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- Thompson, B.A., et al.
(författare)
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Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:2, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.
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- Dominguez-Valentin, M, et al.
(författare)
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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
- 2021
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 10:13
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Tidskriftsartikel (refereegranskat)abstract
- Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
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- Dominguez-Valentin, M, et al.
(författare)
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Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database
- 2020
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35–55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
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- Moller, P, et al.
(författare)
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Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database
- 2017
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 66:3, s. 464-472
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Tidskriftsartikel (refereegranskat)abstract
- Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.DesignWe undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affectingMLH1,MSH2,MSH6orPMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.Results1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards inMLH1andMSH2mutation carriers, and from about 40 years inMSH6andPMS2carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% forMLH1, MSH2, MSH6andPMS2mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.ConclusionsThe four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established athttp://LScarisk.orgenabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.
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| 19. |
- Moller, P, et al.
(författare)
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Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:7, s. 1306-1316
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Tidskriftsartikel (refereegranskat)abstract
- Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.
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- Hemingway, H, et al.
(författare)
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The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.
- 2010
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Ingår i: Health Technology Assessment. - : National Coordinating Centre for Health Technology Assessment. - 1366-5278 .- 2046-4924. ; 14:9, s. 1-178
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the effectiveness and cost-effectiveness of a range of strategies based on conventional clinical information and novel circulating biomarkers for prioritising patients with stable angina awaiting coronary artery bypass grafting (CABG).DATA SOURCES: MEDLINE and EMBASE were searched from 1966 until 30 November 2008.REVIEW METHODS: We carried out systematic reviews and meta-analyses of literature-based estimates of the prognostic effects of circulating biomarkers in stable coronary disease. We assessed five routinely measured biomarkers and the eight emerging (i.e. not currently routinely measured) biomarkers recommended by the European Society of Cardiology Angina guidelines. The cost-effectiveness of prioritising patients on the waiting list for CABG using circulating biomarkers was compared against a range of alternative formal approaches to prioritisation as well as no formal prioritisation. A decision-analytic model was developed to synthesise data on a range of effectiveness, resource use and value parameters necessary to determine cost-effectiveness. A total of seven strategies was evaluated in the final model.RESULTS: We included 390 reports of biomarker effects in our review. The quality of individual study reports was variable, with evidence of small study (publication) bias and incomplete adjustment for simple clinical information such as age, sex, smoking, diabetes and obesity. The risk of cardiovascular events while on the waiting list for CABG was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients with a mean of 59 days at risk). Risk factors associated with an increased risk, and included in the basic risk equation, were age, diabetes, heart failure, previous myocardial infarction and involvement of the left main coronary artery or three-vessel disease. The optimal strategy in terms of cost-effectiveness considerations was a prioritisation strategy employing biomarker information. Evaluating shorter maximum waiting times did not alter the conclusion that a prioritisation strategy with a risk score using estimated glomerular filtration rate (eGFR) was cost-effective. These results were robust to most alternative scenarios investigating other sources of uncertainty. However, the cost-effectiveness of the strategy using a risk score with both eGFR and C-reactive protein (CRP) was potentially sensitive to the cost of the CRP test itself (assumed to be 6 pounds in the base-case scenario).CONCLUSIONS: Formally employing more information in the prioritisation of patients awaiting CABG appears to be a cost-effective approach and may result in improved health outcomes. The most robust results relate to a strategy employing a risk score using conventional clinical information together with a single biomarker (eGFR). The additional prognostic information conferred by collecting the more costly novel circulating biomarker CRP, singly or in combination with other biomarkers, in terms of waiting list prioritisation is unlikely to be cost-effective.
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- Price, RB, et al.
(författare)
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International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators
- 2022
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 27:1112, s. 5096-5112
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Tidskriftsartikel (refereegranskat)abstract
- Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; β*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630
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| 31. |
- Rampe, A, et al.
(författare)
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Magnetic linear dichroism in valence-band photoemission: Experimental and theoretical study of Fe(110)
- 1998
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Ingår i: PHYSICAL REVIEW B-CONDENSED MATTER. - : AMERICAN PHYSICAL SOC. - 0163-1829. ; 57:22, s. 14370-14380
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Magnetic linear dichroism (MLD) in angle-resolved valence-band photoemission of Fe(110) has been investigated by means of symmetry considerations, analytical theory, numerical calculations, and photoemission measurements. The dichroic photoemission spectr
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| 32. |
- Wu, G, et al.
(författare)
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Understanding resilience
- 2013
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Ingår i: Frontiers in behavioral neuroscience. - : Frontiers Media SA. - 1662-5153. ; 7, s. 10-
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Tidskriftsartikel (refereegranskat)
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| 33. |
- Yeung, Andy Wai Kan, et al.
(författare)
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Resveratrol, a popular dietary supplement for human and animal health : Quantitative research literature analysis - a review
- 2019
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Ingår i: Animal Science Papers and Reports. - : POLSKA AKAD NAUK, INST GENETYKI I HODOWLI ZWIERZAT. - 0860-4037. ; 37:2, s. 103-118
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Forskningsöversikt (refereegranskat)abstract
- Resveratrol is a stilbene-type bioactive molecule with a broad spectrum of reported biological effects. In this sense, the current work provides a comprehensive literature analysis on resveratrol, representing a highly-researched commercially available dietary ingredient. Bibliometric data were identified by means of the search string TOPIC=("resveratrol*") and analyzed with the VOSviewer software, which yielded 17,561 publications extracted from the Web of Science Core Collection electronic database. 'I'he ratio of original articles to reviews was 9.5:1. More than half of the overall manuscripts have been published since 2013. Major contributing countries were USA, China, Italy, South Korea, and Spain. Most of the publications appeared in journals specialized in biochemistry and molecular biology, pharmacology and pharmacy, food science technology, cell biology, or oncology. The phytochemicals or phytochemical classes that were frequently mentioned in the keywords of analyzed publications included, in descending order: resveratrol, trans-resveratrol, polyphenols, flavonoids, quercetin, stilbenes, curcumin, piceatannol, cis-resveratrol, and anthocyanins.
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