| 1. |
- Mishra, A, et al.
(author)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Journal article (peer-reviewed)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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| 5. |
- Popat, S, et al.
(author)
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Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease.
- 2002
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In: Annals of human genetics. - 0003-4800 .- 1469-1809. ; 66:Pt 2, s. 125-37
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Journal article (peer-reviewed)abstract
- Susceptibility to coeliac disease involves HLA and non-HLA-linked genes. The CTLA4/CD28 gene region encodes immune regulatory T-cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta-analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non-parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0.004 and 0.039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0.0001 and 0.0014 at D2S2214, respectively, and 0.0008 and 0.0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.
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| 6. |
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| 7. |
- Frisk, U., et al.
(author)
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The Odin satellite - I. Radiometer design and test
- 2003
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In: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 402:3, s. L27-L34
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Journal article (peer-reviewed)abstract
- The Sub-millimetre and Millimetre Radiometer (SMR) is the main instrument on the Swedish, Canadian, Finnish and French spacecraft Odin. It consists of a 1.1 metre diameter telescope with four tuneable heterodyne receivers covering the ranges 486-504 GHz and 541-581 GHz, and one fixed at 118.75 GHz together with backends that provide spectral resolution from 150 kHz to 1 MHz. This Letter describes the Odin radiometer, its operation and performance with the data processing and calibration described in Paper II.
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| 8. |
- Jögi, Annika, et al.
(author)
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Patched 2, located in 1p32-34, is not mutated in high stage neuroblastoma tumors
- 2000
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In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 16:5, s. 943-949
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Journal article (peer-reviewed)abstract
- Neuroblastoma is a childhood malignancy originating from cells of the sympathetic nervous system, exhibiting a marked diversity in outcome, with spontaneous regression at one end of the spectrum and severe disease and death at the other end. Features associated with frequent recurrence, a poor prognosis, and high tumor stage are loss of heterozygosity in the distal region of chromosome 1p and amplification of the N-myc gene. Patched 2 is a novel homologue to the tumor suppressor gene Patched 1, and has been mapped to 1p32-34, a part of chromosome 1 frequently deleted in high stage neuroblastoma tumors. RT-PCR analysis of 9 neuroblastoma cell lines showed expression of both Patched 1 and 2. We analyzed 14, mainly high stage, neuroblastoma tumors for mutations in the Patched 2 gene with denaturing HPLC using the Wave DNA fragment analysis system. In four tumor samples variations were detected within the coding sequence, and two of them gave rise to amino-acid substitutions. These variations were, however, also detected in normal DNA from the respective patients. We conclude that Patched 2 is expressed, but not frequently mutated, in high stage neuroblastomas and is therefore not likely to be involved in the genesis of this tumor.
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| 13. |
- Wu, X. N., et al.
(author)
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Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy
- 2019
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In: Prostate. - : Wiley. - 0270-4137. ; 79:10, s. 1079-1089
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Journal article (peer-reviewed)abstract
- Background Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance. Methods EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and gamma H2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition. Results While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased gamma H2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls. Conclusions Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance.
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| 14. |
- Bonagas, Nadilly, et al.
(author)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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In: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Journal article (peer-reviewed)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 15. |
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| 16. |
- Carlsson, Sigrid, 1982, et al.
(author)
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Long-Term Outcomes of Active Surveillance for Prostate Cancer: The Memorial Sloan Kettering Cancer Center Experience
- 2020
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In: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 203:6, s. 1122-1127
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Journal article (peer-reviewed)abstract
- Purpose: We report oncologic outcomes for men with Grade Group 1 prostate cancer managed with active surveillance at a tertiary cancer center. Materials and Methods: A total of 2,907 patients were managed with active surveillance between 2000 and 2017, of whom 2,664 had Grade Group 1 disease. Patients were recommended confirmatory biopsy to verify eligibility and were followed semiannually with prostate specific antigen, digital rectal examination and review of symptoms. Magnetic resonance imaging was increasingly used in recent years. Biopsy was repeated every 2 to 3 years or after a sustained prostate specific antigen increase or changes in magnetic resonance imaging/digital rectal examination. The Kaplan-Meier method was used to estimate probabilities of treatment, progression and development of metastasis. Results: Median patient age at diagnosis was 62 years. For men with Grade Group 1 prostate cancer the treatment-free probability at 5, 10 and 15 years was 76% (95% CI 74-78), 64% (95% CI 61-68) and 58% (95% CI 51-64), respectively. At 5, 10 and 15 years there were 1,146, 220 and 25 men at risk for metastasis, respectively. Median followup for those without metastasis was 4.3 years (95% CI 2.3-6.9). Distant metastasis developed in 5 men. Upon case note review only 2 of these men were deemed to have disease that could have been cured on immediate treatment. The risk of distant metastasis was 0.6% (95% CI 0.2-2.0) at 10 years. Conclusions: Active surveillance is a safe strategy over longer followup for appropriately selected patients with Grade Group 1 disease following a well-defined monitoring plan.
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| 17. |
- Carlsson, Sigrid, 1982, et al.
(author)
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Risk of Metastasis in Men with Grade Group 2 Prostate Cancer Managed with Active Surveillance at a Tertiary Cancer Center
- 2020
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In: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 203:6, s. 1117-1121
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Journal article (peer-reviewed)abstract
- Purpose: We studied the risk of metastatic prostate cancer development in men with Grade Group 2 disease managed with active surveillance at Memorial Sloan Kettering Cancer Center. Materials and Methods: A total of 219 men with Grade Group 2 prostate cancer had disease managed with active surveillance between 2000 and 2017. Biopsy was performed every 2 to 3 years, or upon changes in magnetic resonance imaging, prostate specific antigen level or digital rectal examination. The primary outcome was development of distant metastasis. The Kaplan-Meier method was used to estimate treatment-free survival. Results: Median age at diagnosis was 67 years (IQR 61-72), median prostate specific antigen was 5 ng/ml (IQR 4-7) and most patients (69%) had nonpalpable disease. During followup 64 men received treatment, including radical prostatectomy in 36 (56%), radiotherapy in 20 (31%), hormone therapy in 3 (5%) and focal therapy in 5 (8%). Of the 36 patients who underwent radical prostatectomy 32 (89%) had Grade Group 2 disease on pathology and 4 (11%) had Grade Group 3 disease. Treatment-free survival was 61% (95% CI 52-70) at 5 years and 49% (95% CI 37-60) at 10 years. Three men experienced biochemical recurrence, no men had distant metastasis and no men died of prostate cancer during the followup. Median followup was 3.1 years (IQR 1.9-4.9). Conclusions: Active surveillance appears to be a safe initial management strategy in the short term for carefully selected and closely monitored men with Grade Group 2 prostate cancer treated at a tertiary cancer center. Definitive conclusions await further followup.
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| 23. |
- Engelmark, O., et al.
(author)
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Ecological effects and management aspects of an exotic tree species : the case of lodgepole pine in Sweden
- 2001
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In: Forest Ecology and Management. - 0378-1127 .- 1872-7042. ; 141:02-jan, s. 3-13
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Journal article (peer-reviewed)abstract
- The North American tree Pinus contorta var, latifolia was experimentally introduced in Sweden already in the 1920s, and has been used in Swedish forestry on a large scale since the 1970s. These plantations now cover 565,000 ha, mainly in the northern area. In this paper we summarize and discuss existing ecological knowledge of this species introduction. With regard to longterm sustainability we suggest management means to minimize harmful effects of the introduction on ecosystems. These include aspects of self dispersal, pests, ecosystem and landscape structures, and also ecological processes and biodiversity. We also focus on observed and possible interactions in the ecosystems. As Pinus contorta seeds are disseminated and trees regenerated outside initial plantations, this may have future bearings on biodiversity. We suggest a strategy which takes account of the uncertainty in predicting future ecological effects. The strategy includes areal restrictions and zones without Pinus contorta, but also to set up a monitoring program. Observations of adverse effects from the plantations would then give the possibility to adjust P. contorta management.
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| 24. |
- Ericsson, Stefan, et al.
(author)
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Towards automatic detection of local bearing defects in rotating machines
- 2005
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In: Mechanical systems and signal processing. - : Elsevier BV. - 0888-3270 .- 1096-1216. ; 19:3, s. 509-535
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Journal article (peer-reviewed)abstract
- In this paper we derive and compare several different vibration analysis techniques for automatic detection of local defects in bearings. Based on a signal model and a discussion on to what extent a good bearing monitoring method should trust it, we present several analysis tools for bearing condition monitoring and conclude that wavelets are especially well suited for this task. Then we describe a large-scale evaluation of several different automatic bearing monitoring methods using 103 laboratory and industrial environment test signals for which the true condition of the bearing is known from visual inspection. We describe the four best performing methods in detail (two wavelet-based, and two based on envelope and periodisation techniques). In our basic implementation, without using historical data or adapting the methods to (roughly) known machine or signal parameters, the four best methods had 9-13% error rate and are all good candidates for further fine-tuning and optimisation. Especially for the wavelet-based methods, there are several potentially performance improving additions, which we finally summarise into a guiding list of suggestion.
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| 29. |
- Hartvig, P, et al.
(author)
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Interaction of a muscarinic cholinergic agonist on acetylcholine and dopamine receptors in the monkey brain studied with positron emission tomography
- 2002
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 13:4, s. 199-204
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Journal article (peer-reviewed)abstract
- The effects on the binding to cholinergic and dopaminergic receptors in the brain during continuous intravenous infusion of the muscarinic cholinergic receptor agonist milameline (CI-979) were studied in the rhesus monkey by means of positron emission tomography. Binding to milameline cholinergic receptors was quantified using the muscarinic receptor antagonist [<sup>11</sup>C]-N-methyl-4-piperidinylbenzilate ([<sup>11</sup>C]NMP), and the effects on nicotine receptor binding were measured with <i>(S)</i>-[<sup>11</sup>C-methyl]nicotine. Changes in the binding of the D<sub>2</sub> dopamine receptor antagonist [<sup>11</sup>C]raclopride were measured as well. The binding of [<sup>11</sup>C]NMP increased in most brain regions with the infusion of increasing doses of milameline from 0.5 to 10 µg/kg/h. <i>(S)</i>-[<sup>11</sup>C-methyl]nicotine binding was unchanged or increased somewhat. Binding of [<sup>11</sup>C]raclopride to the D<sub>2</sub> dopaminergic receptors in the striatum of the brain increased by 10 ± 4% following 2 µg/kg/h of milameline. The results suggest a possible action of milameline both on presynaptic muscarinic receptor subtypes as well as dopamine levels dependent on the receptor reserve of the muscarinic receptor subtypes.
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| 34. |
- Kiessling, R, et al.
(author)
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Tumor-induced immune dysfunction
- 1999
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In: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 48:7, s. 353-362
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Journal article (peer-reviewed)
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| 39. |
- Kuisma, H, et al.
(author)
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Parity associates with chromosomal damage in uterine leiomyomas
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5448-
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Journal article (peer-reviewed)abstract
- Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.
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| 40. |
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| 41. |
- Lonergan, Peter E., et al.
(author)
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Prospective validation of microseminoprotein-β added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort
- 2021
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In: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 128:2, s. 218-224
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Journal article (peer-reviewed)abstract
- Objectives: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-β (MSP) adds predictive value. Patients and Methods: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. Results: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014–0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. Conclusion: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.
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| 42. |
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| 45. |
- Loving, R, et al.
(author)
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Maturation cleavage of the murine leukemia virus Env precursor separates the transmembrane subunits to prime it for receptor triggering
- 2012
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 109:20, s. 7735-7740
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Journal article (peer-reviewed)abstract
- The Env protein of murine leukemia virus matures by two cleavage events. First, cellular furin separates the receptor binding surface (SU) subunit from the fusion-active transmembrane (TM) subunit and then, in the newly assembled particle, the viral protease removes a 16-residue peptide, the R-peptide from the endodomain of the TM. Both cleavage events are required to prime the Env for receptor-triggered activation. Cryoelectron microscopy (cryo-EM) analyses have shown that the mature Env forms an open cage-like structure composed of three SU–TM complexes, where the TM subunits formed separated Env legs. Here we have studied the structure of the R-peptide precursor Env by cryo-EM. TM cleavage in Moloney murine leukemia virus was inhibited by amprenavir, and the Envs were solubilized in Triton X-100 and isolated by sedimentation in a sucrose gradient. We found that the legs of the R-peptide Env were held together by trimeric interactions at the very bottom of the Env. This suggested that the R-peptide ties the TM legs together and that this prevents the activation of the TM for fusion. The model was supported by further cryo-EM studies using an R-peptide Env mutant that was fusion-competent despite an uncleaved R-peptide. The Env legs of this mutant were found to be separated, like in the mature Env. This shows that it is the TM leg separation, normally caused by R-peptide cleavage, that primes the Env for receptor triggering.
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