (n = 83) and drawings (n = 2) from children and adolescents treated for T1D, aged 7–18 years, were subjected to inductive qualitative content analysis.Results: Negative experiences with needle procedures had many facets, such as pain and fear, changing over time and affecting everyday life. All kinds of needle procedures caused difficulties, but venipunctures were described as the worst.Conclusion: All needle procedures involved in diabetes treatment are potentially experienced as creating pain and fear, but the negative experiences are multifaceted and vary between individuals. These experiences create suffering for children and adolescents, and influence their daily lives. Besides finding techniques to decrease the number of needle procedures in the treatment, research should focus on implementing methods to decrease pain, fear, and other negative experiences as well as to promote self-coping. This is urgent, since needle-related fear has an impact on glycaemic control and therefore increases the risk of long-term complications. Clinical Implications: When caring for children and adolescents with diabetes, their previous experiences with needle procedures need to be considered.
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- Hanberger, Lena, et al.
(författare)
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Needle-Related Pain, Affective Reactions, Fear, and Emotional Coping in Children and Adolescents With Type 1 Diabetes : A Cross-Sectional Study
- 2021
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Ingår i: Pain Management Nursing. - : Elsevier. - 1524-9042 .- 1532-8635. ; 22:4, s. 516-521
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Tidskriftsartikel (refereegranskat)abstract
- Background: The self-care of type 1 diabetes (T1D) includes undergoing procedures with needles several times daily, which may cause pain and fear.Aims: The aim was to identify the degree of perceived pain, affective reactions, fear, and emotional coping among children and adolescents with T1D.Design: A cross-sectional survey was performed.Methods: Children and adolescents 7-18 years of age (n = 197) and their parents (n = 123) completed the Coloured Analogue Scale (CAS), the Facial Affective Scale (FAS), the Diabetes Fear of Injection Questionnaire (D-FISQ), and the Faces Emotional Coping Scale (FECS) in relation to needle procedures.Results: The higher the values of the CAS, FAS and D-FISQ scores, the lower values for coping were reported by children and adolescents regarding treatment with insulin pen or pump, blood glucose test, and venipuncture (p < .001). Patients reported strong negative affect regarding insulin injections (35%) and blood glucose tests (32%), as well as negative affect (48%, 69%) and substantial pain (27%, 50%) for inserting a pump needle and venipuncture, respectively. Parents reported significantly higher values than children on all scales and procedures except D-FISQ (blood glucose tests) and FECS (venipuncture).Conclusions: Children and adolescents who perceive greater pain during needle-related procedures have poorer coping ability. Pediatric diabetes teams need to identify those in need of extra support to develop pain coping strategies.
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- Lindblad, Marléne, 1963-, et al.
(författare)
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Development of a trigger tool to identify adverse events and no-harm incidents that affect patients admitted to home healthcare.
- 2018
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Ingår i: BMJ Quality and Safety. - : BMJ. - 2044-5415 .- 2044-5423. ; 27:7, s. 502-511
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Adverse events (AEs) and no-harm incidents are common and of great concern in healthcare. A common method for identification of AEs is retrospective record review (RRR) using predefined triggers. This method has been used frequently in inpatient care, but AEs in home healthcare have not been explored to the same extent. The aim of this study was to develop a trigger tool (TT) for the identification of both AEs and no-harm incidents affecting adult patients admitted to home healthcare in Sweden, and to describe the methodology used for this development.METHODS: The TT was developed and validated in a stepwise manner, in collaboration with experts with different skills, using (1) literature review and interviews, (2) a five-round modified Delphi process, and (3) two-stage RRRs. Ten trained teams from different sites in Sweden reviewed 600 randomly selected records.RESULTS: In all, triggers were found 4031 times in 518 (86.3%) records, with a mean of 6.7 (median 4, range 1-54) triggers per record with triggers. The positive predictive values (PPVs) for AEs and no-harm incidents were 25.4% and 16.3%, respectively, resulting in a PPV of 41.7% (range 0.0%-96.1% per trigger) for the total TT when using 38 triggers. The most common triggers were unplanned contact with physician and/or registered nurse, moderate/severe pain, moderate/severe worry, anxiety, suffering, existential pain and/or psychological pain. AEs were identified in 37.7% of the patients and no-harm incidents in 29.5%.CONCLUSION: This study shows that adapted triggers with definitions and decision support, developed to identify AEs and no-harm incidents that affect patients admitted to home healthcare, may be a valid method for safety and quality improvement work in home healthcare.
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- Lindblad, Marléne, 1963-, et al.
(författare)
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Identifying no-harm incidents in home healthcare : a cohort study using trigger tool methodology
- 2020
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Ingår i: BMC Health Services Research. - : Springer. - 1472-6963. ; 20:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPatient safety in home healthcare is largely unexplored. No-harm incidents may give valuable information about risk areas and system failures as a source for proactive patient safety work. We hypothesized that it would be feasible to retrospectively identify no-harm incidents and thus aimed to explore the cumulative incidence, preventability, types, and potential contributing causes of no-harm incidents that affected adult patients admitted to home healthcare.MethodsA structured retrospective record review using a trigger tool designed for home healthcare. A random sample of 600 home healthcare records from ten different organizations across Sweden was reviewed.ResultsIn the study, 40,735 days were reviewed. In all, 313 no-harm incidents affected 177 (29.5%) patients; of these, 198 (63.2%) no-harm incidents, in 127 (21.2%) patients, were considered preventable. The most common no-harm incident types were “fall without harm,” “deficiencies in medication management,” and “moderate pain.” The type “deficiencies in medication management” was deemed to have a preventability rate twice as high as those of “fall without harm” and “moderate pain.” The most common potential contributing cause was “deficiencies in nursing care and treatment, i.e., delayed, erroneous, omitted or incomplete treatment or care.”ConclusionThis study suggests that it is feasible to identify no-harm incidents and potential contributing causes such as omission of care using record review with a trigger tool adapted to the context. No-harm incidents and potential contributing causes are valuable sources of knowledge for improving patient safety, as they highlight system failures and indicate risks before an adverse event reach the patient.
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