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- Clinchy, Birgitta, 1957-, et al.
(författare)
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Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma
- 2007
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 109:9, s. 1742-1749
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Colorectal cancer is one of the most common forms of cancer in the Western world. Staging based on histopathology is currently the most accurate predictor of outcome after surgery. Colorectal cancer is curable if treated at an early stage (stage I-III). However, for tumors in stages II and III there is a great need for tests giving more accurate prognostic information defining the patient population in need of closer follow-up and/or adjuvant therapy. Furthermore, tests that provide prognostic information preoperatively could provide a guide both for preoperative oncologic treatment and the surgical procedure. METHODS. Peripheral blood mononuclear cells (PBMCs) were isolated preoperatively, within a week before primary surgery, from 39 patients undergoing surgery for colorectal cancer. The PBMCs were cultured in vitro for 24 hours in the presence of autologous serum and lipopolysaccharide (LPS). Interleukin-6 (IL-6) production was measured with enzyme-linked immunosorbent assay (ELISA). Staging based on histopathology was performed in all patients. Patients were followed for at least 54 months. RESULTS. A production of >5000 pg/mL of IL-6 identified colorectal cancer patients with a poor prognosis. Eight out of 13 patients with >5000 pg/mL IL-6 died from cancer within the follow-up period, whereas no cancer-related deaths were recorded among 21 patients with 5000 pg/mL IL-6 or less. A multivariate Cox regression analysis, stratified for T- and N-stage, identified IL-6 production as an independent prognostic factor. CONCLUSIONS. IL-6 production in vitro by PBMC can predict survival after radical surgery for colorectal cancer. © 2007 American Cancer Society.
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| 2. |
- Alken, Jenny, et al.
(författare)
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Rates of Extreme Neonatal Hyperbilirubinemia and Kernicterus in Children and Adherence to National Guidelines for Screening, Diagnosis, and Treatment in Sweden
- 2019
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Ingår i: JAMA Network Open. - : AMER MEDICAL ASSOC. - 2574-3805. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Neonatal hyperbilirubinemia can cause lifelong neurodevelopmental impairment (kernicterus) even in high-resource settings. A better understanding of the incidence and processes leading to kernicterus may help in the design of preventive measures. OBJECTIVES To determine incidence rates of hazardous hyperbilirubinemia and kernicterus among near-term to term newborns and to evaluate health care professional adherence to best practices. DESIGN, SETTING, AND PARTICIPANTS This population-based nationwide cohort study used prospectively collected data on the highest serum bilirubin level for all infants born alive at 35 weeks' gestation or longer and admitted to neonatal care at all 46 delivery and 37 neonatal units in Sweden from 2008 to 2016. Medical records for newborns with hazardous hyperbilirubinemia were evaluated for best neonatal practices and for a diagnosis of kernicterus up to 2 years of age. Data analyses were performed between September 2017 and February 2018. EXPOSURES Extreme (serum bilirubin levels, 25.0-29.9mg/dL [425-509 mu mol/L]) and hazardous (serum bilirubin levels, >30.0mg/dL [>510 mu mol/L]) neonatal hyperbilirubinemia. MAIN OUTCOMES AND MEASURES The primary outcome was kernicterus, defined as hazardous neonatal hyperbilirubinemia followed by cerebral palsy, sensorineural hearing loss, gaze paralysis, or neurodevelopmental retardation. Secondary outcomeswere health care professional adherence to national guidelines using a predefined protocol with 10 key performance indicators for diagnosis and treatment as well as assessment of whether bilirubin-associated brain damage might have been avoidable. RESULTS Among 992 378 live-born infants (958 051 term births and 34 327 near-term births), 494 (320 boys; mean [SD] birth weight, 3505 [527] g) developed extreme hyperbilirubinemia (50 per 100 000 infants), 6.8 per 100 000 infants developed hazardous hyperbilirubinemia, and 1.3 per 100 000 infants developed kernicterus. Among 13 children developing kernicterus, brain injury was assessed as potentially avoidable for 11 children based on the presence of 1 or several of the following possible causes: untimely or lack of predischarge bilirubin screening (n = 6), misinterpretation of bilirubin values (n = 2), untimely or delayed initiation of treatment with intensive phototherapy (n = 1), untimely or no treatment with exchange transfusion (n = 6), or lack of repeated exchange transfusions despite indication (n = 1). CONCLUSIONS AND RELEVANCE Hazardous hyperbilirubinemia in near-term or term newborns still occurs in Sweden and was associated with disabling brain damage in 13 per million births. For most of these cases, health care professional noncompliance with best practices was identified, suggesting that a substantial proportion of these cases might have been avoided.
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| 5. |
- Håkansson, Pelle, 1973-
(författare)
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Ribonucleotide reductase and DNA damage
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A prerequisite for a multicellular organism to survive is the ability to correctly replicate and repair DNA while minimizing the number of heritable mutations. To achieve this, cells need a balanced supply of deoxyribonucleoside triphosphates (dNTPs), the precursors for DNA synthesis. The rate-limiting step in de novo biosynthesis of dNTPs is catalyzed by the enzyme ribonucleotide reductase (RNR). The classic eukaryotic RNR enzyme consists of a large and a small subunit. Together, these subunits form a heterotetrameric RNR complex. The larger subunit harbours active sites whereas the smaller subunit contains a stable tyrosyl free radical. Both subunits are required for RNR activity. Since failure to correctly regulate de novo dNTP biosynthesis can lead to misincorporation of nucleotides into DNA, genetic abnormalities and cell death, RNR activity is tightly regulated. The regulation of RNR activity involves cell cycle-specific expression and degradation of the RNR proteins, as well as binding of allosteric effectors to the large RNR subunit. In this thesis, in vitro assays based on purified recombinant RNR proteins, in combination with in vivo assays, have been used successfully to study the regulation of RNR activity in response to DNA damage. I present new findings regarding the function of an alternative mammalian RNR small subunit, and on the role of a small RNR inhibitor protein of fission yeast, during normal growth and after DNA damage. I also show conclusively that there are fundamental differences in the regulation of dNTP biosynthesis between the cells of higher and lower eukaryotes after DNA damage.
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| 8. |
- Norman, Mikael, et al.
(författare)
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Prevalence of Severe Visual Disability Among Preterm Children With Retinopathy of Prematurity and Association With Adherence to Best Practice Guidelines
- 2019
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 2:1, s. 186801-186801
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Retinopathy of prematurity (ROP) can cause severe visual disability even in high-resource settings. A better understanding of the prevalence and processes leading to ROP-induced severe visual impairment may help health care professionals design preventive measures.Objectives: To determine the prevalence of severe visual disability among children born preterm in Sweden, evaluate adherence to best practice, and determine the health system's structural capacity.Design, Setting, and Participants: Population-based, nationwide cohort study of 1 310 227 children born between January 1, 2004, and December 31, 2015, in Sweden, of whom 17 588 (1.3%) were born very preterm (<32 weeks of gestation). Children born preterm with a verified diagnosis of severe visual disability had their medical records reviewed for evaluation of ROP screening, diagnosis, and treatment. In addition, a questionnaire on structural capacity was sent to all ophthalmology departments.Exposures: Stages 4 and 5 ROP.Main Outcomes and Measures: The primary outcome was prevalence of severe visual disability (visual acuity ≤20/200 for both eyes) associated with ROP stages 4 and 5. Secondary outcomes included adherence to national ROP guidelines using a predefined protocol with 15 key performance indicators for screening, diagnosis, and treatment; assessment of whether visual disability was deemed avoidable; and examination of structural capacity, including information on equipment and facilities, staffing, and patients.Results: Seventeen children (10 boys; mean [range] birth weight, 756 [454-1900] g; mean [range] gestational age, 25 [22-33] weeks) became severely visually disabled because of ROP, corresponding to a prevalence of 1 in 1000 very preterm infants (<32 weeks of gestational age) and 1 in 77 000 for all live births. Severe visual impairment was considered potentially avoidable in 11 of 17 affected children (65%) owing to untimely or no screening, missed diagnosis, or untimely and suboptimal treatment. Large variations in infrastructure (facilities, guidelines, staffing, and annual patient numbers) were also identified as potential contributors to these findings.Conclusions and Relevance: Retinopathy of prematurity still causes severe visual disability in Sweden, resulting in 1 affected infant per 1000 very preterm births. In most of these infants, noncompliance with best practice was identified, indicating that a significant proportion could have been avoided.
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| 9. |
- Pontarin, Giovanna, et al.
(författare)
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p53R2-dependent ribonucleotide reduction provides deoxyribonucleotides in quiescent human fibroblasts in the absence of induced DNA damage
- 2007
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 282:23, s. 16820-16828
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Tidskriftsartikel (refereegranskat)abstract
- Human fibroblasts in culture obtain deoxynucleotides by de novo ribonucleotide reduction or by salvage of deoxynucleosides. In cycling cells the de novo pathway dominates, but in quiescent cells the salvage pathway becomes important. Two forms of active mammalian ribonucleotide reductases are known. Each form contains the catalytic R1 protein, but the two differ with respect to the second protein (R2 or p53R2). R2 is cell cycle-regulated, degraded during mitosis, and absent from quiescent cells. The recently discovered p53-inducible p53R2 was proposed to be linked to DNA repair processes. The protein is not cell cycle-regulated and can provide deoxynucleotides to quiescent mouse fibroblasts. Here we investigate the in situ activities of the R1-p53R2 complex and two other enzymes of the de novo pathway, dCMP deaminase and thymidylate synthase, in confluent quiescent serum-starved human fibroblasts in experiments with [5-3H]cytidine, [6-3H]deoxycytidine, and [C3H3]thymidine. These cells had increased their content of p53R2 2-fold and lacked R2. From isotope incorporation, we conclude that they have a complete de novo pathway for deoxynucleotide synthesis, including thymidylate synthesis. During quiescence, incorporation of deoxynucleotides into DNA was very low. Deoxynucleotides were instead degraded to deoxynucleosides and exported into the medium as deoxycytidine, deoxyuridine, and thymidine. The rate of export was surprisingly high, 25% of that in cycling cells. Total ribonucleotide reduction in quiescent cells amounted to only 2–3% of cycling cells. We suggest that in quiescent cells an important function of p53R2 is to provide deoxynucleotides for mitochondrial DNA replication.
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