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| 3. |
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| 4. |
- Durno, C., et al.
(författare)
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Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
- 2021
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:25
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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| 5. |
- Pierre, M., et al.
(författare)
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The XXL Survey I. Scientific motivations - XMM-Newton observing plan - Follow-up observations and simulation programme
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 592
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Tidskriftsartikel (refereegranskat)abstract
- Context. The quest for the cosmological parameters that describe our universe continues to motivate the scientific community to undertake very large survey initiatives across the electromagnetic spectrum. Over the past two decades, the Chandra and XMM-Newton observatories have supported numerous studies of X-ray-selected clusters of galaxies, active galactic nuclei (AGNs), and the X-ray background. The present paper is the first in a series reporting results of the XXL-XMM survey; it comes at a time when the Planck mission results are being finalised. Aims. We present the XXL Survey, the largest XMM programme totaling some 6.9 Ms to date and involving an international consortium of roughly 100 members. The XXL Survey covers two extragalactic areas of 25 deg(2) each at a point-source sensitivity of similar to 5 x 10(-15) erg s(-1) cm(-2) in the [0.5-2] keV band (completeness limit). The survey's main goals are to provide constraints on the dark energy equation of state from the space-time distribution of clusters of galaxies and to serve as a pathfinder for future, wide-area X-ray missions. We review science objectives, including cluster studies, AGN evolution, and large-scale structure, that are being conducted with the support of approximately 30 follow-up programmes. Methods. We describe the 542 XMM observations along with the associated multi-lambda and numerical simulation programmes. We give a detailed account of the X-ray processing steps and describe innovative tools being developed for the cosmological analysis. Results. The paper provides a thorough evaluation of the X-ray data, including quality controls, photon statistics, exposure and background maps, and sky coverage. Source catalogue construction and multi-lambda associations are briefly described. This material will be the basis for the calculation of the cluster and AGN selection functions, critical elements of the cosmological and science analyses. Conclusions. The XXL multi-lambda data set will have a unique lasting legacy value for cosmological and extragalactic studies and will serve as a calibration resource for future dark energy studies with clusters and other X-ray selected sources. With the present article, we release the XMM XXL photon and smoothed images along with the corresponding exposure maps.
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| 6. |
- Pierre, M., et al.
(författare)
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The XXL survey : First results and future
- 2017
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Ingår i: Astronomical Notes - Astronomische Nachrichten. - : Wiley-VCH Verlagsgesellschaft. - 0004-6337 .- 1521-3994. ; 338:2-3, s. 334-341
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Tidskriftsartikel (refereegranskat)abstract
- The XXL survey currently covers two 25 deg(2) patches with XMM observations of similar to 10 ks. We summarize the scientific results associated with the first release of the XXL dataset, which occurred in mid-2016. We review several arguments for increasing the survey depth to 40 ks during the next decade of XMM operations. X-ray (z < 2) cluster, (z < 4) active galactic nuclei (AGN), and cosmic background survey science will then benefit from an extraordinary data reservoir. This, combined with deep multi-lambda observations, will lead to solid standalone cosmological constraints and provide a wealth of information on the formation and evolution of AGN, clusters, and the X-ray background. In particular, it will offer a unique opportunity to pinpoint the z > 1 cluster density. It will eventually constitute a reference study and an ideal calibration field for the upcoming eROSITA and Euclid missions.
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| 7. |
- Das, A., et al.
(författare)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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| 9. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet Oncology. - 1470-2045. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 11. |
- Gaudet, Mia M., et al.
(författare)
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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
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| 12. |
- Peiris, Heshan, et al.
(författare)
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A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes
- 2016
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.
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| 13. |
- Smolcic, V., et al.
(författare)
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The XXL Survey: XXIX. GMRT 610 MHz continuum observations
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 620
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Tidskriftsartikel (refereegranskat)abstract
- We present the 25 square-degree GMRT-XXL-N 610 MHz radio continuum survey, conducted at 50 cm wavelength with the Giant Metrewave Radio Telescope (GMRT) towards the XXL Northern field (XXL-N). We combined previously published observations of the XMM-Large Scale Structure (XMM-LSS) field, located in the central part of XXL-N, with newly conducted observations towards the remaining XXL-N area, and imaged the combined data-set using the Source Peeling and Atmospheric Modeling (SPAM) pipeline. The final mosaic encompasses a total area of 30:4 square degrees, with rms <150 μJy beam-1 over 60% of the area. The rms achieved in the inner 9.6 square degree area, enclosing the XMM-LSS field, is about 200 μJy beam-1, while that over the outer 12.66 square degree area (which excludes the noisy edges) is about 45 μJy beam-1. The resolution of the final mosaic is 6.5 arcsec. We present a catalogue of 5434 sources detected at ≥7 × rms. We verify, and correct the reliability of, the catalog in terms of astrometry, flux, and false detection rate. Making use of the (to date) deepest radio continuum survey over a relatively large (2 square degree) field, complete at the flux levels probed by the GMRT-XXL-N survey, we also assess the survey's incompleteness as a function of flux density. The radio continuum sensitivity reached over a large field with a wealth of multi-wavelength data available makes the GMRTXXL- N 610 MHz survey an important asset for studying the physical properties, environments and cosmic evolution of radio sources, in particular radio-selected active galactic nuclei (AGN).
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| 14. |
- Brennan, D. J., et al.
(författare)
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The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ER alpha, and is an independent prognostic factor in node-negative breast cancer
- 2012
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 31:30, s. 3483-3494
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Tidskriftsartikel (refereegranskat)abstract
- Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n = 690; P = 0.002, 0.013). We also show that CART increases the transcriptional activity of ER alpha in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. Oncogene (2012) 31, 3483-3494; doi:10.1038/onc.2011.519; published online 5 December 2011
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| 15. |
- Guglielmo, V., et al.
(författare)
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The XXL Survey: XXII. the XXL-North spectrophotometric sample and galaxy stellar mass function in X-ray detected groups and clusters
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 620
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Tidskriftsartikel (refereegranskat)abstract
- Context. The fraction of galaxies bound in groups in the nearby Universe is high (50% at z ∼ 0). Systematic studies of galaxy properties in groups are important in order to improve our understanding of the evolution of galaxies and of the physical phenomena occurring within this environment. Aims. We have built a complete spectrophotometric sample of galaxies within X-ray detected, optically spectroscopically confirmed groups and clusters (G&C), covering a wide range of halo masses at z ≤ 0.6. Methods. In the context of the XXL survey, we analyse a sample of 164 G&C in the XXL-North region (XXL-N), at z ≤ 0.6, with a wide range of virial masses (1.24 × 1013 ≤ M500,scal(Mo) ≤ 6.63 × 1014) and X-ray luminosities ((2.27 × 1041 ≤ L500,scalXXL(erg-s-1) ≤ 2.15 × 1044)). The G&C are X-ray selected and spectroscopically confirmed. We describe the membership assignment and the spectroscopic completeness analysis, and compute stellar masses. As a first scientific exploitation of the sample, we study the dependence of the galaxy stellar mass function (GSMF) on global environment. Results. We present a spectrophotometric characterisation of the G&C and their galaxies. The final sample contains 132 G&C, 22 111 field galaxies and 2225 G&C galaxies with r-band magnitude <20. Of the G&C, 95% have at least three spectroscopic members, and 70% at least ten. The shape of the GSMF seems not to depend on environment (field versus G&C) or X-ray luminosity (used as a proxy for the virial mass of the system). These results are confirmed by the study of the correlation between mean stellar mass of G&C members and L500,scalXXL. We release the spectrophotometric catalogue of galaxies with all the quantities computed in this work. Conclusions. As a first homogeneous census of galaxies within X-ray spectroscopically confirmed G&C at these redshifts, this sample will allow environmental studies of the evolution of galaxy properties.
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| 19. |
- Adami, C., et al.
(författare)
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The XXL Survey VIII. MUSE characterisation of intracluster light in a z similar to 0.53 cluster of galaxies
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 592:A7
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Forskningsöversikt (refereegranskat)abstract
- Aims. Within a cluster, gravitational effects can lead to the removal of stars from their parent galaxies and their subsequent dispersal into the intracluster medium. Gas hydrodynamical effects can additionally strip gas and dust from galaxies; both gas and stars contribute to intracluster light (ICL). The properties of the ICL can therefore help constrain the physical processes at work in clusters by serving as a fossil record of the interaction history. Methods. The present study is designed to characterise this ICL for the first time in a similar to 10(14) M-circle dot and z similar to 0.53 cluster of galaxies from imaging and spectroscopic points of view. By applying a wavelet-based method to CFHT Megacam and WIRCAM images, we detect significant quantities of diffuse light and are able to constrain their spectral energy distributions. These sources were then spectroscopically characterised with ESO Multi Unit Spectroscopic Explorer (MUSE) spectroscopic data. MUSE data were also used to compute redshifts of 24 cluster galaxies and search for cluster substructures. Results. An atypically large amount of ICL, equivalent in i' to the emission from two brightest cluster galaxies, has been detected in this cluster. Part of the detected diffuse light has a very weak optical stellar component and apparently consists mainly of gas emission, while other diffuse light sources are clearly dominated by old stars. Furthermore, emission lines were detected in several places of diffuse light. Our spectral analysis shows that this emission likely originates from low-excitation parameter gas. Globally, the stellar contribution to the ICL is about 2.3 x 10(9) yr old even though the ICL is not currently forming a large number of stars. On the other hand, the contribution of the gas emission to the ICL in the optical is much greater than the stellar contribution in some regions, but the gas density is likely too low to form stars. These observations favour ram pressure stripping, turbulent viscous stripping, or supernovae winds as the origin of the large amount of intracluster light. Since the cluster appears not to be in a major merging phase, we conclude that ram pressure stripping is the most plausible process that generates the observed ICL sources. Conclusions. This is one of the first times that we are able to spectroscopically study diffuse light in such a distant and massive cluster, and it demonstrates the potential of MUSE observations for such studies.
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| 21. |
- Arnegard, Matthew E., et al.
(författare)
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Genetics of ecological divergence during speciation
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7509, s. 307-311
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Tidskriftsartikel (refereegranskat)abstract
- Ecological differences often evolve early in speciation as divergent natural selection drives adaptation to distinct ecological niches, leading ultimately to reproductive isolation. Although this process is a major generator of biodiversity, its genetic basis is still poorly understood. Here we investigate the genetic architecture of niche differentiation in a sympatric species pair of threespine stickleback fish by mapping the environment-dependent effects of phenotypic traits on hybrid feeding and performance under semi-natural conditions. We show that multiple, unlinked loci act largely additively to determine position along the major niche axis separating these recently diverged species. We also find that functional mismatch between phenotypic traits reduces the growth of some stickleback hybrids beyond that expected from an intermediate phenotype, suggesting a role for epistasis between the underlying genes. This functional mismatch might lead to hybrid incompatibilities that are analogous to those underlying intrinsic reproductive isolation but depend on the ecological context.
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| 22. |
- Bergstrom, K, et al.
(författare)
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Core 1- and 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice.
- 2017
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Ingår i: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 10, s. 91-103
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Tidskriftsartikel (refereegranskat)abstract
- Core 1- and 3-derived mucin-type O-glycans are primary components of the mucus layer in the colon. Reduced mucus thickness and impaired O-glycosylation are observed in human ulcerative colitis. However, how both types of O-glycans maintain mucus barrier function in the colon is unclear. We found that C1galt1 expression, which synthesizes core 1 O-glycans, was detected throughout the colon, whereas C3GnT, which controls core 3 O-glycan formation, was most highly expressed in the proximal colon. Consistent with this, mice lacking intestinal core 1-derived O-glycans (IEC C1galt1(-/-)) developed spontaneous colitis primarily in the distal colon, whereas mice lacking both intestinal core 1- and 3-derived O-glycans (DKO) developed spontaneous colitis in both the distal and proximal colon. DKO mice showed an early onset and more severe colitis than IEC C1galt1(-/-) mice. Antibiotic treatment restored the mucus layer and attenuated colitis in DKO mice. Mucins from DKO mice were more susceptible to proteolysis than wild-type mucins. This study indicates that core 1- and 3-derived O-glycans collectively contribute to the mucus barrier by protecting it from bacterial protease degradation and suggests new therapeutic targets to promote mucus barrier function in colitis patients.Mucosal Immunology advance online publication, 4 May 2016; doi:10.1038/mi.2016.45.
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| 25. |
- Boon, Hanneke, 1981-, et al.
(författare)
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Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients
- 2008
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Ingår i: Diabetologia. - Heidelberg : Springer Berlin/Heidelberg. - 0012-186X .- 1432-0428. ; 51:10, s. 1893-1900
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The 5'-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients. METHODS: Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg(-1) min(-1)) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 +/- 2 years; BMI 28 +/- 1 kg/m(2)). RESULTS: Plasma glucose rate of appearance (R (a)) was reduced following AICAR administration, while plasma glucose rate of disappearance (R (d)) was similar in the AICAR and control test. Consequently, blood glucose disposal (R (d) expressed as a percentage of R (a)) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R (a) and R (d) were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001). CONCLUSIONS/INTERPRETATION: The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration. © 2008 The Author(s).
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| 26. |
- Fu, Jianxin, et al.
(författare)
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Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice.
- 2011
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Ingår i: The Journal of clinical investigation. - 1558-8238. ; 121:4, s. 1657-66
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Tidskriftsartikel (refereegranskat)abstract
- Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.
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| 27. |
- Greenbaum, Carla, et al.
(författare)
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Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes
- 2008
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Ingår i: Diabetes Care. - 0149-5992 .- 1935-5548. ; 31:10, s. 1966-1971
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS: In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. RESULTS: Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R(2) = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. CONCLUSIONS: The MMTT is preferred for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.
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| 28. |
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| 29. |
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| 30. |
- Iorizzo, L., et al.
(författare)
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Proposed cutoff for fetal scalp blood lactate in intrapartum fetal surveillance based on neonatal outcomes : a large prospective observational study
- 2022
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Ingår i: BJOG: An International Journal of Obstetrics and Gynaecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 129:4, s. 636-646
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Determination of lactate in fetal scalp blood (FBS) during labour has been recognised since the 1970s. The internationally accepted cutoff of >4.8 mmol/l indicating fetal acidosis is exclusive for the point-of-care device (POC) LactatePro™, which is no longer in production. The aim of this study was to establish a new cutoff for scalp lactate based on neonatal outcomes with the use of the StatstripLactate® /StatstripXpress® Lactate system, the only POC designed for hospital use.DESIGN: Observational study.SETTING: January 2016 to March 2020 labouring women with indication for FBS were prospectively included from seven Swedish and one Australian delivery unit.POPULATION: Inclusion criteria: singleton pregnancy, vertex presentation, ≥35+0 weeks of gestation.METHOD: Based on the optimal correlation between FBS lactate and cord pH/lactate, only cases with ≤25 minutes from FBS to delivery were included in the final calculations.MAIN OUTCOME MEASURES: Metabolic acidosis in cord blood defined as pH <7.05 plus BDecf >10 mmol/l and/or lactate >10 mmol/l.RESULTS: A total of 3334 women were enrolled of whom 799 were delivered within 25 minutes. The areas under the receiver operating characteristics curves (AUC) and corresponding optimal cutoff values were as follows; metabolic acidosis AUC 0.87 (95% CI 0.77-0.97), cutoff 5.7 mmol/l; pH <7.0 AUC 0.83 (95% CI 0.68-0.97), cutoff 4.6 mmol/l; pH <7.05 plus BDecf ≥12 mmol/l AUC 0.97 (95% CI 0.92-1), cutoff 5.8 mmol/l; Apgar score <7 at 5 minutes AUC 0.74 (95% CI 0.63-0.86), cutoff 5.2 mmol/l; and pH <7.10 plus composite neonatal outcome AUC 0.76 (95% CI 0.67-0.85), cutoff 4.8 mmol/l.CONCLUSION: A scalp lactate level <5.2 mmol/l using the StatstripLactate® /StatstripXpress® system will safely rule out fetal metabolic acidosis.TWEETABLE ABSTRACT: Scalp blood lactate <5.2 mmol/l using the StatstripLactate® /StatstripXpress system has an excellent ability to rule out fetal acidosis.
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| 31. |
- Iorizzo, L., et al.
(författare)
-
Proposed cutoff for fetal scalp blood lactate in intrapartum fetal surveillance based on neonatal outcomes: a large prospective observational study
- 2022
-
Ingår i: BJOG: An International Journal of Obstetrics and Gynaecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 129:4, s. 636-646
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Determination of lactate in fetal scalp blood (FBS) during labour has been recognised since the 1970s. The internationally accepted cutoff of >4.8mmol/l indicating fetal acidosis is exclusive for the point-of-care device (POC) LactatePro™, which is no longer in production. The aim of this study was to establish a new cutoff for scalp lactate based on neonatal outcomes with the use of the StatstripLactate®/StatstripXpress® Lactate system, the only POC designed for hospital use. Design: Observational study. Setting: January 2016 to March 2020 labouring women with indication for FBS were prospectively included from seven Swedish and one Australian delivery unit. Population: Inclusion criteria: singleton pregnancy, vertex presentation, ≥35+0weeks of gestation. Method: Based on the optimal correlation between FBS lactate and cord pH/lactate, only cases with ≤25minutes from FBS to delivery were included in the final calculations. Main outcome measures: Metabolic acidosis in cord blood defined as pH <7.05 plus BDecf >10mmol/l and/or lactate >10mmol/l. Results: A total of 3334 women were enrolled of whom 799 were delivered within 25minutes. The areas under the receiver operating characteristics curves (AUC) and corresponding optimal cutoff values were as follows; metabolic acidosis AUC 0.87 (95% CI 0.77–0.97), cutoff 5.7mmol/l; pH <7.0 AUC 0.83 (95% CI 0.68–0.97), cutoff 4.6mmol/l; pH <7.05 plus BDecf ≥12mmol/l AUC 0.97 (95% CI 0.92–1), cutoff 5.8mmol/l; Apgar score <7 at 5minutes AUC 0.74 (95% CI 0.63–0.86), cutoff 5.2mmol/l; and pH <7.10 plus composite neonatal outcome AUC 0.76 (95% CI 0.67–0.85), cutoff 4.8mmol/l. Conclusion: A scalp lactate level <5.2mmol/l using the StatstripLactate®/StatstripXpress® system will safely rule out fetal metabolic acidosis. Tweetable abstract: Scalp blood lactate <5.2mmol/l using the StatstripLactate®/StatstripXpress system has an excellent ability to rule out fetal acidosis.
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| 32. |
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| 33. |
- Jackson, Sarah S., et al.
(författare)
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Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project
- 2019
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:15, s. 3973-3982
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Tidskriftsartikel (refereegranskat)abstract
- Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m(2) increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. Significance: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
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| 34. |
- McGee, Emma E., et al.
(författare)
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Smoking, Alcohol, and Biliary Tract Cancer Risk : A Pooling Project of 26 Prospective Studies
- 2019
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Ingår i: Journal of the National Cancer Institute. - : OXFORD UNIV PRESS INC. - 0027-8874 .- 1460-2105. ; 111:12, s. 1263-1278
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Forskningsöversikt (refereegranskat)abstract
- Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; P-trend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
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| 35. |
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| 36. |
- Perez, LG, et al.
(författare)
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TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 2608-
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Tidskriftsartikel (refereegranskat)abstract
- IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-β1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-β signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-β1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-β signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-β signaling. We show that TGF-β, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.
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| 37. |
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| 38. |
- Ring, Lena, et al.
(författare)
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Individual quality of life : can it be accounted for by psychological or subjective well-being?
- 2007
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Ingår i: Social Indicators Research. - : Springer Science and Business Media LLC. - 0303-8300 .- 1573-0921. ; 82:3, s. 443-461
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Tidskriftsartikel (refereegranskat)abstract
- There is ongoing discussion in the scientific literature about the need for a more theoretical foundation to underpin quality of life (QoL) measurement. This paper applied Keyes et al.'s [J. Pers. Soc. Psychol. 82 (2002) 1007] model of well-being as a framework to assess whether respondents (n = 136 students) focus on elements of subjective well-being (SWB), such as satisfaction and happiness, or on elements of psychological well-being (PWB), such as meaning and personal growth, when making individual QoL (IQoL) judgments using the Schedue of the Evaluation of Individual Quality of Life (SEIQoL). The Keyes et al.'s model was confirmed and explained 41% of the variance in SEIQoL scores. Both SWB and PWB were correlated with the SEIQoL Index Score and SWB was found to be an important mediating variable in the relationship between PWB and SEIQoL. When analyzing different well-being combinations, respondents with high SWB/high PWB had significantly higher SEIQoL scores than did those with low SWB/low PWB. Respondents with high PWB/high SWB had higher SEIQoL scores than did those with high PWB/low SWB. Longitudinal studies in different patient groups are needed to explore the dynamic relationship between IQoL and well-being. Further investigation of the relationship between PWB and SWB with other instruments purporting to measure QoL would contribute to an enhanced understanding of the underlying nature of QoL.
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| 39. |
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| 40. |
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| 41. |
- Smolčić, Vernesa, et al.
(författare)
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The XXL Survey: XI. ATCA 2.1 GHz continuum observations?
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 592:Art. no A10
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Forskningsöversikt (refereegranskat)abstract
- We present 2.1 GHz imaging with the Australia Telescope Compact Array (ATCA) of a 6.5 deg2 region within the XXM-Newton XXL South field using a band of 1.1-3.1 GHz.We achieve an angular resolution of 4:7″ × 4:2″ in the final radio continuum map with a median rms noise level of 50 μJy/beam. We identify 1389 radio sources in the field with peak S=N ≥ 5 and present the catalogue of observed parameters. We find that 305 sources are resolved, of which 77 consist of multiple radio components. These number counts are in agreement with those found for the COSMOS-VLA 1.4 GHz survey. We derive spectral indices by a comparison with the Sydney University Molongolo Sky Survey (SUMSS) 843MHz data. We find an average spectral index of -0:78 and a scatter of 0.28, in line with expectations. This pilot survey was conducted in preparation for a larger ATCA program to observe the full 25 deg2 southern XXL field. When complete, the survey will provide a unique resource of sensitive, wide-field radio continuum imaging with complementary X-ray data in the field. This will facilitate studies of the physical mechanisms of radio-loud and radio-quiet AGNs and galaxy clusters, and the role they play in galaxy evolution. The source catalogue is publicly available online via the XXL Master Catalogue browser and the Centre de Données astronomiques de Strasbourg (CDS).
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| 42. |
- Staubach, F., et al.
(författare)
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Expression of the blood-group-related glycosyltransferase B4galnt2 influences the intestinal microbiota in mice
- 2012
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Ingår i: Isme Journal. - : Springer Science and Business Media LLC. - 1751-7362 .- 1751-7370. ; 6:7, s. 1345-1355
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Tidskriftsartikel (refereegranskat)abstract
- Glycans on mucosal surfaces have an important role in host-microbe interactions. The locus encoding the blood-group-related glycosyltransferase beta-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) is subject to strong selective forces in natural house-mouse populations that contain a common allelic variant that confers loss of B4galnt2 gene expression in the gastrointestinal (GI) tract. We reasoned that altered glycan-dependent intestinal host-microbe interactions may underlie these signatures of selection. To determine whether B4galnt2 influences the intestinal microbial ecology, we profiled the microbiota of wild-type and B4galnt2-deficient siblings throughout the GI tract using 16S rRNA gene pyrosequencing. This revealed both distinct communities at different anatomic sites and significant changes in composition with respect to genotype, indicating a previously unappreciated role of B4galnt2 in host-microbial homeostasis. Among the numerous B4galnt2-dependent differences identified in the abundance of specific bacterial taxa, we unexpectedly detected a difference in the pathogenic genus, Helicobacter, suggesting Helicobacter spp. also interact with B4galnt2 glycans. In contrast to other glycosyltransferases, we found that the host intestinal B4galnt2 expression is not dependent on presence of the microbiota. Given the long-term maintenance of alleles influencing B4galnt2 expression by natural selection and the GI phenotypes presented here, we suggest that variation in B4galnt2 GI expression may alter susceptibility to GI diseases such as infectious gastroenteritis. The ISME Journal (2012) 6, 1345-1355; doi:10.1038/ismej.2011.204; published online 26 January 2012
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| 43. |
- Wijk, Lena, 1971-, et al.
(författare)
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International validation of Enhanced Recovery After Surgery Society guidelines on enhanced recovery for gynecologic surgery
- 2019
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Ingår i: American Journal of Obstetrics and Gynecology. - : Harcourt International Publishers. - 0002-9378 .- 1097-6868. ; 221:3, s. 237.e1-237.e11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Enhanced Recovery After Surgery (ERAS) Society publishes guidelines on perioperative care, but these guidelines should be validated prospectively.OBJECTIVES: To evaluate the association between compliance to ERAS Gynecologic/Oncology guideline elements and postoperative outcomes in an international cohort.STUDY DESIGN: The study was comprised of 2,101 patients undergoing elective gynecologic/oncology surgery between January 2011 - November 2017 in 10 hospitals across Canada, the United States and Europe. Patient demographics, surgical/anesthesia details and ERAS protocol compliance elements (pre-, intra- and post-operative phases) were entered into the ERAS Interactive Audit System. Surgical complexity was stratified according to the Aletti scoring system (low versus medium/high). The following covariates were accounted for in the analysis: age, Body Mass Index, smoking status, presence of diabetes, American Society of Anesthesiologists class, International Federation of Gynecology and Obstetrics stage, preoperative chemotherapy, radiotherapy, operating time, surgical approach (open versus minimally invasive), intra-operative blood loss, hospital and ERAS implementation status. The primary end-points were primary hospital length of stay and complications. Negative binomial regression was used to model length of stay, and logistic regression to model complications, as a function of compliance score and covariates.RESULTS: Patient demographics: median age 56 years, 35.5% obese,15% smokers, 26.7% American Society of Anesthesiologists Class III-IV. Final diagnosis was malignant in 49% of patients. Laparotomy was used in 75.9% of cases, and the remainder minimally invasive surgery. The majority of cases (86%) were of low complexity (Aletti score ≤ 3). In patients with ovarian cancer, 69.5% had a medium/high complexity surgery (Aletti score 4-11). Median length of stay was 2 days in the low- and 5 days in the medium/high-complexity group. Every unit increase in ERAS guideline score was associated with 8% (IRR: 0.92 (95% CI: 0.90 - 0.95; p<0.001)) decrease in days in hospital among low-complexity, and 12% (IRR: 0.88 (95% CI: 0.82 - 0.93; p<0.001) decrease among patients with medium/high complexity scores. For every unit increase in ERAS guideline score, the odds of total complications were estimated to be 12% lower (p<0.05) among low-complexity patients.CONCLUSION: Audit of surgical practices demonstrates that improved compliance with ERAS Gynecologic/Oncology guidelines is associated with an improvement in clinical outcomes, including length of stay, highlighting the importance of ERAS implementation.
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| 44. |
- Winbanks, Catherine E., et al.
(författare)
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The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass
- 2013
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 203:2, s. 345-357
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Tidskriftsartikel (refereegranskat)abstract
- Although the canonical transforming growth factor. signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin-dependent process, whereas increased BMP-Smad1/5 activity protected muscles from denervation- induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.
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