| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 3. |
- Keogan, Katharine, et al.
(författare)
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Global phenological insensitivity to shifting ocean temperatures among seabirds
- 2018
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Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 8:4, s. 313-318
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Tidskriftsartikel (refereegranskat)abstract
- Reproductive timing in many taxa plays a key role in determining breeding productivity(1), and is often sensitive to climatic conditions(2). Current climate change may alter the timing of breeding at different rates across trophic levels, potentially resulting in temporal mismatch between the resource requirements of predators and their prey(3). This is of particular concern for higher-trophic-level organisms, whose longer generation times confer a lower rate of evolutionary rescue than primary producers or consumers(4). However, the disconnection between studies of ecological change in marine systems makes it difficult to detect general changes in the timing of reproduction(5). Here, we use a comprehensive meta-analysis of 209 phenological time series from 145 breeding populations to show that, on average, seabird populations worldwide have not adjusted their breeding seasons over time (-0.020 days yr(-1)) or in response to sea surface temperature (SST) (-0.272 days degrees C-1) between 1952 and 2015. However, marked between-year variation in timing observed in resident species and some Pelecaniformes and Suliformes (cormorants, gannets and boobies) may imply that timing, in some cases, is affected by unmeasured environmental conditions. This limited temperature-mediated plasticity of reproductive timing in seabirds potentially makes these top predators highly vulnerable to future mismatch with lower-trophic-level resources(2).
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| 4. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 5. |
- Kerr, Keith M, et al.
(författare)
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Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer : In what state is this art?
- 2015
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Ingår i: Journal of Thoracic Oncology. - 1556-0864 .- 1556-1380. ; 10:7, s. 985-989
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic antibodies to programmed death receptor 1 (PD-1) and its ligand PD-L1 show promising clinical results. Anti-PD-L1 immunohistochemistry (IHC) may be a biomarker to select patients more likely to respond to these treatments. However, the development of at least four different therapeutics, each with a different anti-PD-L1 IHC assay, has raised concerns among pathologists and oncologists alike. This article reviews existing data on the IHC biomarker aspects of studies using these drugs in non-small-cell lung cancer (NSCLC) and considers the challenges ahead, should these drug/IHC assay combinations reach routine practice. For each the known biomarker assays in development, there is a different monoclonal IHC antibody clone, produced by one of two diagnostics companies. Each test requires proprietary staining platforms and uses different definitions of a "positive" test for PD-L1 expression, on tumor cells and, in one test, also on tumor infiltrating immune cells. There are still considerable gaps in our knowledge of the technical aspects of these tests, and of the biological implications and associations of PD-L1 expression in NSCLC, considering heterogeneity of expression, dynamic changes in expression, and prognostic implications among other factors. The International Association for the Study of Lung Cancer Pathology Committee raises the prospect of trying not only to harmonize and standardize testing for PD-L1 by IHC, at least at a technical level, but also, ideally, as a predictive marker, to facilitate availability of this test and a promising treatment for patients with NSCLC.
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| 6. |
- Nicholson, Andrew G., et al.
(författare)
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Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung
- 2018
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Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 13:2, s. 205-217
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Tidskriftsartikel (refereegranskat)abstract
- Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen kappa statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (kappa score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.
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| 7. |
- Thunnissen, Erik, et al.
(författare)
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The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases
- 2017
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 12:2, s. 334-346
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise K scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC.Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3).Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, K scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64.Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided. (C) 2017 International Association for the Study of Lung Cancer.
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| 8. |
- Tsao, Ming Sound, et al.
(författare)
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PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples : Results of Blueprint Phase 2 Project
- 2018
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 13:9, s. 1302-1311
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.Methods: BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.Results: The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient [ICC] = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).Conclusion: BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
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| 9. |
- Yatabe, Yasushi, et al.
(författare)
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Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer
- 2019
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 14:3, s. 377-407
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Tidskriftsartikel (refereegranskat)abstract
- Since the 2015 WHO classification was introduced into clinical practice, immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small cell versus non-small cell carcinoma, patients' treatment of choice is directly linked to histologic subtypes of non-small cell carcinoma, which pertains to IHC results, particularly for poorly differentiated tumors. The use of IHC has improved diagnostic accuracy in the classification of lung carcinoma, but the interpretation of IHC results remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The International Association for the Study of Lung Cancer Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several International Association for the Study of Lung Cancer Pathology Committee meetings, the issues and caveats were summarized in terms of 11 key questions covering common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions cover topics such as the best IHC markers for distinguishing NSCLC subtypes, differences in thyroid transcription factor 1 clones, and the utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors. This article provides answers and explanations for the key questions about the use of IHC in diagnosis of lung carcinoma, representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology.
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