| 1. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
- Oddsson, Asmundur, et al.
(författare)
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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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| 3. |
- Domínguez-Gil, B., et al.
(författare)
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The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation
- 2022
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Ingår i: Transplantation. ; 106:11, s. 2111-2117
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| 5. |
- Wang, J., et al.
(författare)
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Final report of the CCQM-K145 : Toxic and essential elements in bovine liver
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 57:1 A
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Tidskriftsartikel (refereegranskat)abstract
- Liver plays a major role in metabolism and acts as a source of energy for the body by storing glycogen. With the growing interest and investigation in the biological effects in recent years, it is important and necessary to develop accurate and comparable analytical methods for elements in bio-samples. It has, however, been 10 years since the tissue sample (bovine liver) of CCQM-K49 key comparison. The purpose of CCQM-K145 is to ensure the comparable and traceable measurement results for essential and toxic elements such as P, S, Zn, Mn, Ni, Mo, Sr, Cr, Co, Pb, As and Hg in bovine liver among NMIs and other designated measurement bodies worldwide. The comparison was agreed by IAWG as 6th IAWG Benchmarking Exercise with Zn and Ni as exemplary elements at the meeting in Korea in the early October 2016. The results of CCQM-K145 are expected to cover the measurement capability and support CMCs claiming for inorganic elements in the similar biological tissue materials and food samples. 30 NMIs and DIs registered in CCQM-K145. With respect to the methodology, a variety of techniques such as IDMS, ICP-OES, ICP-MS(non-ID), AAS and NAA were adopted by the participants. For Zn, Ni, Sr, Pb and Hg measurements, most participants chose ID-ICP-MS method, which showed the better performance in terms of consistency and reliability of the measurement results. In aspect of the traceability for the measurement results in CCQM-K145, most participants used their own (in house) CRMs or other NMI's CRMs to guarantee trace to SI unit. Most participants used similar matrix CRMs for quality control or method validation. Base on different statistic way to calculate the reference mass fraction values and associated uncertainties for each measurand, removal of the suspected extreme values, and discussion at the IAWG meetings, the median values are proposed as the KCRV for Zn, Ni, Mn, Mo, Cr, Pb and Hg; the arithmetic mean values are proposed as the KCRV for P, S, Sr, Co and As. In general, the performances of the majority of CCQM-K145 participants are very good, illustrating their measurement capabilities for Zn, Ni, P, S, Mn, Mo, Sr, Cr, As, Co, Pb and Hg in a complex biological tissue matrix. Bovine liver contains many kinds of nutrients and microelements, it can be regarded as a typical representative material of biological tissue and food. In CCQM-K145, the analytes involved alkali metals and transition elements, metalloids/semi-metals and non metals with a range of mass fraction from mg/g to μg/kg. CCQM-K145 also tested the ability of NMIs/DIs to determine elements that were easy to be lost and polluted, and interfered significantly. The chemical pretreatment methods of samples used in the comparison is suitable for general food and biological matrix samples. A variety of measurement methods used in the comparison represent the main instrumental technology for elemental analysis. Therefore, for supporting CMC claim, CCQM-K145 is readily applicable to measurement of more elements in a wide range of biological materials (including liquids and solids) and meat products. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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| 6. |
- Lindberg, K., et al.
(författare)
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The HILUS-Trial—a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy
- 2021
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864. ; 16:7, s. 1200-1210
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. Methods: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. Results: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0–10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the “hottest” 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. Conclusions: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions). © 2021 International Association for the Study of Lung Cancer
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| 7. |
- Öfverholm, Anna, et al.
(författare)
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Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer
- 2023
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Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.
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| 10. |
- Giovannucci, Tatiana A., et al.
(författare)
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Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy
- 2022
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Ingår i: Autophagy. - : Taylor & Francis. - 1554-8627 .- 1554-8635. ; 18:7, s. 1486-1502
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.
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