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| 7. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 17. |
- Bastard, P, et al.
(författare)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1
- 2021
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 18. |
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| 19. |
- Ny, A, et al.
(författare)
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Ovulation in plasminogen-deficient mice.
- 1999
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Ingår i: Endocrinology. - 0013-7227 .- 1945-7170. ; 140:11, s. 5030-5
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Tidskriftsartikel (refereegranskat)abstract
- Many different studies suggest that plasmin generated from plasminogen plays a crucial role in the degradation of the follicular wall at the time of ovulation. We have assessed the physiological relevance of plasmin on ovulation by studying plasminogen-deficient mice. Ovulation efficiency (mean number of ova released per mouse) was determined both in a standardized ovulation model in which 25-day-old immature mice were injected with finite amounts of gonadotropins to induce ovulation and during physiological ovulation using adult normally cycling mice. Our results revealed that the temporal onset of follicular wall rupture (first ova observed in bursa or oviduct) was not delayed in plasminogen-deficient mice during gonadotropin-induced ovulation. However, there was a trend toward slightly reduced ovulation efficiency in the plasminogen-deficient mice. This reduction was only 13% and not statistically significant (P = 0.084) and may be connected to a delayed maturation of these mice manifested in reduced body and ovary weights. During physiological ovulation adult plasminogen-deficient mice had normal ovulation efficiency compared with plasminogen wild-type mice. Taken together our results indicate that under the conditions used in this study plasmin is not required for efficient follicular rupture or for activation of other proteases involved in this process. Alternatively, the role of plasmin may be effectively compensated for by other mechanisms in the absence of plasmin.
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| 20. |
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| 21. |
- Bicsak, T A, et al.
(författare)
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Tissue-type plasminogen activator in rat oocytes : expression during the periovulatory period, after fertilization, and during follicular atresia.
- 1989
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Ingår i: Endocrinology. - 0013-7227 .- 1945-7170. ; 124:1, s. 187-94
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of tissue-type plasminogen activator (tPA) in rat oocytes during the periovulatory period, in early embryos, and in oocytes during induced follicular atresia was studied using a quantitative chromogenic substrate assay. Oocytes and early embryos were collected from three ovulation models: 1) intact immature female rats treated with PMSG, followed by hCG 48 h later; 2) hypophysectomized immature rats treated with PMSG, followed by a GnRH agonist (GnRHa) 56 h later; and 3) adult cyclic rats on the mornings of proestrus and estrus and up to 5 days after fertilization. In addition, follicular atresia was induced by either withdrawal of diethylstilbestrol (DES) for 2 days or injection of GnRHa for 2 days in hypophysectomized DES-implanted immature rats. Treatment with PMSG alone did not increase oocyte tPA content (5-20 microIU/oocyte) in either immature rat model, but treatment with either hCG or GnRHa induced meiotic maturation and ovulation and increased tPA activity to 80 and 140 microIU/oocyte 24 h after hCG and GnRHa treatment, respectively. Northern blot analysis of total RNA extracted from oocytes of PMSG-treated rats indicated the presence of a specific tPA message at 22S. tPA levels were low in preovulatory oocytes obtained on proestrus morning and increased in ovulated oocytes on estrus morning. After fertilization, tPA levels remained high in the embryos on days 1-4 of pregnancy, but dropped dramatically on day 5. Furthermore, oocytes from atretic follicles of hypophysectomized DES-implanted rats after either DES withdrawal or GnRHa treatment contained elevated levels of tPA, coincident with germinal vesicle breakdown (GVBD). Immunohistochemical staining revealed tPA antigen only in those oocytes that had undergone apparent meiotic maturation, as confirmed by GVBD. Thus, oocytes contain tPA mRNA and synthesize the active protease under a variety of stimuli which result in GVBD. The observed periovulatory increase in oocyte tPA activity, its maintenance until day 5 of pregnancy, and expression of tPA in nonovulatory oocytes of atretic follicles suggest diverse functions for the oocyte and embryo tPA.
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| 22. |
- Lemoine, J E, et al.
(författare)
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Factor structure and psychometric properties of the Body Appreciation Scale-2 among adolescents and young adults in Danish, Portuguese, and Swedish
- 2018
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Ingår i: Body image. - 1740-1445 .- 1873-6807. ; 26, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, the study of body image shifted from focusing on the negative aspects to a more extensive view of body image. The present study seeks to validate a measure of positive body image, the Body Appreciation Scale-2 (BAS-2; Tylka & Wood-Barcalow, 2015a) in Denmark, Portugal, and Sweden. Participants (N = 1012) were adolescents and young adults aged from 12 to 19. Confirmatory factor analyses confirmed the one-dimensional factor structure of the scale. Multi-group confirmatory factor analyses indicated that the scale was invariant across sex and country. Further results showed that BAS-2 was positively correlated with self-esteem, psychological well-being, and intuitive eating. It was negatively correlated with BMI among boys and girls in Portugal but not in Denmark and Sweden. Additionally, boys had higher body appreciation than girls. Results indicated that the BAS-2 has good psychometric properties in the three languages.
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| 23. |
- Mikus, P, et al.
(författare)
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Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms.
- 1993
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Ingår i: European Journal of Biochemistry. - 0014-2956 .- 1432-1033. ; 218:3, s. 1071-82
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Tidskriftsartikel (refereegranskat)abstract
- Plasminogen-activator inhibitor type 2 (PAI-2) is a specific inhibitor of plasminogen activators (PA) that exists in an intracellular, low-molecular-mass form and a secreted, high-molecular-mass form that varies with respect to glycosylation. Here we have developed expression systems for both forms of PAI-2 and biochemically characterised the purified proteins. In order to obtain efficient secretion, we constructed an artificial signal sequence and fused it to the coding region of PAI-2. With this construct, more than 90% of PAI-2 was secreted as a glycosylated, 60-kDa molecular-mass form, but the level of expression was low and unstable. To obtain higher expression of secreted PAI-2, a novel expression vector based on the Semliki-forest-virus replicon was used. Secreted PAI-2 was purified to homogeneity and N-terminal sequence analysis showed that the artificial signal peptide was correctly removed. The intracellular, non-glycosylated form of PAI-2 was expressed in Escherichia coli and purified to homogeneity. Both the secreted and the intracellular forms of PAI-2 were found to inhibit plasminogen activators by forming SDS-resistant complexes and the second-order rate constants were similar for both forms, ranging over 2.4-2.7 x 10(6) M-1s-1 for urokinase-type PA, 2.5-2.7 x 10(5) M-1s-1 for two-chain tissue-type PA and 0.8-1.2 x 10(4) M-1s-1 for single-chain tissue-type PA. None of the purified PAI-2 forms bound to vitronectin. Circular-dichroism spectral analysis revealed that PAI-2 has a CD spectrum that resembles ovalbumin more than PA-inhibitor type 1, confirming the greater similarity between these two members of the serine-protease inhibitor family. Similar to what has been described for the Z-form of alpha 1-antitrypsin, purified PAI-2 was found to spontaneously form polymers during incubation at room temperature. Attempts to convert PAI-2 to a stable locked conformation resembling the conformation of latent PAI-1 by treatment with diluted guanidinium chloride were unsuccessful. Instead, this treatment enhanced the formation of PAI-2 polymers, possibly by the loop-sheet polymerisation mechanism described for alpha 1-antitrypsin.
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| 24. |
- Ny, A, et al.
(författare)
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Studies of mice lacking plasminogen activator gene function suggest that plasmin production prior to ovulation exceeds the amount needed for optimal ovulation efficiency.
- 1997
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Ingår i: European Journal of Biochemistry. - 0014-2956 .- 1432-1033. ; 244:2, s. 487-93
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Tidskriftsartikel (refereegranskat)abstract
- Many studies suggest that the plasminogen activator (PA) system plays a role in the proteolytic degradation of the follicle wall at the time of ovulation. Consistently, the ovulation efficiency is reduced by 26% in mice where both physiological PA genes have been inactivated. To reveal the mechanism behind reduced ovulation efficiency in PA-deficient mice and its effect on ovarian proteolysis. we have studied the regulation of plasmin activity in the ovaries of 25-day-old wild-type mice and mice with deficient PA gene function during gonadotropin-induced ovulation. In wild-type mice the plasmin activity was low in ovarian extracts from mice treated with pregnant mare's serum gonadotropin. However, this activity was increased between 2-8 h after an ovulatory dose of human choriogonadotropins. In mice lacking either tissue-type PA (tPA) or PA inhibitor type 1 (PAI-1) the plasmin activity levels prior to ovulation were similar to wild-type mice, while extracts prepared from urokinase-type PA (uPA) deficient mice had 10% or less of the plasmin activity. This indicates that most of the plasmin activity in the mouse ovary is generated by uPA. In addition, as the ovulation efficiency is impaired in tPA/uPA-deficient mice but appears normal in uPA-deficient mice, our data indicates that the amount of plasmin generated by PAs prior to ovulation in wild-type mice greatly exceeds the amount required for efficient ovulation.
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| 25. |
- Ny, L, et al.
(författare)
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Carbon monoxide as a putative messenger molecule in the feline lower oesophageal sphincter of the cat
- 1995
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Ingår i: NeuroReport. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4965. ; 6:10, s. 1389-1393
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Tidskriftsartikel (refereegranskat)abstract
- The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO) type 1 and 2 were studied in the feline lower oesophageal sphincter (LOS), as were HO activity and functional effects of CO. HO-2 immunoreactivity was observed in nerve cell bodies in the submucosal and myenteric plexus, nerve fibres, non-neuronal cells surrounding smooth muscle bundles, and in arterial endothelium, HO-1 immunoreactivity was confined to non-neuronal cells in the smooth muscle layer. CO production, indicating HO activity, was demonstrated in tissue homogenates. CO relaxed the LOS, and activated the cyclic GMP system. These results show that HO is present in the LOS, and suggest that CO can be generated by neuronal and non-neuronal structures and may have a role as a peripheral messenger.
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| 26. |
- Ny, L, et al.
(författare)
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Localization and activity of haem oxygenase and functional effects of carbon monoxide in the feline lower oesophageal sphincter
- 1996
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 118:2, s. 392-399
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Tidskriftsartikel (refereegranskat)abstract
- 1. In the feline lower oesophageal sphincter (LOS), the distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry and confocal microscopy, the HO activity was measured and the possible role for CO as a mediator of relaxation was investigated. 2. HO-2 immunoreactivity was abundant in nerve cell bodies of the submucosal and myenteric plexus. Approximately 50% of the HO-2-containing myenteric cell bodies were also nitric oxide synthase- and vasoactive intestinal peptide (VIP)-immunoreactive. In addition, HO-2 immunoreactivity was seen in nerve fibres, in non-neuronal cells dispersed in the smooth muscle and in arterial endothelium. HO-1 immunoreactivity was confined to non-neuronal cells in the smooth muscle, similar to those positive for HO-2. 3. Activity of HO, measured as CO production, was observed in LOS homogenates at a rate of 1.00 +/- 0.05 nmol mg-1 protein h-1. This production was inhibited by the HO inhibitor, zinc protoporphyrin-IX (ZnPP). 4. In isolated circular smooth muscle strips of LOS, developing spontaneous tone, exogenously administered CO evoked a concentration-dependent relaxation reaching a maximum of 93 +/- 3%. This relaxation was accompanied by an increase in cyclic GMP, but not cyclic AMP levels. The relaxant response was attenuated by methylene blue, but unaffected by tetrodotoxin. Repeated exposure to CO resulted in a progressive reduction of the relaxant response. 5. ZnPP caused a rightward-shift of the concentration-response curves for the relaxant responses to VIP, peptide histidine isoleucine, and pituitary adenylate cyclase activating peptide 27. 6. ZnPP and tin protoporphyrin-IX (another inhibitor of HO) did not affect nonadrenergic, noncholinergic relaxations induced by electrical field stimulation. Nor did ZnPP affect relaxations induced by 3-morpholino-sydnonimine or forskolin. 7. The present findings, showing localization of HO immunoreactivity to both neuronal and nonneuronal cells of the feline LOS, ability of LOS to produce CO and a relaxant effect of CO in circular LOS muscle, suggest a role for CO as a peripheral messenger.
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| 27. |
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| 28. |
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| 29. |
- von Heijne, G, et al.
(författare)
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The efficiency of the uncleaved secretion signal in the plasminogen activator inhibitor type 2 protein can be enhanced by point mutations that increase its hydrophobicity.
- 1991
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 266:23, s. 15240-3
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Tidskriftsartikel (refereegranskat)abstract
- Plasminogen-activator inhibitor type 2 (PAI-2) is a specific inhibitor of plasminogen activators that belongs to the serine protease inhibitor superfamily (SERPINS). PAI-2 exists in two molecular forms: an intracellular, non-glycosylated form and a secreted, glycosylated form. Like ovalbumin, PAI-2 contains an uncleaved internal secretion signal. By deletion analysis, we have mapped the secretion signal to two mildly hydrophobic regions near the NH2 terminus. We also show that both of these regions become more efficient translocation signals when their hydrophobicities are increased. The PAI-2 secretion signal provides a unique example of a signal that, by virtue of its poor efficiency, allows the synthesis of both an extracellular and an intracellular form of the protein.
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| 30. |
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| 31. |
- Atsawawaranunt, Kamolphat, et al.
(författare)
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The SISAL database : a global resource to document oxygen and carbon isotope records from speleothems
- 2018
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 10:3, s. 1687-1713
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Tidskriftsartikel (refereegranskat)abstract
- Stable isotope records from speleothems provide information on past climate changes, most particularly information that can be used to reconstruct past changes in precipitation and atmospheric circulation. These records are increasingly being used to provide "out-of-sample" evaluations of isotope-enabled climate models. SISAL (Speleothem Isotope Synthesis and Analysis) is an international working group of the Past Global Changes (PAGES) project. The working group aims to provide a comprehensive compilation of speleothem isotope records for climate reconstruction and model evaluation. The SISAL database contains data for individual speleothems, grouped by cave system. Stable isotopes of oxygen and carbon (delta O-18, delta C-13) measurements are referenced by distance from the top or bottom of the speleothem. Additional tables provide information on dating, including information on the dates used to construct the original age model and sufficient information to assess the quality of each data set and to erect a standardized chronology across different speleothems. The metadata table provides location information, information on the full range of measurements carried out on each speleothem and information on the cave system that is relevant to the interpretation of the records, as well as citations for both publications and archived data.
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| 32. |
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| 33. |
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| 34. |
- Bagge, R. Olofsson, et al.
(författare)
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A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial)
- 2024
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Ingår i: ESMO Open. - : Elsevier. - 2059-7029. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- Background:Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high -dose melphalan. This phase I trial investigates the safety and clinical ef fi cacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO).Patients and methods:Immunotherapy-na & iuml;ve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post -operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year.Results:Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/ 18 patients (6 in the post -operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post -operative arm (4/7) and 22% in the pre-post-operative arm (2/9).Conclusions:Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Bergström, F, et al.
(författare)
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The use of site-directed fluorophore labeling and donor-donor energy migration to investigate solution structure and dynamics in proteins.
- 1999
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 96:22, s. 12477-81
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Tidskriftsartikel (refereegranskat)abstract
- The use of molecular genetics for introducing fluorescent molecules enables the use of donor-donor energy migration to determine intramolecular distances in a variety of proteins. This approach can be applied to examine the overall molecular dimensions of proteins and to investigate structural changes upon interactions with specific target molecules. In this report, the donor-donor energy migration method is demonstrated by experiments with the latent form of plasminogen activator inhibitor type 1. Based on the known x-ray structure of plasminogen activator inhibitor type 1, three positions forming the corners of a triangle were chosen. Double Cys substitution mutants (V106C-H185C, H185C-M266C, and M266C-V106C) and corresponding single substitution mutants (V106C, H185C, and M266C) were created and labeled with a sulfhydryl specific derivative of BODIPY (=the D molecule). The side lengths of this triangle were obtained from analyses of the experimental data. The analyses account for the local anisotropic order and rotational motions of the D molecules, as well as for the influence of a partial DD-labeling. The distances, as determined from x-ray diffraction, between the C(alpha)-atoms of the positions V106C-H185C, H185C-M266C, and M266C-V106C were 60.9, 30.8, and 55.1 A, respectively. These are in good agreement with the distances of 54 +/- 4, 38 +/- 3, and 55 +/- 3 A, as determined between the BODIPY groups attached via linkers to the same residues. Although the positions of the D-molecules and the C(alpha)-atoms physically cannot coincide, there is a reasonable agreement between the methods.
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| 39. |
- Comas-Bru, Laia, et al.
(författare)
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Evaluating model outputs using integrated global speleothem records of climate change since the last glacial
- 2019
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 15:4, s. 1557-1579
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Tidskriftsartikel (refereegranskat)abstract
- Although quantitative isotope data from speleothems has been used to evaluate isotope-enabled model simulations, currently no consensus exists regarding the most appropriate methodology through which to achieve this. A number of modelling groups will be running isotope-enabled palaeoclimate simulations in the framework of the Coupled Model Intercomparison Project Phase 6, so it is timely to evaluate different approaches to using the speleothem data for data-model comparisons. Here, we illustrate this using 456 globally distributed speleothem delta O-18 records from an updated version of the Speleothem Isotopes Synthesis and Analysis (SISAL) database and palaeoclimate simulations generated using the ECHAM5-wiso isotope-enabled atmospheric circulation model. We show that the SISAL records reproduce the first-order spatial patterns of isotopic variability in the modern day, strongly supporting the application of this dataset for evaluating model-derived isotope variability into the past. However, the discontinuous nature of many speleothem records complicates the process of procuring large numbers of records if data-model comparisons are made using the traditional approach of comparing anomalies between a control period and a given palaeoclimate experiment. To circumvent this issue, we illustrate techniques through which the absolute isotope values during any time period could be used for model evaluation. Specifically, we show that speleothem isotope records allow an assessment of a model's ability to simulate spatial isotopic trends. Our analyses provide a protocol for using speleothem isotope data for model evaluation, including screening the observations to take into account the impact of speleothem mineralogy on delta O-18 values, the optimum period for the modern observational baseline and the selection of an appropriate time window for creating means of the isotope data for palaeo-time-slices.
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| 40. |
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| 41. |
- Egeler, M.D., et al.
(författare)
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Understanding quality of life issues in patients with advanced melanoma : Phase 1 and 2 in the development of the EORTC advanced melanoma module
- 2024
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 207
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy.Methods: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module.Results: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates.Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items.Conclusion: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.
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| 42. |
- Egeler, M. D., et al.
(författare)
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Understanding quality of life issues in patients with advanced melanoma: Phase 1 and 2 in the development of the EORTC advanced melanoma module
- 2024
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 207
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy. Methods: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module. Results: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates. Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items. Conclusion: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.
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| 43. |
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| 44. |
- Feng, P, et al.
(författare)
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The structure of the TATA-less rat tissue-type plasminogen activator gene. Species-specific sequence divergences in the promoter predict differences in regulation of gene expression.
- 1990
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 265:4, s. 2022-7
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Tidskriftsartikel (refereegranskat)abstract
- The genomic region carrying the rat tissue-type plasminogen activator (tPA) gene including its 5'-flanking sequence has been isolated and characterized by restriction enzyme analysis, Southern blotting, and DNA sequencing of all coding parts and the promoter region. The gene is approximately 25 kilobase pairs in size and comprises 14 exons separated by 13 introns. All the exon/intron boundaries agree with the GT-AG rule. The organization of the rat tPA gene is very similar to its human counterpart, and the location of the introns in the protein structure is identical to the human tPA gene. To characterize the promoter region, the transcription initiation site was identified by S1 nuclease protection experiments. A DNA fragment carrying 621 nucleotides of the 5'-flanking sequence was found to confer basal promoter activity and hormone responsiveness to a reporter gene construct in primary cultures of rat granulosa cells. Analysis of the rat tPA promoter sequence and a comparison with the human and mouse counterparts reveal several species-specific differences: the rat and mouse tPA promoters lack typical TATA and CAAT sequences found in the human tPA gene. Furthermore, the rat tPA promoter contains a consensus cAMP-responsive element shown to be required for cAMP responsiveness in eucaryotic genes. At the same position as the cAMP-responsive element in the rat gene, the mouse and human tPA genes have a 12-O-tetradecanoylphorbol-13-acetate-responsive element known to mediate activation by phorbol esters. The differences in the promoter sequences of the rat, mouse, and human tPA genes may have implications for the regulation of the tPA gene in different species.
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| 45. |
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| 46. |
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| 47. |
- Gizaw, NY, et al.
(författare)
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PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:49, s. e2116220119-
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Tidskriftsartikel (refereegranskat)abstract
- Rhabdomyosarcoma (RMS) is an aggressive pediatric soft-tissue cancer with features of skeletal muscle. Because of poor survival of RMS patients and severe long-term side effects of RMS therapies, alternative RMS therapies are urgently needed. Here we show that the prospero-related homeobox 1 (PROX1) transcription factor is highly expressed in RMS tumors regardless of their cell type of origin. We demonstrate that PROX1 is needed for RMS cell clonogenicity, growth and tumor formation. PROX1 gene silencing repressed several myogenic and tumorigenic transcripts and transformed the RD cell transcriptome to resemble that of benign mesenchymal stem cells. Importantly, we found that fibroblast growth factor receptors (FGFR) mediated the growth effects of PROX1 in RMS. Because of receptor cross-compensation, paralog-specific FGFR inhibition did not mimic the effects of PROX1 silencing, whereas a pan-FGFR inhibitor ablated RMS cell proliferation and induced apoptosis. Our findings uncover the critical role of PROX1 in RMS and offer insights into the mechanisms that regulate RMS development and growth. As FGFR inhibitors have already been tested in clinical phase I/II trials in other cancer types, our findings provide an alternative option for RMS treatment.
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| 48. |
- Holmberg, Carl Jacob, et al.
(författare)
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The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study
- 2022
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Ingår i: EUROPEAN JOURNAL OF CANCER. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 40:16
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. Results: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. Conclusion: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
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| 49. |
- Hosokawa, K, et al.
(författare)
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Dominant expression and distribution of oestrogen receptor beta over oestrogen receptor alpha in the human corpus luteum
- 2001
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Ingår i: Molecular human reproduction. - : Oxford University Press (OUP). - 1360-9947 .- 1460-2407. ; 7:2, s. 137-145
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the potential importance of oestrogen as a local regulator of human corpus luteum function, the mRNA expression pattern and cellular localization of oestrogen receptors (ERs), ER-alpha and ER-beta, were studied in corpora lutea grouped according to age, where days 2-5 post-LH rise were designated as the early luteal phase, days 6-10 as mid-luteal and days 11-14 as the late luteal phase respectively. Northern blot analysis using an ER-beta probe in samples from whole ovarian tissue and isolated corpora lutea, revealed a major band at 7.5 kb and several minor bands between 4-10 kb, while no signals for ER-alpha mRNA were obtained. However, using a semi-quantitative reverse transcription-polymerase chain reaction followed by Southern blotting, ER-beta mRNA levels were found to be 63% lower (P: < 0.05, n = 39) in the mid-luteal phase compared with the early luteal phase, while ER-alpha mRNA expression showed no statistical differences between the different age groups. Using in-situ hybridization, ER-beta mRNA expression was localized to the steroidogenic luteal cells as well as perivascular cells and fibroblasts in the corpus luteum. Immunohistochemistry confirmed the localization of ER-beta protein, but no clear staining of luteal cells was found using antibodies against ER-alpha. Collectively, the findings of low to moderate expression of ER-beta mRNA and protein in the steroidogenic cells, and also in vascular endothelial cells of the corpus luteum, as opposed to diminutive amounts of ER-alpha mRNA, suggest that oestrogen activity is primarily transduced via ER-beta in the human corpus luteum.
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| 50. |
- Hsueh, A J, et al.
(författare)
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Gonadotropin-releasing hormone induces ovulation in hypophysectomized rats : studies on ovarian tissue-type plasminogen activator activity, messenger ribonucleic acid content, and cellular localization.
- 1988
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Ingår i: Endocrinology. - 0013-7227 .- 1945-7170. ; 122:4, s. 1486-95
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Tidskriftsartikel (refereegranskat)abstract
- GnRH and its agonists are known to induce ovulation in hypophysectomized rats by acting directly at the ovary. Because tissue-type plasminogen activator (tPA) has been implicated in the gonadotropin induction of ovulation, we examined the effect of an ovulatory dose of GnRH on ovarian tPA activity, mRNA content, and cellular localization. Hypophysectomized immature rats were injected sc with 20 IU PMSG and a single dose of a GnRH agonist (GnRHa; des-Gly10,DLeu6(N alpha Me)Leu7,Pro9NHEt-GnRH) 58 h later. At different times after treatment, ovaries were prepared for morphological analysis. Using a fibrin overlay method, tPA activities were measured in ovarian homogenates and cumulus-oocyte complexes, whereas granulosa cells were cultured for 24 h to estimate tPA secretion. Total ovarian RNA was prepared for hybridization analysis of tPA message levels, and tPA localization was studied by immunohistochemistry of ovarian sections. GnRHa induced ovulation in PMSG-primed hypophysectomized rats 14-16 h after injection in a dose-dependent manner, and the GnRHa action was blocked by concomitant treatment with a GnRH antagonist. GnRHa stimulated the induction of tPA, but not urokinase-type PA, activity in ovarian homogenates and granulosa cell-conditioned medium in a time-dependent manner, reaching a maximum before ovulation. tPA activity in cumulus-oocyte complexes was also increased before ovulation, but this increase was sustained. Hybridization analysis of steady state tPA mRNA levels was performed using a rat cRNA probe. Northern blot analysis of total ovarian RNA demonstrated that GnRHa stimulated tPA mRNA levels 12 h after treatment, with a subsequent decrease 24 h after treatment. Immunohistochemistry indicated substantial increases in tPA staining in granulosa cells and oocytes of preovulatory follicles before ovulation. Thus, GnRHa acts through specific receptors to increase ovarian tPA enzyme activity, mRNA content, as well as immunostaining in granulosa cells and oocytes. Like gonadotropins, GnRH may induce ovulation by directly stimulating tPA levels in the ovary.
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