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Sökning: WFRF:(Nielsen Soren)

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1.
  • Oddsson, Asmundur, et al. (författare)
  • Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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2.
  • Dengjel, Joern, et al. (författare)
  • Identification of Autophagosome-associated Proteins and Regulators by Quantitative Proteomic Analysis and Genetic Screens
  • 2012
  • Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 11:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Autophagy is one of the major intracellular catabolic pathways, but little is known about the composition of autophagosomes. To study the associated proteins, we isolated autophagosomes from human breast cancer cells using two different biochemical methods and three stimulus types: amino acid deprivation or rapamycin or concanamycin A treatment. The autophagosome- associated proteins were dependent on stimulus, but a core set of proteins was stimulus- independent. Remarkably, proteasomal proteins were abundant among the stimulus- independent common autophagosome- associated proteins, and the activation of autophagy significantly decreased the cellular proteasome level and activity supporting interplay between the two degradation pathways. A screen of yeast strains defective in the orthologs of the human genes encoding for a common set of autophagosome- associated proteins revealed several regulators of autophagy, including subunits of the retromer complex. The combined spatiotemporal proteomic and genetic data sets presented here provide a basis for further characterization of autophagosome biogenesis and cargo selection.
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3.
  • Habel, Joachim, et al. (författare)
  • Selecting analytical tools for characterization of polymersomes in aqueous solution
  • 2015
  • Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 5:97, s. 79924-79946
  • Forskningsöversikt (refereegranskat)abstract
    • Selecting the appropriate analytical methods for characterizing the assembly and morphology of polymer-based vesicles, or polymersomes are required to reach their full potential in biotechnology. This work presents and compares 17 different techniques for their ability to adequately report size, lamellarity, elastic properties, bilayer surface charge, thickness and polarity of polybutadiene-polyethylene oxide (PB-PEO) based polymersomes. The techniques used in this study are broadly divided into scattering techniques, visualization methods, physical and electromagnetical manipulation and sorting/purification. Of the analytical methods tested, Cryo-transmission electron microscopy and atomic force microscopy (AFM) turned out to be advantageous for polymersomes with smaller diameter than 200 nm, whereas confocal microscopy is ideal for diameters >400 nm. Polymersomes in the intermediate diameter range can be characterized using freeze fracture Cryo-scanning electron microscopy (FF-Cryo-SEM) and nanoparticle tracking analysis (NTA). Small angle X-ray scattering (SAXS) provides reliable data on bilayer thickness and internal structure, Cryo-TEM on multilamellarity. Taken together, these tools are valuable for characterizing polymersomes per se but the comparative overview is also intended to serve as a starting point for selecting methods for characterizing polymersomes with encapsulated compounds or polymersomes with incorporated biomolecules (e.g. membrane proteins).
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4.
  • Hedegaard, Jakob, et al. (författare)
  • Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma
  • 2016
  • Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 30:1, s. 27-42
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal-and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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5.
  • Holm, Anne I. S., et al. (författare)
  • Electronic coupling between cytosine bases in DNA single strands and i-motifs revealed from synchrotron radiation circular dichroism experiments
  • 2010
  • Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 12:14, s. 3426-3430
  • Tidskriftsartikel (refereegranskat)abstract
    • In this work we have recorded synchrotron radiation circular dichroism (SRCD) spectra from 180 nm to 360 nm of cytosine strands [(dC)(n), n = 1, 2,..., 10] in aqueous solution at different pH values to reveal electronic coupling between bases in different ionisation states. The geometry of the strands is determined by the pH value and the strand length and the local organisation of the cytosines will determine the base-to-base interaction that impacts on the CD signal. At low pH where all bases are protonated, there is no signature of electronic coupling between the bases, and the SRCD spectrum is simply n times that of the n = 1 spectrum. At higher pH where all bases are neutral, the spectra for n > 1 differ from the monomer spectrum, which implies electronic coupling between bases. The correlation between the CD signal and n is linear, and the spatial extent of the excited state wavefunction is therefore over just two stacked bases both in the UV and VUV. At intermediate pH, the low-n spectra are different from the high-n spectra, and a transition is seen to occur at n = 6-8. We ascribe this behavior to the formation of i-motif structures between four (dC)(n) strands for high n.
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6.
  • Risum, Malene, et al. (författare)
  • Introduction of a Comprehensive Diagnostic and Interdisciplinary Management Approach in Haematological Patients with Mucormycosis : A Pre and Post-Intervention Analysis
  • 2020
  • Ingår i: JOURNAL OF FUNGI. - : MDPI. - 2309-608X. ; 6:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Mucormycosis is a life threatening infection in patients with haematological disease. We introduced a Mucorales-PCR and an aggressive, multidisciplinary management approach for mucormycosis during 2016-2017 and evaluated patient outcomes in 13 patients diagnosed and treated in 2012-2019. Management principle: repeated surgical debridement until biopsies from the resection margins were clean as defined by negative Blankophor microscopy, Mucorales-PCR (both reported within 24 h), and cultures. Cultured isolates underwent EUCAST E.Def 9.3.1 susceptibility testing. Antifungal therapy (AFT) (mono/combination) combined with topical AFT (when possible) was given according to the minimal inhibitory concentration (MIC), severity of the infection, and for azoles, specifically, it was guided by therapeutic drug monitoring. The outcome was evaluated by case record review. All patients underwent surgery guided by diagnostic biopsies from tissue and resection margins (195 samples in total). Comparing 2012-2015 and 2016-2019, the median number of patients of surgical debridements was 3 and 2.5 and of diagnostic samples: microscopy/culture/PCR was 3/3/6 and 10.5/10/10.5, respectively. The sensitivity of microscopy (76%) and Mucorales-PCR (70%) were similar and microscopy was superior to that of culture (53%; p = 0.039). Initial systemic AFT was liposomal amphotericin B (n = 12) or posaconazole (n = 1) given as monotherapy (n = 4) or in combination with isavuconazole/posaconazole (n = 3/6) and terbinafine (n = 3). Nine patients received topical amphotericin B. All received isavuconazole or posaconazole consolidation therapy (n = 13). Mucormycosis related six month mortality was 3/5 in 2012-2015 and 0/7 patients in 2016-2019 (one patient was lost for follow-up). Implementation of combination therapy (systemic+topical AFT/combination systemic AFT) and aggressive surgical debridement guided by optimised diagnostic tests may improve the outcome of mucormycosis in haematologic patients.
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7.
  • Agren, Johan, et al. (författare)
  • Antenatal Corticosteroids and Postnatal Fluid Restriction Produce Differential Effects on AQP3 Expression, Water Handling, and Barrier Function in Perinatal Rat Epidermis
  • 2010
  • Ingår i: Dermatology research and practice. - : Hindawi Limited. - 1687-6113 .- 1687-6105.
  • Tidskriftsartikel (refereegranskat)abstract
    • Loss of water through the immature skin can lead to hypothermia and dehydration in preterm infants. The water and glycerol channel aquaglyceroporin-3 (AQP3) is abundant in fetal epidermis and might influence epidermal water handling and transepidermal water flux around birth. To investigate the role of AQP3 in immature skin, we measured in vivo transepidermal water transport and AQP3 expression in rat pups exposed to clinically relevant fluid homeostasis perturbations. Preterm (E18) rat pups were studied after antenatal corticosteroid exposure (ANS), and neonatal (P1) rat pups after an 18 h fast. Transepidermal water loss (TEWL) and skin hydration were determined, AQP3 mRNA was quantified by RT-PCR, and in-situ hybridization and immunocytochemistry were applied to map AQP3 expression. ANS resulted in an improved skin barrier (lower TEWL and skin hydration), while AQP3 mRNA and protein increased. Fasting led to loss of barrier integrity along with an increase in skin hydration. These alterations were not paralleled by any changes in AQP3. To conclude, antenatal corticosteroids and early postnatal fluid restriction produce differential effects on skin barrier function and epidermal AQP3 expression in the rat. In perinatal rats, AQP3 does not directly determine net water transport through the skin.
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8.
  • Bedding, Timothy R., et al. (författare)
  • A multi-site campaign to measure solar-like oscillations in Procyon. II. mode frequencies
  • 2010
  • Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 713:2, s. 935-949
  • Tidskriftsartikel (refereegranskat)abstract
    • We have analyzed data from a multi-site campaign to observe oscillations in the F5 star Procyon. The data consist of high-precision velocities that we obtained over more than three weeks with 11 telescopes. A new method for adjusting the data weights allows us to suppress the sidelobes in the power spectrum. Stacking the power spectrum in a so-called echelle diagram reveals two clear ridges, which we identify with even and odd values of the angular degree (l = 0 and 2, and l = 1 and 3, respectively). We interpret a strong, narrow peak at 446 mu Hz that lies close to the l = 1 ridge as a mode with mixed character. We show that the frequencies of the ridge centroids and their separations are useful diagnostics for asteroseismology. In particular, variations in the large separation appear to indicate a glitch in the sound-speed profile at an acoustic depth of similar to 1000 s. We list frequencies for 55 modes extracted from the data spanning 20 radial orders, a range comparable to the best solar data, which will provide valuable constraints for theoretical models. A preliminary comparison with published models shows that the offset between observed and calculated frequencies for the radial modes is very different for Procyon than for the Sun and other cool stars. We find the mean lifetime of the modes in Procyon to be 1.29(-0.49)(+0.55) days, which is significantly shorter than the 2-4 days seen in the Sun.
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9.
  • Burisch, Johan, et al. (författare)
  • Initial Disease Course and Treatment in an Inflammatory Bowel Disease Inception Cohort in Europe : The ECCO-EpiCom Cohort
  • 2014
  • Ingår i: Inflammatory Bowel Diseases. - : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 20:1, s. 36-46
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:The EpiCom cohort is a prospective, population-based, inception cohort of inflammatory bowel disease (IBD) patients from 31 European centers covering a background population of 10.1 million. The aim of this study was to assess the 1-year outcome in the EpiCom cohort.Methods:Patients were followed-up every third month during the first 12 (3) months, and clinical data, demographics, disease activity, medical therapy, surgery, cancers, and deaths were collected and entered in a Web-based database (www.epicom-ecco.eu).Results:In total, 1367 patients were included in the 1-year follow-up. In western Europe, 65 Crohn's disease (CD) (16%), 20 ulcerative colitis (UC) (4%), and 4 IBD unclassified (4%) patients underwent surgery, and in eastern Europe, 12 CD (12%) and 2 UC (1%) patients underwent surgery. Eighty-one CD (20%), 80 UC (14%), and 13 (9%) IBD unclassified patients were hospitalized in western Europe compared with 17 CD (16%) and 12 UC (8%) patients in eastern Europe. The cumulative probability of receiving immunomodulators was 57% for CD in western (median time to treatment 2 months) and 44% (1 month) in eastern Europe, and 21% (5 months) and 5% (6 months) for biological therapy, respectively. For UC patients, the cumulative probability was 22% (4 months) and 15% (3 months) for immunomodulators and 6% (3 months) and 1% (12 months) for biological therapy, respectively in the western and eastern Europe.Discussion:In this cohort, immunological therapy was initiated within the first months of disease. Surgery and hospitalization rates did not differ between patients from eastern and western Europe, although more western European patients received biological agents and were comparable to previous population-based inception cohorts.
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10.
  • Dalgaard, Marlene D., et al. (författare)
  • A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation
  • 2012
  • Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:1, s. 58-65
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population. Methods To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health. Furthermore, they developed a novel integrative method that combines GWAS data with other TDS-relevant data types and identified additional TDS markers. The most significant findings were replicated in an independent cohort of 671 Nordic men. Results Markers located in the region of TGFBR3 and BMP7 showed association with all TDS phenotypes in both the discovery and replication cohorts. An immunohistochemistry investigation confirmed the presence of transforming growth factor beta receptor type III (TGFBR3) in peritubular and Leydig cells, in both fetal and adult testis. Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer. Conclusions The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor b signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can highlight findings in GWAS that are biologically relevant despite having border significance at currently accepted statistical levels.
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11.
  • de Jong, Jasper M. A., et al. (författare)
  • Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
  • 2019
  • Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:8, s. 830-843
  • Tidskriftsartikel (refereegranskat)abstract
    • Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 degrees C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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12.
  • Diederichsen, Soren Z., et al. (författare)
  • Impact of fasting glucose on electrocardiographic left ventricular hypertrophy in an elderly general population
  • 2015
  • Ingår i: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 24:3, s. 164-173
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To evaluate relationships between fasting plasma glucose (FPG), other cardiovascular risk markers and left ventricular hypertrophy (LVH) as detected by electrocardiography. Methods. Subjects were selected randomly from groups defi ned by FPG. Traditional risk markers were assessed. LVH was defi ned by either Cornell voltage -duration product (CP) or Sokolow -Lyon voltage combination (SL), and univariate and multivariable regressions were performed in search of explanatory factors for the presence of LVH and the values of CP and SL. Results. Of the 1759 subjects included, 1007 had a history of cardiovascular disease and/or medical treatment, while 752 subjects appeared to be healthy. We found an independent association between FPG and LVH (odds ratio 1.152, p = 0.042] as well as continuous CP (beta = 0.126, p = 0.007) in healthy men. As expected, we found an association between systolic blood pressure and LVH (odds ratio 1.020, p < 0.001) among healthy subjects, but only in subjects with FPG < 6 mmol/l (p = 0.04 for interaction). Conclusions. We found an independent association between FPG and LVH in healthy men, and no potentiating effect by FPG on the impact of hypertension.
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13.
  • Ejlertsen, Bent, et al. (författare)
  • Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer
  • 2006
  • Ingår i: J Clin Oncol. - : American Society of Clinical Oncology (ASCO). - 1527-7755. ; 24:31, s. 4956-4962
  • Tidskriftsartikel (refereegranskat)abstract
    • To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor–positive disease. Patients and Methods We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor–positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks. Results Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group. Conclusion In this study, ablation of ovarian function in premenopausal women with hormone receptor–positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.
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14.
  • Eltschkner, Sandra, et al. (författare)
  • The structure of songbird MHC class I reveals antigen binding that is flexible at the N-terminus and static at the C-terminus
  • 2023
  • Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Long-distance migratory animals such as birds and bats have evolved to withstand selection imposed by pathogens across the globe, and pathogen richness is known to be particularly high in tropical regions. Immune genes, so-called Major Histocompatibility Complex (MHC) genes, are highly duplicated in songbirds compared to other vertebrates, and this high MHC diversity has been hypothesised to result in a unique adaptive immunity. To understand the rationale behind the evolution of the high MHC genetic diversity in songbirds, we determined the structural properties of an MHC class I protein, Acar3, from a long-distance migratory songbird, the great reed warbler Acrocephalus arundinaceus (in short: Acar). The structure of Acar3 was studied in complex with pathogen-derived antigens and shows an overall antigen presentation similar to human MHC class I. However, the peptides bound to Acar3 display an unusual conformation: Whereas the N-terminal ends of the peptides display enhanced flexibility, the conformation of their C-terminal halves is rather static. This uncommon peptide-binding mode in Acar3 is facilitated by a central Arg residue within the peptide-binding groove that fixes the backbone of the peptide at its central position, and potentially permits successful interactions between MHC class I and innate immune receptors. Our study highlights the importance of investigating the immune system of wild animals, such as birds and bats, to uncover unique immune mechanisms which may neither exist in humans nor in model organisms.
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15.
  • Hildenbrand, Anna, et al. (författare)
  • Aquaporin 1 is expressed in the human endometrium during normal cycle and increases after mifepristone treatment.
  • 2008
  • Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 22:1, s. 49-53
  • Tidskriftsartikel (refereegranskat)abstract
    • Aquaporin-1 (AQP1) is involved in the angiogenesis and structural modifications of microvessels and possibly also in the pathogenesis of idiopathic menhorrhagia, where a reduced AQP1 expression is seen in the endometrium. Mifepristone treatment induces reduced menstrual bleeding and amenorrhea and also has a direct effect on endometrial arterioles. Administered with gestagen-only contraceptive methods, antiprogestins improve the bleeding pattern. The objective of this study was to evaluate the AQP1 expression in endometrial blood vessels during normal cycle and after mifepristone treatment. Localization and expression of AQP1 was determined using immunohistochemistry and reverse transcriptase chain reaction (RT-PCR) in 43 biopsies from human endometrium taken during a normal cycle and after mifepristone treatment. AQP1 expression in human endometrial vessels is not cycle dependent and is stronger in capillaries and arteries than in veins. After mifepristone treatment the staining intensity was increased, but not the number of stained vessels. The presence of AQP1 was also confirmed using RT-PCR. The changes in AQP1 expression could contribute to the reduced bleeding seen following mifepristone treatment and could be an effect of either antagonizing progesterone or cortisol.
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16.
  • Holm, Anne I. S., et al. (författare)
  • Synchrotron Radiation Circular Dichroism of Various G-Guadruplex Structures
  • 2010
  • Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 93:5, s. 429-433
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we report synchrotron radiation circular dichroism spectra of various G-quadruplexes from 179 to 350 nm, and a number of bands in the vacuum ultraviolet (VUV) are reported for the first time. For a tetramolecular parallel structure, the strongest band in the spectrum is a negative band in the VUV at 182 nm; for a bimolecular antiparallel structure with diagonal loops, a new strong positive band is found at 190 nm; for a bimolecular parallel structure with edgewise loops, a strong positive band at 189 nm is observed; and for a self-folded chair-type structure, the strongest band in the spectrum is a positive band at 187 nm. For the tetramolecular parallel structure, the CD signals at all wavelengths are dominated by contributions from quartets of G bases, and the signal strength is approximately proportional to the number of quartets. Our experiments on well-characterized G-quadruplex structures lead us to question past attributions of CD signals to helix handedness and G quartet polarity. Although differences can be observed in the VUV region for the various quadruplex types, there do not appear to be clear-cut spectral features that can be used to identify specific topological features. It is suggested that this is because a dominant positive band in the VUV seen near 190 nm in all quadruplex structures is due to intrastrand guanine guanine base stacking. However, our spectra can serve as reference spectra for the G-quadruplex structures investigated and, not least, to benchmark theoretical calculations and empirical models.
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17.
  • Holm, Paetur M., et al. (författare)
  • Effects of neuromuscular control and strengthening exercises on MRI-measured thigh tissue composition and muscle properties in people with knee osteoarthritis - an exploratory secondary analysis from a randomized controlled trial
  • 2024
  • Ingår i: SEMINARS IN ARTHRITIS AND RHEUMATISM. - 0049-0172 .- 1532-866X. ; 65
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To investigate the effects of adding strength training to neuromuscular control exercises on thigh tissue composition and muscle properties in people with radiographic -symptomatic knee osteoarthritis (KOA). Methods: In this exploratory secondary analysis of a randomized controlled trial, using a complete -case approach, participants performed 12 weeks of twice -weekly neuromuscular control exercise and patient education (NEMEX, n = 34) or NEMEX plus quadriceps strength training (NEMEX+ST, n = 29). Outcomes were MRImeasured inter- and intramuscular adipose tissue (InterMAT, IntraMAT), quadriceps muscle cross-sectional area (CSA), knee -extensor strength, specific strength (strength/lean CSA) and 30 s chair -stands. Betweengroup effects were compared using a mixed model analysis of variance. Results: At 12 weeks, responses to NEMEX+ST overlapped with NEMEX for all outcomes. Both groups reduced InterMAT (NEMEX+ST=25 %, NEMEX=21 %); between -group difference: 0.8cm2 (95 % CI: -0.1, 1.7). NEMEX+ST decreased IntraMAT (2 %) and NEMEX increased IntraMAT (4 %); between -group difference 0.1 %-points (-0.3, 0.5). Both groups increased quadriceps CSA and lean CSA (CSA minus IntraMAT), improved knee -extensor strength and specific strength, and improved chair -stand performance with a trend towards greater effects in NEMEX+ST. Conclusion: Adding strength training to 12 weeks of neuromuscular control exercises provided largely similar effects to neuromuscular control exercises alone in decreasing InterMAT and IntraMAT, in improving kneeextensor strength, CSA and in improving performance -based function in KOA persons, with a trend towards greater effects with additional strength training. Notably, both groups substantially reduced InterMAT and improved specific strength (an index of muscle quality). Our hypothesis -generating work warrants exploration of the roles played by InterMAT and IntraMAT in exercise effects in KOA.
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18.
  • Huber, Vincent J., et al. (författare)
  • Aquaporins : Chemical inhibition by small molecules
  • 2016
  • Ingår i: Aquaporins in Health and Disease : New Molecular Targets for Drug Discovery - New Molecular Targets for Drug Discovery. - 9781498707831 - 9781498707848 ; , s. 249-271
  • Bokkapitel (refereegranskat)abstract
    • The human genome encodes 13 aquaporin isoforms with characteristic substrate specificity that are expressed at specific locations throughout the body. Of these isoforms, AQPs 1-4 serve important functions in renal water reabsorption. Consequently, specific AQP inhibitors have been proposed as 'aquaretics', a new class of drugs suitable to induce diuresis without concomitant salt wasting. Furthermore, animal experiments suggested that AQP4 inhibitors could be useful to treat some forms of brain edema. Other proposed applications for AQP inhibitors involve amongst others treatment of diabetes, inflammatory skin diseases and cancer. However, few of these putative applications have been critically evaluated against current forms of therapy. Furthermore, development of AQP inhibitors remains difficult and despite numerous efforts during at least the last 15 years very few AQP inhibitors have been described. Moreover, none of the hitherto described substances have been developed to a level where meaningful verification of proposed AQP drug targets in preclinical or clinical settings was possible. Nonetheless, encouraging progress towards development of such substances has been made during recent years. Novel cell-based assays facilitate high throughput screening of chemical compound libraries for hit discovery. AQP 3D structures have been solved for 10 isoforms, which can support rapidly evolving computational hit discovery methods, as well as hit to lead programs. In this chapter, we will provide a critical review of current evidence supporting relevance of AQPs as drug targets, describe current methods for AQP inhibitor discovery and will try to highlight challenges that remain before successful AQP inhibitor development.
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19.
  • Jelen, Sabina, et al. (författare)
  • AQP9 Expression in Glioblastoma Multiforme Tumors Is Limited to a Small Population of Astrocytic Cells and CD15(+)/CalB(+) Leukocytes
  • 2013
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Aquaporin-9 (AQP9) is a membrane protein channel that is permeable to a range of small solutes, including glycerol, urea and nucleobases. Expression of AQP9 in normal brain is limited, while widespread AQP9 expression has previously been reported in human glioblastoma. However, the specific cellular expression of AQP9 in glioblastoma remains unclear. In this study, we have examined microarrays to corroborate AQP9 mRNA expression in glioma. These analyses suggested that AQP9 mRNA expression in glioblastoma is primarily explained by tumor infiltration with AQP9 expressing leukocytes. Immunolabeling confirmed that within tumor regions, AQP9 was expressed in CD15(+) and Calgranulin B+ leukocytes, but also in larger cells that morphologically resembled glioma cells. Specificity of immunoreagents was tested in recombinant cell lines, leukocyte preparations, and sections of normal human brain and liver tissue. Apparent AQP9(+) glioma cells were frequently observed in proximity to blood vessels, where brain tumor stem cells have been observed previously. A fraction of these larger AQP9 expressing cells co-expressed the differentiated astrocyte marker GFAP. AQP9 expressing glioma cells were negative for the brain tumor stem cell marker CD15, but were observed in proximity to CD15(+) glioma cells. AQP9 expression may therefore require signals of the perivascular tumor environment or alternatively it may be restricted to a population of glioma stem cell early progenitor cells.
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20.
  • Jelen, Sabina, et al. (författare)
  • Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice
  • 2011
  • Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 286:52, s. 44319-44325
  • Tidskriftsartikel (refereegranskat)abstract
    • It has been hypothesized that aquaporin-9 (AQP9) is part of the unknown route of hepatocyte glycerol uptake. In a previous study, leptin receptor-deficient wild-type mice became diabetic and suffered from fasting hyperglycemia whereas isogenic AQP9(-/-) knock-out mice remained normoglycemic. The reason for this improvement in AQP9(-/-) mice was not established before. Here, we show increased glucose output (by 123% +/- 36% S. E.) in primary hepatocyte culture when 0.5 mM extracellular glycerol was added. This increase depended on AQP9 because it was absent in AQP9(-/-) cells. Likewise, the increase was abolished by 25 mu M HTS13286 (IC(50) similar to 2 mu M), a novel AQP9 inhibitor, which we identified in a small molecule library screen. Similarly, AQP9 deletion or chemical inhibition eliminated glycerol-enhanced glucose output in perfused liver preparations. The following control experiments suggested inhibitor specificity to AQP9: (i) HTS13286 affected solute permeability in cell lines expressing AQP9, but not in cell lines expressing AQPs 3, 7, or 8. (ii) HTS13286 did not influence lactate-and pyruvate-dependent hepatocyte glucose output. (iii) HTS13286 did not affect glycerol kinase activity. Our experiments establish AQP9 as the primary route of hepatocyte glycerol uptake for gluconeogenesis and thereby explain the previously observed, alleviated diabetes in leptin receptor-deficient AQP9(-/-) mice.
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21.
  • Kehler, Jan, et al. (författare)
  • Discovery and Development of C-11-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain
  • 2014
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:9, s. 1513-1518
  • Tidskriftsartikel (refereegranskat)abstract
    • Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-C-11-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (C-11-Lu AE92686) and its tritiated analog H-3-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and C-11-labeled compounds were synthesized. 3H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and C-11-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: C-11-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3H-Lu AE92686. The binding of C-11-Lu AE92686 and 3H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of C-11-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible-that is, BP(ND)s were 6.5 +/- 0.3 (n = 3) and 7.5 +/- 1.0 (n = 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that C-11-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.
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22.
  • Kristiansen, Jesper, et al. (författare)
  • A study of classroom acoustics and school teachers' noise exposure, voice load and speaking time during teaching, and the effects on vocal and mental fatigue development
  • 2014
  • Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 87:8, s. 851-860
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives The study investigated the noise exposure in a group of Danish school teachers. The aims were to investigate if noise posed a risk of impairment of hearing and to study the association between classroom acoustical conditions, noise exposure, vocal symptoms, and cognitive fatigue. Methods Background noise levels, vocal load and speaking time were measured on 35 teachers during actual classroom teaching. The classrooms were characterized acoustically by measurements of reverberation time. Before and after the workday, the teachers answered a questionnaire on fatigue symptoms and carried out two cognitive test tasks sensitive to mental fatigue. Results The average noise level during the lessons was 72 dB(A), but during indoor sports activities the average noise level increased 6.6 dB(A). Room reverberation time (range 0.39-0.83 s) had no significant effect on the noise level. The teachers were talking with a raised voice in 61 % of the time, and the vocal load increased 0.65 dB(A) per dB(A) increase in the average lesson noise level. An increase in voice symptoms during the workday correlated significantly with individual average noise exposure, and a decrease in performance in the two-back test correlated significantly with individual average vocal load. Conclusions Noise exposure in general classrooms posed no risk of noise-induced hearing impairment in school teachers. However, the results provide evidence for an association between noise exposure and vocal load and development of vocal symptoms and cognitive fatigue after work.
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23.
  • Larsen, Anders Hostrup, et al. (författare)
  • A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes
  • 2020
  • Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 22:9, s. 1628-1637
  • Tidskriftsartikel (refereegranskat)abstract
    • AimsThe present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes. Methods and resultsThirty-six HFrEF patients (ejection fraction 378%; median age 66years) were randomised to metformin (n = 19) or placebo (n = 17) for 3months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by C-11-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 +/- 550 mg/day) increased WMI [absolute mean difference, 1.0mmHg.mL.m(-2).10(6); 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6mL O-2.100 g(-1).min(-1); P = 0.014). Cardiac stroke work was preserved (-2J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups. ConclusionMetformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes.
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24.
  • Lindskog, Cecilia, et al. (författare)
  • A Systematic Characterization of Aquaporin-9 Expression in Human Normal and Pathological Tissues
  • 2016
  • Ingår i: Journal of Histochemistry and Cytochemistry. - : SAGE Publications. - 0022-1554 .- 1551-5044. ; 64:5, s. 287-300
  • Tidskriftsartikel (refereegranskat)abstract
    • AQP9 is known to facilitate hepatocyte glycerol uptake. Murine AQP9 protein expression has been verified in liver, skin, epididymis, epidermis and neuronal cells using knockout mice. Further expression sites have been reported in humans. We aimed to verify AQP9 expression in a large set of human normal organs, different cancer types, rheumatoid arthritis synovial biopsies as well as in cell lines and primary cells. Combining standardized immunohistochemistry with high-throughput mRNA sequencing, we found that AQP9 expression in normal tissues was limited, with high membranous expression only in hepatocytes. In cancer tissues, AQP9 expression was mainly found in hepatocellular carcinomas, suggesting no general contribution of AQP9 to carcinogenesis. AQP9 expression in a subset of rheumatoid arthritis synovial tissue samples was affected by Humira, thereby supporting a suggested role of TNF alpha in AQP9 regulation in this disease. Among cell lines and primary cells, LP-1 myeloma cells expressed high levels of AQP9, whereas low expression was observed in a few other lymphoid cell lines. AQP9 mRNA and protein expression was absent in HepG2 hepatocellular carcinoma cells. Overall, AQP9 expression in human tissues appears to be more selective than in mice.
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25.
  • Liu Carlsen, Anting, et al. (författare)
  • Circulating MicroRNA Expression Profiles Associated With Systemic Lupus Erythematosus
  • 2013
  • Ingår i: Arthritis and Rheumatism. - : Wiley-Blackwell. - 0004-3591 .- 1529-0131. ; 65:5, s. 1324-1334
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Methods Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Results Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P andlt; 2 x 109). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Conclusion Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor signaling pathways. Other targets include regulation of apoptosis, cytokinecytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.
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26.
  • Lund, Soren S., et al. (författare)
  • Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial
  • 2009
  • Ingår i: BMJ (International Edition). - : BMJ. - 0959-8146 .- 0959-8138 .- 1468-5833. ; 339
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives To study the effect of insulin treatment in combination with metformin or an insulin secretagogue, repaglinide, on glycaemic regulation in non-obese patients with type 2 diabetes. Design Randomised, double blind, double dummy, parallel trial. Setting Secondary care in Denmark between 2003 and 2006. Participants Non-obese patients (BMI <= 27) with preserved beta cell function. Interventions After a four month run-in period with repaglinide plus metformin combination therapy, patients with a glycated haemoglobin (HbA(1c)) concentration of 6.5% or more were randomised to repaglinide 6 mg or metformin 2000 mg. All patients also received biphasic insulin aspart 70/30 (30% soluble insulin aspart and 70% intermediate acting insulin aspart) 6 units once a day before dinner for 12 months. Insulin dose was adjusted aiming for a fasting plasma glucose concentration of 4.0-6.0 mmol/l. The target of HbA(1c) concentration was less than 6.5%. Treatment was intensified to two or three insulin injections a day if glycaemic targets were not reached. Main outcome measure HbA(1c) concentration. Results Of the 459 patients who were eligible, 102 were randomised, and 97 completed the trial. Patients had had type 2 diabetes for approximately 10 years. At the end of treatment, HbA(1c) concentration was reduced by a similar amount in the two treatment groups (insulin plus metformin: mean (standard deviation) HbA(1c) 8.15% (1.32) v 6.72% (0.66); insulin plus repaglinide: 8.07% (1.49) v 6.90% (0.68); P=0.177). Total daily insulin dose and risk of hypoglycaemia were also similar in the two treatment groups. Weight gain was less with metformin plus biphasic insulin aspart 70/30 than with repaglinide plus biphasic insulin aspart 70/30 (difference in mean body weight between treatments -2.51 kg, 95% confidence interval -4.07 to -0.95). Conclusions In non-obese patients with type 2 diabetes and poor glycaemic regulation on oral hypoglycaemic agents, overall glycaemic regulation with insulin in combination with metformin was equivalent to that with insulin plus repaglinide. Weight gain seemed less with insulin plus metformin than with insulin plus repaglinide.
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27.
  • Nielsen-Kudsk, Jens Erik, et al. (författare)
  • Left atrial appendage occlusion versus standard medical care in patients with atrial fibrillation and intracerebral haemorrhage : a propensity score-matched follow-up study
  • 2017
  • Ingår i: EuroIntervention. - : EUROPA EDITION. - 1774-024X .- 1969-6213. ; 13:3, s. 371-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: The aim of this study was to investigate the prognosis in patients with atrial fibrillation (AF) and intracerebral haemorrhage (ICH) having a left atrial appendage occlusion (LAAO) versus patients receiving standard medical therapy. Methods and results: A total of 151 patients from the Nordic countries with AF and previous ICH who underwent LAAO using the AMPLATZER Cardiac Plug or the AMPLATZER AMULET were compared to a propensity score-matched group of 151 patients receiving standard medical therapy. The two groups were matched so that their risks for stroke and bleeding were similar (CHA2DS2-VASc and HAS-BLED scores). The standard care patients were identified from the Danish Stroke Registry among 787 patients with AF and ICH. The primary endpoint was a composite of all-cause mortality, ischaemic stroke and major bleeding. Patients with AF and a prior ICH treated with LAAO had a lower risk of the composite outcome as compared to patients treated with standard medical care (events/1,000 years [95% confidence interval]: 53.3 [44.3-64.1] vs. 366.7 [298.2-450.9]; hazard ratio 0.16 [0.07-0.37]). Conclusions: LAAO is suggested to be of major clinical benefit in AF patients having sustained an ICH. These results have to be confirmed in a randomised clinical trial.
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28.
  • Nielsen, Niklas, et al. (författare)
  • Targeted Temperature Management at 33 degrees C versus 36 degrees C after Cardiac Arrest
  • 2013
  • Ingår i: New England Journal of Medicine. - 0028-4793. ; 369:23, s. 2197-2206
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundUnconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. MethodsIn an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33 degrees C or 36 degrees C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. ResultsIn total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33 degrees C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36 degrees C group (225 of 466 patients) (hazard ratio with a temperature of 33 degrees C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33 degrees C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36 degrees C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. ConclusionsIn unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33 degrees C did not confer a benefit as compared with a targeted temperature of 36 degrees C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.)
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29.
  • Nielsen, Roni, et al. (författare)
  • Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients
  • 2019
  • Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 139:18, s. 2129-2141
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential doseresponse relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO 2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers.METHODS: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37 +/- 3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a doseresponse study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO 2 were evaluated using 11C-acetate positron emission tomography.RESULTS: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4 +/- 0.3 to 3.3 +/- 0.4 mM (P< 0.001). CO rose by 2.0 +/- 0.2 L/min (P< 0.001) because of an increase in stroke volume of 20 +/- 2 mL (P< 0.001) and heart rate of 7 +/- 2 beats per minute (bpm) (P< 0.001). Left ventricular ejection fraction increased 8 +/- 1% (P< 0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM (P< 0.001). 3-OHB increased MVO 2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers.CONCLUSIONS: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.
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30.
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31.
  • Nyblom, Maria, et al. (författare)
  • Regulation of eukaryotic aquaporins
  • 2016
  • Ingår i: Aquaporins in Health and Disease : New Molecular Targets for Drug Discovery - New Molecular Targets for Drug Discovery. - 9781498707831 - 9781498707848 ; , s. 53-76
  • Bokkapitel (refereegranskat)abstract
    • Membrane-bound water channels known as aquaporins (AQPs) facilitate water transport across biological membranes along osmotic gradients. Since all living cells depend on their ability to maintain water homeostasis, this must be tightly regulated. In eukaryotes, this is achieved by gating, which involves a conformational change of the protein, thereby physically blocking water transport, or by trafficking in which AQPs are shuttled between intracellular storage sites and the plasma membrane. Gating is common amongst plant AQPs in response to environmental stress and has been shown to be triggered by phosphorylation, pH and binding of divalent cations. Gating has been demonstrated for yeast AQPs for which it is believed to confer protection against osmotic shock and rapid freezing. In mammals, AQP regulation is mainly achieved through trafficking. Thirteen AQPs have been identified in humans, the majority of which are regulated by trafficking in response to a wide range of stimuli. The far best characterized trafficking mechanism is that of AQP2 in the kidney collecting duct where it plays a key role in urine concentration. AQP2 trafficking is controlled by the pituitary hormone vasopressin that stimulates phosphorylation of the AQP2 C-terminus, triggering translocation of AQP2 from intracellular storage vesicles to the apical membrane. Defective trafficking of human AQPs can lead to several disease states, for example nephrogenic diabetes insipidus (AQP2) and Sjögren's syndrome (AQP5). In this chapter, we give an overview of what is known about the regulation of eukaryotic AQPs, focusing particularly on structure-function relationships. We discuss the physiological role of AQP regulation, specific regulatory mechanisms and reoccurring themes in both gating and trafficking.
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32.
  • Orlando, Ludovic, et al. (författare)
  • Recalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse
  • 2013
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 499:7456, s. 74-
  • Tidskriftsartikel (refereegranskat)abstract
    • The rich fossil record of equids has made them a model for evolutionary processes(1). Here we present a 1.12-times coverage draft genome from a horse bone recovered from permafrost dated to approximately 560-780 thousand years before present (kyr BP)(2,3). Our data represent the oldest full genome sequence determined so far by almost an order of magnitude. For comparison, we sequenced the genome of a Late Pleistocene horse (43 kyr BP), and modern genomes of five domestic horse breeds (Equus ferus caballus), a Przewalski's horse (E. f. prze-walskii) and a donkey (E. asinus). Our analyses suggest that the Equus lineage giving rise to all contemporary horses, zebras and donkeys originated 4.0-4.5 million years before present (Myr BP), twice the conventionally accepted time to the most recent common ancestor of the genus Equus(4,5). We also find that horse population size fluctuated multiple times over the past 2 Myr, particularly during periods of severe climatic changes. We estimate that the Przewalski's and domestic horse populations diverged 38-72 kyr BP, and find no evidence of recent admixture between the domestic horse breeds and the Przewalski's horse investigated. This supports the contention that Przewalski's horses represent the last surviving wild horse population(6). We find similar levels of genetic variation among Przewalski's and domestic populations, indicating that the former are genetically viable and worthy of conservation efforts. We also find evidence for continuous selection on the immune system and olfaction throughout horse evolution. Finally, we identify 29 genomic regions among horse breeds that deviate from neutrality and show low levels of genetic variation compared to the Przewalski's horse. Such regions could correspond to loci selected early during domestication.
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33.
  • Raghavan, Maanasa, et al. (författare)
  • Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans
  • 2014
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 505:7481, s. 87-
  • Tidskriftsartikel (refereegranskat)abstract
    • The origins of the First Americans remain contentious. Although Native Americans seem to be genetically most closely related to east Asians(1-3), there is no consensus with regard to which specific Old World populations they are closest to(4-8). Here we sequence the draft genome of an approximately 24,000-year-old individual (MA-1), from Mal'ta in south-central Siberia(9), to an average depth of 1x. To our knowledge this is the oldest anatomically modern human genome reported to date. The MA-1 mitochondrial genome belongs to haplogroup U, which has also been found at high frequency among Upper Palaeolithic and Mesolithic European hunter-gatherers(10-12), and the Y chromosome of MA-1 is basal to modern-day western Eurasians and near the root of most Native American lineages(5). Similarly, we find autosomal evidence that MA-1 is basal to modern-day western Eurasians and genetically closely related to modern-day Native Americans, with no close affinity to east Asians. This suggests that populations related to contemporary western Eurasians had a more north-easterly distribution 24,000 years ago than commonly thought. Furthermore, we estimate that 14 to 38% of Native American ancestry may originate through gene flow from this ancient population. This is likely to have occurred after the divergence of Native American ancestors from east Asian ancestors, but before the diversification of Native American populations in the New World. Gene flow from the MA-1 lineage into Native American ancestors could explain why several crania from the First Americans have been reported as bearing morphological characteristics that do not resemble those of east Asians(2,13). Sequencing of another south-central Siberian, Afontova Gora-2 dating to approximately 17,000 years ago(14), revealed similar autosomal genetic signatures as MA-1, suggesting that the region was continuously occupied by humans throughout the Last Glacial Maximum. Our findings reveal that western Eurasian genetic signatures in modern-day Native Americans derive not only from post-Columbian admixture, as commonly thought, but also from a mixed ancestry of the First Americans.
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34.
  • Rasmussen, Morten, et al. (författare)
  • The genome of a Late Pleistocene human from a Clovis burial site in western Montana
  • 2014
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 506:7487, s. 225-229
  • Tidskriftsartikel (refereegranskat)abstract
    • Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 C-14 years before present (BP) (13,000 to 12,600 calendar years BP)(1,2). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology(3). However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans(2). An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum(4). Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 +/- 35 C-14 years BP (approximately 12,707-12,556 calendar years BP) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4x and show that the gene flow from the Siberian Upper Palaeolithic Mal'ta population(5) into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years BP. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.
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35.
  • Roder, Gustav, et al. (författare)
  • The outermost N-terminal region of tapasin facilitates folding of major histocompatibility complex class I
  • 2009
  • Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 39:10, s. 2682-2694
  • Tidskriftsartikel (refereegranskat)abstract
    • Tapasin (Tpn) is an ER chaperone that is uniquely dedicated to MHC-I biosynthesis. It binds MHC-I molecules, integrates them into peptide-loading complexes, and exerts quality control of the bound peptides; only when an "optimal peptide" is bound will the MHC-I be released and exported to the cell surface for presentation to T cells. The exact mechanisms of Tpn quality control and the criteria for being an optimal peptide are still unknown. Here, we have generated a recombinant fragment of human Tpn, Tpn(1-87) (representing the 87 N-terminal and ER-luminal amino acids of the mature Tpn protein). Using a biochemical peptide-MHC-I-binding assay, recombinant Tpn(1-87) was found to specifically facilitate peptide-dependent folding of HLA-A*0201. Furthermore, we used Tpn(1-87) to generate a monoclonal antibody, alpha Tpn(1-87/80), specific for natural human Tpn and capable of cellular staining of ER localized Tpn. Using overlapping peptides, the epitope of alpha Tpn(1-87)/80 was located to Tpn(40-44), which maps to a surface-exposed loop on the Tpn structure. Together, these results demonstrate that the N-terminal region of Tpn can be recombinantly expressed and adopt a structure, which at least partially resembles that of WT Tpn, and that this region of Tpn features chaperone activity facilitating peptide binding of MHC-I.
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36.
  • Siersbaek, Majken S., et al. (författare)
  • Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor gamma in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression
  • 2012
  • Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 32:17, s. 3452-3463
  • Tidskriftsartikel (refereegranskat)abstract
    • Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipocyte differentiation and function. We and others have previously mapped PPAR gamma binding at a genome-wide level in murine and human adipocyte cell lines and in primary human adipocytes. However, little is known about how binding patterns of PPAR gamma differ between brown and white adipocytes and among different types of white adipocytes. Here we have employed chromatin immunoprecipitation combined with deep sequencing to map and compare PPAR gamma binding in in vitro differentiated primary mouse adipocytes isolated from epididymal, inguinal, and brown adipose tissues. While these PPAR gamma binding profiles are overall similar, there are clear depot-selective binding sites. Most PPAR gamma binding sites previously mapped in 3T3-L1 adipocytes can also be detected in primary adipocytes, but there are a large number of PPAR gamma binding sites that are specific to the primary cells, and these tend to be located in closed chromatin regions in 3T3-L1 adipocytes. The depot-selective binding of PPAR gamma is associated with highly depot-specific gene expression. This indicates that PPAR gamma plays a role in the induction of genes characteristic of different adipocyte lineages and that preadipocytes from different depots are differentially preprogrammed to permit PPAR gamma lineage-specific recruitment even when differentiated in vitro.
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37.
  • Stephenson, Randell, et al. (författare)
  • Late Cretaceous-Cenozoic basin inversion and palaeostress fields in the North Atlantic-western Alpine-Tethys realm : Implications for intraplate tectonics
  • 2020
  • Ingår i: Earth-Science Reviews. - : Elsevier BV. - 0012-8252 .- 1872-6828. ; 210
  • Forskningsöversikt (refereegranskat)abstract
    • Intraplate basin/structural inversion (indicating tectonic shortening) is a good marker of ("far-field") tectonic stress regime changes that are linked to plate geometries and interactions, a premise that is qualitatively well-established in the literature. There is also quantitative evidence that Late Cretaceous-Palaeocene inversion of sedimentary basins in north-central Europe was explicitly driven by an intraplate, relaxational response to forces developed during rapid reconfigurations of the Alpine-Tethys (Europe-Africa) convergent plate boundary. Although with a degree of temporal ambiguity, three main periods of intraplate tectonics (marked primarily by structural inversion in initially extensional sedimentary basins) are indicated in the North Atlantic-western Alpine-Tethys realm. These are in the Late Cretaceous-Palaeocene, the Eocene-Oligocene and the Miocene. Examples recording these periods are primarily interpreted seismic reflection profiles (of varying quality and resolution) from the published literature. Additional examples where seismic data are not present, but timing constraints are robust from other observations, have also been considered. The schematic distribution and orientation of the literature-compiled intraplate inversion structures are compared to the model palaeostress fields derived from Late Cretaceous-Palaeocene, Eocene-Oligocene and Miocene tectonic reconstructions of the North Atlantic-western Alpine-Tethys realm. The modelled palaeostress fields include geopotential effects from palaeobathymetry and palaeotopography of the Earths surface as well as laterally variable lithosphere and crustal palaeo-thicknesses but do not include any component of the stress field produced by processes occurring at contiguous convergent plate margins. The former satisfactorily provides the background stress field of most of the Earth's plate interiors and it is inferred that the latter is paramount in producing "stress trauma" in the interior of plates resulting in permanent intraplate deformation such as basin inversion.
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38.
  • Stormlund, Sacha, et al. (författare)
  • The prevalence of late-follicular phase progesterone elevation and impact on the ongoing pregnancy rate after fresh and frozen blastocyst transfer. Sub-study of an RCT
  • 2024
  • Ingår i: HUMAN FERTILITY. - 1464-7273 .- 1742-8149. ; 27:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The effect of late-follicular phase progesterone elevation (LFPE) during ovarian stimulation on reproductive outcomes in ART treatment remains controversial, but recent studies indicate lower pregnancy rates with rising progesterone levels. This study aims to investigate the prevalence of late-follicular phase progesterone elevation (LFPE) and possible impact on ongoing pregnancy rate after fresh or frozen blastocyst transfer in a sub-study setting of a randomised controlled trial. A total of 288 women were included (n=137 and n=151 in the fresh transfer and freeze-all group, respectively). Among these 11(3.8%) had a progesterone level >= 1.5 ng/ml, and 20(6.9%) had a progesterone level >= 1.2 ng/ml on trigger day. Spline regression analysis showed no significant effect of late follicular phase progesterone levels on ongoing pregnancy. In the multivariate regression analysis (n = 312) only age, but not progesterone level on trigger day was significantly associated with ongoing pregnancy. In conclusion, in a clinical setting with moderate gonadotrophin stimulation and well-defined trigger and fresh transfer cancellation criteria, the prevalence of women with LFPE >= 1.5 ng/ml was low and did not indicate the clinical value of routine measurement of progesterone in the late follicular phase.
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39.
  • Timmons, James A., et al. (författare)
  • Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans
  • 2010
  • Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 108:6, s. 1487-1496
  • Tidskriftsartikel (refereegranskat)abstract
    • Timmons JA, Knudsen S, Rankinen T, Koch LG, Sarzynski M, Jensen T, Keller P, Scheele C, Vollaard NB, Nielsen S, Akerstrom T, MacDougald OA, Jansson E, Greenhaff PL, Tarnopolsky MA, van Loon LJ, Pedersen BK, Sundberg CJ, Wahlestedt C, Britton SL, Bouchard C. Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans. J Appl Physiol 108: 1487-1496, 2010. First published February 4, 2010; doi:10.1152/japplphysiol.01295.2009.-A low maximal oxygen consumption ((V) over dotO(2max)) is a strong risk factor for premature mortality. Supervised endurance exercise training increases (V) over dotO(2max) with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts (V) over dotO(2max) training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous (V) over dotO(2max) response. Two independent preintervention RNA expression data sets were generated (n = 41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in (V) over dotO(2max) (""predictor"" genes). The HERITAGE Family Study (n = 473) was used for genotyping. We discovered a 29-RNA signature that predicted (V) over dotO(2max) training response on a continuous scale; these genes contained similar to 6 new single-nucleotide polymorphisms associated with gains in (V) over dotO(2max) in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., ""reciprocal"" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in (V) over dotO(2max), corresponding to similar to 50% of the estimated genetic variance for (V) over dotO(2max). In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. (V) over dotO(2max) responses to endurance training can be predicted by measuring a similar to 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.
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40.
  • Tolbod, Lars P., et al. (författare)
  • Non-invasive quantification of tumor blood flow in prostate cancer using O-15-H2O PET/CT
  • 2018
  • Ingår i: American Journal of Nuclear Medicine and Molecular Imaging. - : E-CENTURY PUBLISHING CORP. - 2160-8407. ; 8:5, s. 292-302
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor blood flow (TBF) measurements in prostate cancer (PCa) provide an integrative index of tumor growth, which could be important for primary diagnosis and therapy response evaluation. O-15-water PET is the noninvasive gold standard but is technically demanding. The aim of this study was to compare the accuracy of three different non-invasive strategies with an invasively measured arterial input function (BSIF): Using image-derived input functions (IDIF) from either 1) a separate heart scan or 2) the pelvic scan or 3) a populations-based input function (PBIF). Nine patients with biopsy-verified PCa scheduled for prostatectomy were included. All patients were characterized with serum levels of PSA (s-PSA), multiparametric magnetic resonance imaging (mpMRl) and post-surgical histopathology Gleason Grade. Dynamic O-15-water was performed of the heart and the pelvic area 15 minutes apart. TBF estimated from both wash-in (K-1) and wash-out (k(2)) constants was calculated using a one-compartmental model. Results: Mean (range) s PSA was 12 (3-27) ng/mL, Gleason Grade Group was 2.9 (1-5), k(2) was 0.44 (0.007-1.2), and K-1 was 0.24 (0.07-0.55) mL,/mL/min. k(2) (BSIF)correlated with s-PSA (r=0.86, P<0.01) and Gleason Grade Group (rho=0.78, P=0.01). BSIF, heart-IDIF and PBIF provided near-identical k(2) and K-1 (r>0.95, P<0.001) with slopes near unity. The correlations of BSIF and pelvic-IDIF rate constants were good (r>0.95, P<0.001), but individual errors high. In conclusion, non-invasive protocols for O-15-water PET with IDIF or PBIF accurately measures perfusion in prostate cancer and might be useful for evaluation of tumor aggressiveness and treatment response.
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41.
  • Wacker, Soeren J., et al. (författare)
  • The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site
  • 2013
  • Ingår i: Molecular Membrane Biology. - : Informa UK Limited. - 0968-7688 .- 1464-5203. ; 30:3, s. 246-260
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The involvement of aquaporin (AQP) water and small solute channels in the etiology of several diseases, including cancer, neuromyelitis optica and body fluid imbalance disorders, has been suggested previously. Furthermore, results obtained in a mouse model suggested that AQP9 function contributes to hyperglycemia in type-2 diabetes. In addition, the physiological role of several AQP family members remains poorly understood. Small molecule inhibitors of AQPs are therefore desirable to further study AQP physiological and pathophysiological functions. Methods: The binding of recently established AQP9 inhibitors to a homology model of AQP9 was investigated by molecular dynamics simulations and molecular docking. Putative inhibitor binding sites identified with this procedure were modified by site-directed mutagenesis. Active compounds were measured in a mammalian cell water permeability assay of mutated AQP9 isoforms and tested for changes in inhibitory effects. Controls: Three independent cell lines were established for each mutated AQP9 isoform and functionality of mutant isoforms was established. Principal findings: We have identified putative binding sites of recently established AQP9 inhibitors. This information facilitated successful identification of novel AQP9 inhibitors with low micromolar IC50 values in a cell based assay by in silico screening of a compound library targeting specifically this binding site. Significance: We have established a successful strategy for AQP small molecule inhibitor identification. AQP inhibitors may be relevant as experimental tools, to enhance our understanding of AQP function, and in the treatment of various diseases.
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42.
  • Watts, Eleanor L., et al. (författare)
  • Observational and genetic associations between cardiorespiratory fitness and cancer : a UK Biobank and international consortia study
  • 2024
  • Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130, s. 114-124
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The association of fitness with cancer risk is not clear.Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.
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43.
  • Wille-Jorgensen, Peer, et al. (författare)
  • Effect of More vs Less Frequent Follow-up Testing on Overall and Colorectal Cancer-Specific Mortality in Patients With Stage II or III Colorectal Cancer The COLOFOL Randomized Clinical Trial
  • 2018
  • Ingår i: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 319:20, s. 2095-2103
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Intensive follow-up of patients after curative surgery for colorectal cancer is common in clinical practice, but evidence of a survival benefit is limited.OBJECTIVE To examine overall mortality, colorectal cancer-specific mortality, and colorectal cancer-specific recurrence rates among patients with stage II or III colorectal cancer who were randomized after curative surgery to 2 alternative schedules for follow-up testing with computed tomography and carcinoembryonic antigen.DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized trial including 2509 patients with stage II or III colorectal cancer treated at 24 centers in Sweden, Denmark, and Uruguay from January 2006 through December 2010 and followed up for 5 years; follow-up ended on December 31, 2015.INTERVENTIONS Patients were randomized either to follow-up testing with computed tomography of the thorax and abdomen and serum carcinoembryonic antigen at 6, 12, 18, 24, and 36 months after surgery (high-frequency group; n = 1253 patients) or at 12 and 36 months after surgery (low-frequency group; n = 1256 patients).MAIN OUTCOMES AND MEASURES The primary outcomes were 5-year overall mortality and colorectal cancer-specific mortality rates. The secondary outcome was the colorectal cancer-specific recurrence rate. Both intention-to-treat and per-protocol analyses were performed.RESULTS Among 2555 patients who were randomized, 2509 were included in the intention-to-treat analysis (mean age, 63.5 years; 1128 women [45%]) and 2365 (94.3%) completed the trial. The 5-year overall patient mortality rate in the high-frequency group was 13.0%(161/1253) compared with 14.1%(174/1256) in the low-frequency group (risk difference, 1.1% [95% CI, -1.6% to 3.8%]; P =.43). The 5-year colorectal cancer-specific mortality rate in the high-frequency group was 10.6%(128/1248) compared with 11.4%(137/1250) in the low-frequency group (risk difference, 0.8%[ 95% CI, -1.7% to 3.3%]; P =.52). The colorectal cancer-specific recurrence rate was 21.6%(265/1248) in the high-frequency group compared with 19.4%(238/1250) in the low-frequency group (risk difference, 2.2%[ 95% CI, -1.0% to 5.4%]; P =.15).CONCLUSIONS AND RELEVANCE Among patients with stage II or III colorectal cancer, follow-up testing with computed tomography and carcinoembryonic antigen more frequently compared with less frequently did not result in a significant rate reduction in 5-year overall mortality or colorectal cancer-specific mortality.
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44.
  • Xue-Franzen, Yongtao, et al. (författare)
  • Genomewide identification of pheromone-targeted transcription in fission yeast
  • 2006
  • Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 7, s. 303-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Fission yeast cells undergo sexual differentiation in response to nitrogen starvation. In this process haploid M and P cells first mate to form diploid zygotes, which then enter meiosis and sporulate. Prior to mating, M and P cells communicate with diffusible mating pheromones that activate a signal transduction pathway in the opposite cell type. The pheromone signalling orchestrates mating and is also required for entry into meiosis. Results: Here we use DNA microarrays to identify genes that are induced by M-factor in P cells and by P-factor in M-cells. The use of a cyr1 genetic background allowed us to study pheromone signalling independently of nitrogen starvation. We identified a total of 163 genes that were consistently induced more than two-fold by pheromone stimulation. Gene disruption experiments demonstrated the involvement of newly discovered pheromone-induced genes in the differentiation process. We have mapped Gene Ontology ( GO) categories specifically associated with pheromone induction. A direct comparison of the M- and P-factor induced expression pattern allowed us to identify cell-type specific transcripts, including three new M- specific genes and one new P-specific gene. Conclusion: We found that the pheromone response was very similar in M and P cells. Surprisingly, pheromone control extended to genes fulfilling their function well beyond the point of entry into meiosis, including numerous genes required for meiotic recombination. Our results suggest that the SteII transcription factor is responsible for the majority of pheromone-induced transcription. Finally, most cell-type specific genes now appear to be identified in fission yeast.
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