| 1. |
- Cornford, Philip, et al.
(author)
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EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent.
- 2024
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In: European urology. - 1873-7560.
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Journal article (peer-reviewed)abstract
- The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa.The panel performed a literature review of all new data published in English, covering the time frame between May 2020 and 2023. The guidelines were updated, and a strength rating for each recommendation was added based on a systematic review of the evidence.A risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50yr of age and based on individualised life expectancy. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is considered, a combination of targeted and regional biopsies should be performed. Prostate-specific membrane antigen positron emission tomography imaging is the most sensitive technique for identifying metastatic spread. Active surveillance is the appropriate management for men with low-risk PCa, as well as for selected favourable intermediate-risk patients with International Society of Urological Pathology grade group 2 lesions. Local therapies are addressed, as well as the management of persistent prostate-specific antigen after surgery. A recommendation to consider hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term intensified hormonal treatment.The evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. These PCa guidelines reflect the multidisciplinary nature of PCa management.This article is the summary of the guidelines for "curable" prostate cancer. Prostate cancer is "found" through a multistep risk-based screening process. The objective is to find as many men as possible with a curable cancer. Prostate cancer is curable if it resides in the prostate; it is then classified into low-, intermediary-, and high-risk localised and locally advanced prostate cancer. These risk classes are the basis of the treatments. Low-risk prostate cancer is treated with "active surveillance", a treatment with excellent prognosis. For low-intermediary-risk active surveillance should also be discussed as an option. In other cases, active treatments, surgery, or radiation treatment should be discussed along with the potential side effects to allow shared decision-making.
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| 2. |
- Kahnberg, Pia, et al.
(author)
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Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor
- 2002
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In: Journal of Medicinal Chemistry. - 1520-4804. ; 45:19, s. 4188-4201
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Journal article (peer-reviewed)abstract
- To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995,12,193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 8'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5'-bromo-2'-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (K-i = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made.
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| 3. |
- Lager, Erik, et al.
(author)
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4-quinolone derivatives: High-affinity ligands at the benzodiazepine site of brain GABA(A) receptors. synthesis, pharmacology, and pharmacophore modeling
- 2006
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:8, s. 2526-2533
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Journal article (peer-reviewed)abstract
- The 3-ethoxycarbonyl-4-quinolone compound I has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2s) and alpha(3)beta(2)gamma(2s) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1) versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2s) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.
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| 4. |
- Lager, Erik, et al.
(author)
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Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors.
- 2008
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:14, s. 6936-6948
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Journal article (peer-reviewed)abstract
- The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.
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| 5. |
- Lager, Erik, et al.
(author)
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Diels-Alder adducts derived from the natural phthalide Z-ligustilide
- 2007
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In: Tetrahedron Letters. - : Elsevier BV. - 0040-4039. ; 48:24, s. 4215-4218
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Journal article (peer-reviewed)abstract
- Z-Ligustilide, a naturally occurring phthalide isolated from Ligusticum porteri, underwent Diels-Alder reactions with different dienophiles yielding novel tricyclic products with potentially interesting biological properties. Where selectivity was possible, the reactions performed showed regio- and stereoselectivity. The experimental results with ethyl acrylate were compared with the selectivity predicted by ab initio calculations.
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| 6. |
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| 7. |
- Lager, Erik
(author)
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Pharmacophore Refinement and Lead Optimization - A study of the benzodiazepine site of the GABAA receptors
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Structure activity relationship studies of synthetic flavone derivatives have been utilized to refine and evaluate a pharmacophore model of the benzodiazepine binding site of the GABAA receptors, originally developed by Zhang et al. (Drug Des. Discovery 1995, 12, 193-248). In addition to the previously proposed pharmacophore elements, two steric repulsive regions have been added to the model and the receptor region in the vicinity of the 3´-position of flavones has been characterized. The knowledge obtained in the affinity study has been used to design 5´-bromo-2´-hydroxy-6-methylflavone 53 (Ki = 0.9 nM), the highest affinity flavone derivative reported so far. Based on the refined model, pharmacophore-guided lead optimization of 3-ethoxycarbonyl-6-trifluoromethyl-4-quinolone 58 (Ki = 122 nM), a compound previously presented by Kahnberg et al. (J. Mol. Graphics Modelling 2004, 23, 253-261), has resulted in several 4-quinolone derivatives with subnanomolar affinity. The highest affinity, Ki = 48 picomolar, is displayed by 6-benzyl-3-propylaminocarbonyl-4-quinolone 134. Several 4-quinolone derivatives have been tested on ?1?2?2S, ?2?2?2S and ?3?2?2S GABAA receptor subtypes. All tested derivatives display a varied range of selectivity for ?1- versus ?2- and ?3-containing receptors. 6-Benzyl-3-ethoxycarbonyl-4-quinolone 121 displays the highest selectivity for ?1- versus ?3-containing receptors, by a factor of 27, of the compounds investigated in this study.
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| 8. |
- Lager, Ida, et al.
(author)
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Changes in external pH rapidly alter plant gene expression and modulate auxin and elicitor responses
- 2010
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In: Plant, Cell and Environment. - : Wiley. - 0140-7791 .- 1365-3040. ; 33:9, s. 1513-1528
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Journal article (peer-reviewed)abstract
- pH is a highly variable environmental factor for the root, and plant cells can modify apoplastic pH for nutrient acquisition and in response to extracellular signals. Nevertheless, surprisingly few effects of external pH on plant gene expression have been reported. We have used microarrays to investigate whether external pH affects global gene expression. In Arabidopsis thaliana roots, 881 genes displayed at least twofold changes in transcript abundance 8 h after shifting medium pH from 6.0 to 4.5, identifying pH as a major affector of global gene expression. Several genes responded within 20 min, and gene responses were also observed in leaves of seedling cultures. The pH 4.5 treatment was not associated with abiotic stress, as evaluated from growth and transcriptional response. However, the observed patterns of global gene expression indicated redundancies and interactions between the responses to pH, auxin and pathogen elicitors. In addition, major shifts in gene expression were associated with cell wall modifications and Ca2+ signalling. Correspondingly, a marked overrepresentation of Ca2+/calmodulin-associated motifs was observed in the promoters of pH-responsive genes. This strongly suggests that plant pH recognition involves intracellular Ca2+. Overall, the results emphasize the previously underappreciated role of pH in plant responses to the environment.
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| 9. |
- Lager, Susanne, 1978, et al.
(author)
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Perinatal lack of maternal IL-6 promotes increased adiposity during adulthood in mice.
- 2011
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In: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:4, s. 1336-46
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Journal article (peer-reviewed)abstract
- The perinatal environment appears important in establishing metabolic phenotypes in adulthood. Mice deficient in IL-6 (IL-6(-/-)) tend to develop mature-onset obesity, but it is unknown whether perinatal exposure to IL-6 produced by the dam influences the metabolism of adult offspring. To address this issue, we monitored IL-6(-/-) offspring of IL-6(-/-) or IL-6(+/-) dams, as well as wild-type (WT) mice. At adult age, IL-6(-/-) mice weighed significantly more and had more body fat than WT mice, regardless of maternal genotype, and had lower insulin sensitivity. This phenotype was more pronounced in IL-6(-/-) offspring of IL-6(-/-) dams, because they gained weight significantly faster than IL-6(-/-) offspring of IL-6(+/-) dams and had more body fat and higher serum leptin levels at an earlier age. The leptin content was 2-fold higher in milk from IL-6(-/-) than WT dams. However, cross-fostering IL-6(-/-) mice with WT dams did not alter body weight, body composition, or adipocyte size at adult age compared with IL-6(-/-) mice fostered by IL-6(-/-) dams. Conversely, WT mice fostered by IL-6(-/-) dams weighed significantly more than those fostered by WT dams and had more body fat, larger adipocytes, and altered hypothalamic gene expression. We conclude that body fat of adult mice can be increased by perinatal exposure to factors affected by lack of maternal IL-6.
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| 10. |
- Marra, Giancarlo, et al.
(author)
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Impact of Epithelial Histological Types, Subtypes, and Growth Patterns on Oncological Outcomes for Patients with Nonmetastatic Prostate Cancer Treated with Curative Intent: A Systematic Review.
- 2023
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In: European urology. - 0302-2838 .- 1873-7560. ; 84:1, s. 65-85
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Journal article (peer-reviewed)abstract
- The optimal management for men with prostate cancer (PCa) with unconventional histology (UH) is unknown. The outcome for these cancers might be worse than for conventional PCa and so different approaches may be needed.To compare oncological outcomes for conventional and UH PCa in men with localized disease treated with curative intent.A systematic review adhering to the Referred Reporting Items for Systematic Reviews and Meta-Analyses was prospectively registered on PROSPERO (CRD42022296013) was performed in July 2021.We screened 3651 manuscripts and identified 46 eligible studies (reporting on 1871814 men with conventional PCa and 6929 men with 10 different PCa UHs). Extraprostatic extension and lymph node metastases, but not positive margin rates, were more common with UH PCa than with conventional tumors. PCa cases with cribriform pattern, intraductal carcinoma, or ductal adenocarcinoma had higher rates of biochemical recurrence and metastases after radical prostatectomy than for conventional PCa cases. Lower cancer-specific survival rates were observed for mixed cribriform/intraductal and cribriform PCa. By contrast, pathological findings and oncological outcomes for mucinous and prostatic intraepithelial neoplasia (PIN)-like PCa were similar to those for conventional PCa. Limitations of this review include low-quality studies, a risk of reporting bias, and a scarcity of studies that included radiotherapy.Intraductal, cribriform, and ductal UHs may have worse oncological outcomes than for conventional and mucinous or PIN-like PCa. Alternative treatment approaches need to be evaluated in men with these cancers.We reviewed the literature to explore whether prostate cancers with unconventional growth patterns behave differently to conventional prostate cancers. We found that some unconventional growth patterns have worse outcomes, so we need to investigate if they need different treatments. Urologists should be aware of these growth patterns and their clinical impact.
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| 11. |
- Slevin, Finbar, et al.
(author)
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A Systematic Review of the Efficacy and Toxicity of Brachytherapy Boost Combined with External Beam Radiotherapy for Nonmetastatic Prostate Cancer.
- 2023
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In: European urology oncology. - 2588-9311.
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Journal article (peer-reviewed)abstract
- The optimum use of brachytherapy (BT) combined with external beam radiotherapy (EBRT) for localised/locally advanced prostate cancer (PCa) remains uncertain.To perform a systematic review to determine the benefits and harms of EBRT-BT.Ovid MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials databases were systematically searched for studies published between January 1, 2000 and June 7, 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Eligible studies compared low- or high-dose-rate EBRT-BT against EBRT±androgen deprivation therapy (ADT) and/or radical prostatectomy (RP)±postoperative radiotherapy (RP±EBRT). The main outcomes were biochemical progression-free survival (bPFS), severe late genitourinary (GU)/gastrointestinal toxicity, metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS), at/beyond 5 yr. Risk of bias was assessed and confounding assessment was performed. A meta-analysis was performed for randomised controlled trials (RCTs).Seventy-three studies were included (two RCTs, seven prospective studies, and 64 retrospective studies). Most studies included participants with intermediate-or high-risk PCa. Most studies, including both RCTs, used ADT with EBRT-BT. Generally, EBRT-BT was associated with improved bPFS compared with EBRT, but similar MFS, CSS, and OS. A meta-analysis of the two RCTs showed superior bPFS with EBRT-BT (estimated fixed-effect hazard ratio [HR] 0.54 [95% confidence interval {CI} 0.40-0.72], p<0.001), with absolute improvements in bPFS at 5-6 yr of 4.9-16%. However, no difference was seen for MFS (HR 0.84 [95% CI 0.53-1.28], p=0.4) or OS (HR 0.87 [95% CI 0.63-1.19], p=0.4). Fewer studies examined RP±EBRT. There is an increased risk of severe late GU toxicity, especially with low-dose-rate EBRT-BT, with some evidence of increased prevalence of severe GU toxicity at 5-6 yr of 6.4-7% across the two RCTs.EBRT-BT can be considered for unfavourable intermediate/high-risk localised/locally advanced PCa in patients with good urinary function, although the strength of this recommendation based on the European Association of Urology guideline methodology is weak given that it is based on improvements in biochemical control.We found good evidence that radiotherapy combined with brachytherapy keeps prostate cancer controlled for longer, but it could lead to worse urinary side effects than radiotherapy without brachytherapy, and its impact on cancer spread and patient survival is less clear.
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| 12. |
- Tarvainen, Ilari, et al.
(author)
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Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro
- 2023
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In: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 119
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Journal article (peer-reviewed)abstract
- Chemical health risk assessment is based on single chemicals, but humans and wildlife are exposed to extensive mixtures of industrial substances and pharmaceuticals. Such exposures are life-long and correlate with multiple morbidities, including infertility. How combinatorial effects of chemicals should be handled in hazard charac-terization and risk assessment are open questions. Further, test systems are missing for several relevant health outcomes including reproductive health and fertility in women. Here, our aim was to screen multiple ovarian cell models for phthalate induced effects to identify biomarkers of exposure. We used an epidemiological cohort study to define different phthalate mixtures for in vitro testing. The mixtures were then tested in five cell models representing ovarian granulosa or stromal cells, namely COV434, KGN, primary human granulosa cells, primary mouse granulosa cells, and primary human ovarian stromal cells. Exposures at epidemiologically relevant levels did not markedly elicit cytotoxicity or affect steroidogenesis in short 24-hour exposure. However, significant effects on gene expression were identified by RNA-sequencing. Altogether, the exposures changed the expression of 124 genes on the average (9-479 genes per exposure) in human cell models, without obvious concentration or mixture-dependent effects on gene numbers. The mixtures stimulated distinct changes in different cell models. Despite differences, our analyses suggest commonalities in responses towards phthalates, which forms a starting point for follow-up studies on identification and validation of candidate biomarkers that could be developed to novel assays for regulatory testing or even into clinical tests.
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