| 1. |
- Dwane, Lisa, et al.
(author)
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A Functional Genomic Screen Identifies the Deubiquitinase USP11 as a Novel Transcriptional Regulator of ERα in Breast Cancer
- 2020
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In: Cancer Research. - 1538-7445. ; 80:22, s. 5076-5088
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Journal article (peer-reviewed)abstract
- Approximately 70% of breast cancers express estrogen receptor α (ERα) and depend on this key transcriptional regulator for proliferation and differentiation. While patients with this disease can be treated with targeted antiendocrine agents, drug resistance remains a significant issue, with almost half of patients ultimately relapsing. Elucidating the mechanisms that control ERα function may further our understanding of breast carcinogenesis and reveal new therapeutic opportunities. Here, we investigated the role of deubiquitinases (DUB) in regulating ERα in breast cancer. An RNAi loss-of-function screen in breast cancer cells targeting all DUBs identified USP11 as a regulator of ERα transcriptional activity, which was further validated by assessment of direct transcriptional targets of ERα. USP11 expression was induced by estradiol, an effect that was blocked by tamoxifen and not observed in ERα-negative cells. Mass spectrometry revealed a significant change to the proteome and ubiquitinome in USP11-knockdown (KD) cells in the presence of estradiol. RNA sequencing in LCC1 USP11-KD cells revealed significant suppression of cell-cycle-associated and ERα target genes, phenotypes that were not observed in LCC9 USP11-KD, antiendocrine-resistant cells. In a breast cancer patient cohort coupled with in silico analysis of publicly available cohorts, high expression of USP11 was significantly associated with poor survival in ERα-positive (ERα+) patients. Overall, this study highlights a novel role for USP11 in the regulation of ERα activity, where USP11 may represent a prognostic marker in ERα+ breast cancer. SIGNIFICANCE: A newly identified role for USP11 in ERα transcriptional activity represents a novel mechanism of ERα regulation and a pathway to be exploited for the management of ER-positive breast cancer.
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| 2. |
- Grabherr, Manfred G, et al.
(author)
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Full-length transcriptome assembly from RNA-Seq data without a reference genome
- 2011
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 29:7, s. 644-652
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Journal article (peer-reviewed)abstract
- Massively parallel sequencing of cDNA has enabled deep and efficient probing of transcriptomes. Current approaches for transcript reconstruction from such data often rely on aligning reads to a reference genome, and are thus unsuitable for samples with a partial or missing reference genome. Here we present the Trinity method for de novo assembly of full-length transcripts and evaluate it on samples from fission yeast, mouse and whitefly, whose reference genome is not yet available. By efficiently constructing and analyzing sets of de Bruijn graphs, Trinity fully reconstructs a large fraction of transcripts, including alternatively spliced isoforms and transcripts from recently duplicated genes. Compared with other de novo transcriptome assemblers, Trinity recovers more full-length transcripts across a broad range of expression levels, with a sensitivity similar to methods that rely on genome alignments. Our approach provides a unified solution for transcriptome reconstruction in any sample, especially in the absence of a reference genome.
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| 3. |
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| 4. |
- Kang, Bong Joo, et al.
(author)
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Rim Sign in Breast Lesions on Diffusion-Weighted Magnetic Resonance Imaging: Diagnostic Accuracy and Clinical Usefulness
- 2015
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In: Journal of Magnetic Resonance Imaging. - : Wiley. - 1522-2586 .- 1053-1807. ; 41:3, s. 616-623
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Journal article (peer-reviewed)abstract
- PurposeTo investigate the diagnostic accuracy and clinical usefulness of the rim sign in breast lesions observed in diffusion-weighted magnetic resonance imaging (DWI). Materials and MethodsThe magnetic resonance imaging (MRI) findings of 98 pathologically confirmed lesions (62 malignant and 36 benign) in 84 patients were included. Five breast radiologists were asked to independently review the breast MRI results, to grade the degree of high peripheral signal, the rim sign, in the DWI, and to confirm the mean apparent diffusion coefficient (ADC(mean)) values. We analyzed the diagnostic accuracy and compared the consensus (when 4 of 5 independent reviewers agreed) results of the rim sign with the ADC(mean) values. Additionally, we evaluated the correlation between the dynamic contrast-enhanced (DCE)-MRI morphologic appearance and DWI rim sign. ResultsAccording to the consensus results, the rim sign in DWI was observed on 59.7% of malignant lesions and 19.4% of benign lesions. The sensitivity, specificity, and area under the curve (AUC) value for the rim sign in DWI were 59.7%, 80.6%, and 0.701, respectively. The sensitivity, specificity, and AUC value for the ADC(mean) value (criteria 1.46 x 10(-3) mm(2)/sec) were 82.3%, 63.9%, and 0.731, respectively. Based on consensus, no correlation was observed between the DCE-MRI and DWI rim signs. ConclusionIn DWI, a high-signal rim is a valuable morphological feature for improving specificity in DWI. J. Magn. Reson. Imaging 2015;41:616-623. (c) 2014 Wiley Periodicals, Inc.
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| 5. |
- Marklund, Matti, et al.
(author)
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Hypertension treatment capacity in India by increased workforce, greater task-sharing, and extended prescription period : a modelling study
- 2023
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In: The Lancet Regional Health - Southeast Asia. - : Elsevier. - 2772-3682. ; 10
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Journal article (peer-reviewed)abstract
- Background The worldwide control rate for hypertension is dismal. An inadequate number of physicians to treat patients with hypertension is one key obstacle. Innovative health system approaches such as delegation of basic tasks to non-physician health workers (task-sharing) might alleviate this problem. Massive scale up of population-wide hypertension management is especially important for low-and middle-income countries such as India. Methods Using constrained optimization models, we estimated the hypertension treatment capacity and salary costs of staff involved in hypertension care within the public health system of India and simulated the potential effects of (1) an increased workforce, (2) greater task-sharing among health workers, and (3) extended average prescription periods that reduce treatment visit frequency (e.g., quarterly instead of monthly).Findings Currently, only an estimated 8% (95% uncertainty interval 7%-10%) of -245 million adults with hypertension can be treated by physician-led services in the Indian public health system (assuming the current number of health workers, no greater task-sharing, and monthly visits for prescriptions). Without task-sharing and with continued monthly visits for prescriptions, the least costly workforce expansion to treat 70% of adults with hypertension would require -1.6 (1.0-2.5) million additional staff (all non-physicians), with -INR 200 billion (approximate to USD 2.7 billion) in additional annual salary costs. Implementing task-sharing among health workers (without increasing the overall time on hypertension care) or allowing a 3-month prescription period was estimated to allow the current workforce to treat -25% of patients. Joint implementation of task-sharing and a longer prescription period could treat -70% of patients with hypertension in India.Interpretation The combination of greater task-sharing and extended prescription periods could substantially increase the hypertension treatment capacity in India without any expansion of the current workforce in the public health system. By contrast, workforce expansion alone would require considerable, additional human and financial resources.
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| 6. |
- OLSSON HAU, SOFIE, et al.
(author)
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A translational effort to identify prognostic and predictive biomarkers in pancreatic cancer among RBM3-regulated genes
- 2018
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In: ; , s. 305-305
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Conference paper (peer-reviewed)abstract
- Background Pancreatic cancer has a dismal prognosis and clinical protocols are still lacking predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker in several solid cancers, including pancreatic cancer.. High RBM3 expression in human tumors has been associated with good response to chemotherapy, as well as to confer increased chemosensitivity in vitro. The aim of this study was to identify RBM3-regulated genes in pancreatic cells in vitro, and further interrogate their potential utility as prognostic and predictive biomarkers in a translational setting. Methods Next generation RNA-sequencing was applied to compare gene expression between MIAPaCa-2 cells with siRNA-downregulated RBM3 and control cells. Single genes with the strongest association to RBM3 were further selected by gene set enrichment analysis, and their prognostic value in pancreatic cancer was examined in The Cancer Genome Atlas (TCGA). The most promising biomarker candidates with well-validated antibodies were then analyzed by immunohistochemistry in tissue microarrays with tumors from a consecutive, retrospective cohort of 175 patients with periampullary and pancreatic adenocarcinoma. Results MIAPaCa-2 cells with downregulated RBM3 displayed 21 differentially expressed genes (p<0.01). One of the top downregulated genes was PDS cohesion associated factor A (PDS5A) encoding a protein involved in sister chromatid cohesion. PDS5A protein expression was reduced in siRBM3-treated MIAPaCa-2 cells compared to control cells. High PDS5A mRNA expression was significantly associated with a reduced survival in pancreatic cancer in the TCGA (n=176, p=0.026). High PDS5A protein expression in the separate cohort was significantly associated with a poor prognosis but predictive of improved response to adjuvant chemotherapy in KRAS-mutated, but not wild-type, pancreatobiliary-type tumors (p for interaction=0.043). Conclusions Here, we provide the first report of the expression of PDS5A in pancreatic and periampullary cancer, suggesting its potential utility as a prognostic and predictive biomarker. Further studies to unravel the underlying mechanisms are encouraged.
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| 7. |
- Olsson Hau, Sofie, et al.
(author)
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PRR11 unveiled as a top candidate biomarker within the RBM3-regulated transcriptome in pancreatic cancer
- 2022
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In: Journal of Pathology: Clinical Research. - : Wiley. - 2056-4538. ; 8:1, s. 65-77
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Journal article (peer-reviewed)abstract
- The outlook for patients with pancreatic cancer remains dismal. Treatment options are limited and chemotherapy remains standard of care, leading to only modest survival benefits. Hence, there is a great need to further explore the mechanistic basis for the intrinsic therapeutic resistance of this disease, and to identify novel predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker of disease severity and chemotherapy response in several types of cancer, including pancreatic cancer. The aim of this study was to unearth RBM3-regulated genes and proteins in pancreatic cancer cells in vitro, and to examine their expression and prognostic significance in human tumours. Next-generation RNA sequencing was applied to compare transcriptomes of MIAPaCa-2 cells with and without RBM3 knockdown. The prognostic value of differentially expressed genes (DEGs) was examined in The Cancer Genome Atlas (TCGA). Top deregulated genes were selected for further studies in vitro and for immunohistochemical analysis of corresponding protein expression in tumours from a clinically well-annotated consecutive cohort of 46 patients with resected pancreatic cancer. In total, 19 DEGs (p < 0.01) were revealed, among which some with functions in cell cycle and cell division stood out; PDS5A (PDS cohesin associated factor A) as the top downregulated gene, CCND3 (cyclin D3) as the top upregulated gene, and PRR11 (proline rich 11) as being highly prognostic in TCGA. Silencing of RBM3 in MiaPaCa-2 cells led to congruent alterations of PDS5A, cyclin D3, and PRR11 levels. High protein expression of PRR11 was associated with adverse clinicopathological features and shorter overall survival. Neither PDS5A nor cyclin D3 protein expression was prognostic. This study unveils several RBM3-regulated genes with potential clinical relevance in pancreatic cancer, among which PRR11 shows the most consistent association with disease severity, at both transcriptome and protein levels.
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| 8. |
- Rhind, Nicholas, et al.
(author)
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Comparative Functional Genomics of the Fission Yeasts
- 2011
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 332:6032, s. 930-936
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Journal article (peer-reviewed)abstract
- The fission yeast clade-comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus-occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres. Expression analysis established that meiotic genes are subject to antisense transcription during vegetative growth, which suggests a mechanism for their tight regulation. In addition, trans-acting regulators control new genes within the context of expanded functional modules for meiosis and stress response. Differences in gene content and regulation also explain why, unlike the budding yeast of Saccharomycotina, fission yeasts cannot use ethanol as a primary carbon source. These analyses elucidate the genome structure and gene regulation of fission yeast and provide tools for investigation across the Schizosaccharomyces clade.
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| 9. |
- Roth, Gregory A, et al.
(author)
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Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019 : Update From the GBD 2019 Study
- 2020
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 76:25, s. 2982-3021
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Journal article (peer-reviewed)abstract
- Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.
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| 10. |
- Wahlin, Sara, et al.
(author)
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Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer : longitudinal expression, transcriptome-level effects and modulation of chemosensitivity
- 2022
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 22:1
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Journal article (peer-reviewed)abstract
- Background: The response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. The proto-oncogene RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response in several solid tumours but has a hitherto unrecognized role in MIBC. Methods: RBM3 protein expression level in tumour cells was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from a consecutive cohort of 145 patients, 65 of whom were treated with NAC. Kaplan-Meier and Cox regression analyses were applied to estimate the impact of RBM3 expression on time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS) in strata according to NAC treatment. The effect of siRNA-mediated silencing of RBM3 on chemosensitivity was examined in RT4 and T24 human bladder carcinoma cells in vitro. Cellular functions of RBM3 were assessed using RNA-sequencing and gene ontology analysis, followed by investigation of cell cycle distribution using flow cytometry. Results: RBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. Patients with high-tumour specific RBM3 expression treated with NAC had a significantly reduced risk of recurrence and a prolonged CSS and OS compared to NAC-untreated patients. In high-grade T24 carcinoma cells, which expressed higher RBM3 mRNA levels compared to RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. Transcriptomic analysis revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G1-phase as well as altered levels of recognised regulators of G1-phase progression, including Cyclin D1/CDK4 and CDK2. Conclusions: The presented data highlight the potential value of RBM3 as a predictive biomarker of chemotherapy response in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.
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