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  • 1
    Online Resource
    Online Resource
    Individualizing Follow-Up Strategies in High-Grade Soft Tissue Sarcoma with Flexible Parametric Competing Risk Regression Models
    MDPI AG ; 2019
    In:  Cancers Vol. 12, No. 1 ( 2019-12-21), p. 47-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 1 ( 2019-12-21), p. 47-
    Abstract: Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local recurrence (LR) and distant metastasis (DM), aiming at providing guidance on how to individually follow-up patients. Three thousand sixteen patients (1931 test, 1085 validation cohort) with high-grade eSTS were included in this retrospective, multicenter study. Histology (9 categories), grading (time-varying covariate), gender, age, tumor size, margins, (neo)adjuvant radiotherapy (RTX), and neoadjuvant chemotherapy (CTX) were used in the FPCRRMs and performance tested with Harrell-C-index. Median follow-up was 50 months (interquartile range: 23.3–95 months). Two hundred forty-two (12.5%) and 603 (31.2%) of test cohort patients developed LR and DM. Factors significantly associated with LR were gender, size, histology, neo- and adjuvant RTX, and margins. Parameters associated with DM were margins, grading, gender, size, histology, and neoadjuvant RTX. C-statistics was computed for internal (C-index for LR: 0.705, for DM: 0.723) and external cohort (C-index for LR: 0.683, for DM: 0.772). Depending on clinical, pathological, and patient-related parameters, LR- and DM-risks vary. With the present model, implemented in the updated Personalised Sarcoma Care (PERSARC)-app, more individualized prediction of LR/DM-risks is made possible.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12010047
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study
    MDPI AG ; 2020
    In:  Nutrients Vol. 12, No. 2 ( 2020-02-23), p. 580-
    Details
    In: Nutrients, MDPI AG, Vol. 12, No. 2 ( 2020-02-23), p. 580-
    Abstract: Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60–75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu12020580
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2518386-2
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  • 3
    Online Resource
    Online Resource
    Nutrients and Saltwater Exchange as Drivers of Environmental Change in a Danish Brackish Coastal Lake over the Past 100 Years
    MDPI AG ; 2023
    In:  Water Vol. 15, No. 6 ( 2023-03-14), p. 1116-
    Details
    In: Water, MDPI AG, Vol. 15, No. 6 ( 2023-03-14), p. 1116-
    Abstract: Many northwest European lake systems are suffering from the effects of eutrophication due to continued loading and/or poor, ineffective management strategies. Coastal brackish lakes are particularly difficult to manage due to complex nitrogen, phosphorus, and salinity dynamics that may exert varying influence on lake biological communities, but long-term data on how these important and often biodiverse systems respond to change are rare. In this study, palaeolimnological data (including sedimentary parameters, diatoms, and plant macrofossils) and environmental monitoring data (for the last ~40 years) have been used to assess environmental change over the last 100 years in Kilen, a brackish lake in northwest Jutland, Denmark. Kilen has been regularly monitored for salinity (since 1972), TP (from 1975), TN (from 1976), and since 1989 for biological data (phytoplankton, zooplankton, and macrophytes), which allows a robust comparison of contemporary and paleolimnological data at high temporal resolution. The palaeolimnological data indicate that the lake has been nutrient rich for the last 100 years, with eutrophication peaking from the mid-1980s to the late 1990s. Reduced nutrient concentrations have occurred since the late 1990s, though this is not reflected in the sediment core diatom assemblage, highlighting that caution must be taken when using quantitative data from biological transfer functions in paleolimnology. Lake recovery over the last 20 years has been driven by a reduction in TN and TP loading from the catchment and shows improvements in the lake water clarity and, recently, in macrophyte cover. Reduced salinity after 2004 has also changed the composition of the dominant macrophyte community within the lake. The low N:P ratio indicates that in summer, the lake is predominately N-limited, likely explaining why previous management, mainly focusing on TP reduction measures, had a modest effect on the water quality of the lake. Despite a slight recovery, the lake is still nutrient-rich, and future management of this system must continue to reduce the nutrient loads of both TN and TP to ensure sustained recovery. This study provides an exceptional opportunity to validate the palaeolimnological record with monitoring data and demonstrates the power of using this combined approach in understanding environmental change in these key aquatic ecosystems.
    Type of Medium: Online Resource
    ISSN: 2073-4441
    URL: Article
    DOI: 10.3390/w15061116
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2521238-2
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  • 4
    Online Resource
    Online Resource
    PKM2 Determines Myofiber Hypertrophy In Vitro and Increases in Response to Resistance Exercise in Human Skeletal Muscle
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 19 ( 2020-09-25), p. 7062-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 19 ( 2020-09-25), p. 7062-
    Abstract: Nearly 100 years ago, Otto Warburg investigated the metabolism of growing tissues and discovered that tumors reprogram their metabolism. It is poorly understood whether and how hypertrophying muscle, another growing tissue, reprograms its metabolism too. Here, we studied pyruvate kinase muscle (PKM), which can be spliced into two isoforms (PKM1, PKM2). This is of interest, because PKM2 redirects glycolytic flux towards biosynthetic pathways, which might contribute to muscle hypertrophy too. We first investigated whether resistance exercise changes PKM isoform expression in growing human skeletal muscle and found that PKM2 abundance increases after six weeks of resistance training, whereas PKM1 decreases. Second, we determined that Pkm2 expression is higher in fast compared to slow fiber types in rat skeletal muscle. Third, by inducing hypertrophy in differentiated C2C12 cells and by selectively silencing Pkm1 and/or Pkm2 with siRNA, we found that PKM2 limits myotube growth. We conclude that PKM2 contributes to hypertrophy in C2C12 myotubes and indicates a changed metabolic environment within hypertrophying human skeletal muscle fibers. PKM2 is preferentially expressed in fast muscle fibers and may partly contribute to the increased potential for hypertrophy in fast fibers.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21197062
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    The Frequency of Primary Healthcare Contacts Preceding the Diagnosis of Lower-Extremity Arterial Disease: Do Women Consult General Practice Differently?
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 13 ( 2022-06-24), p. 3666-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 13 ( 2022-06-24), p. 3666-
    Abstract: Background. Women with lower-extremity arterial disease (LEAD) are often underdiagnosed, present themselves with more advanced disease at diagnosis, and fare worse than men. Objective. To investigate to what extent potential gender differences exist in the frequency and reasons for general practitioner (GP) consultation six months prior to the diagnosis of LEAD, as potential indicators of diagnostic delay. Methods. Individuals older than 18 years diagnosed with LEAD, sampled from the Julius General Practitioner’s Network (JGPN), were included and compared with a reference population, matched (1:2.6 ratio) in terms of age, sex, and general practice. We applied a zero-inflated negative binomial (ZINB) regression model. Results. The study population comprised 4044 patients with LEAD (43.5% women) and 10,486 subjects in the reference population (46.3% women). In the LEAD cohort, the number of GP contacts was 2.70 (95% CI: 2.42, 3.02) in women and 2.54 (2.29, 2.82) in men. In the reference cohort, 1.77 (95% CI: 1.62, 1.94) in women and 1.63 (95% CI: 1.50, 1.78) in men. In the LEAD cohort, 21.9% of GP contacts occurred one month prior to diagnosis. In both cohorts and both sexes, the most common cause of consultation during the last month before the index date was cardiovascular problems. Conclusions. Six months preceding the initial diagnosis of LEAD, patients visit the GP more often than a similar population without LEAD, regardless of gender. Reported gender differences in the severity of LEAD at diagnosis do not seem to be explained by a delay in presentation to the GP.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11133666
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 6
    Online Resource
    Online Resource
    Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 16 ( 2021-08-19), p. 8948-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 16 ( 2021-08-19), p. 8948-
    Abstract: Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22168948
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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