| 1. |
- Carninci, P, et al.
(författare)
-
The transcriptional landscape of the mammalian genome
- 2005
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
-
Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Xie, L, et al.
(författare)
-
Off-tumor IDO1 target engagements determine the cancer-immune set point and predict the immunotherapeutic efficacy
- 2021
-
Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:6
-
Tidskriftsartikel (refereegranskat)abstract
- Indoleamine-2,3-dioxygenase 1 (IDO1) has been intensively pursued as a therapeutic target to reverse the immunosuppressive cancer-immune milieu and promote tumor elimination. However, recent failures of phase III clinical trials with IDO1 inhibitors involved in cancer immunotherapies highlight the urgent need to develop appropriate methods for tracking IDO1 when the cancer-immune milieu is therapeutically modified.MethodsWe utilized a small-molecule radiotracer, 11C-l-1MTrp, to quantitatively and longitudinally visualize whole-body IDO1 dynamics. Specifically, we first assessed 11C-l-1MTrp in mice-bearing contralateral human tumors with distinct IDO1 expression patterns. Then, we applied 11C-l-1MTrp to longitudinally monitor whole-body IDO1 variations in immunocompetent melanoma-bearing mice treated with 1-methyl-l-tryptophan plus either chemotherapeutic drugs or antibodies targeting programmedcell death 1 and cytotoxic T-lymphocyte-associated protein 4.Results11C-l-1MTrp positron emission tomography (PET) imaging accurately delineated IDO1 expression in xenograft mouse models. Moreover, we were able to visualize dynamic IDO1 regulation in the mesenteric lymph nodes (MLNs), an off-tumor IDO1 target, where the percentage uptake of 11C-l-1MTrp accurately annotated the therapeutic efficacy of multiple combination immunotherapies in preclinical models. Remarkably, 11C-l-1MTrp signal intensity in the MLNs was inversely related to the specific growth rates of treated tumors, suggesting that IDO1 expression in the MLNs can serve as a new biomarker of the cancer-immune set point.ConclusionsPET imaging of IDO1 with 11C-l-1MTrp is a robust method to assess the therapeutic efficacy of multiple combinatorial immunotherapies, improving our understanding of the merit and challenges of IDO1 regimens. Further validation of this animal data in humans is ongoing. We envision that our results will provide a potential precision medicine paradigm for noninvasive visualizing each patient’s individual response in combinatorial cancer immunotherapy, and tailoring optimal personalized combination strategies.
|
|
| 5. |
- Ammirati, Enrico, et al.
(författare)
-
Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction
- 2019
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 74:3, s. 299-311
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support. A single-center study found that a patient with FM had better outcomes than those with acute nonfulminant myocarditis (NFM) presenting with left ventricular systolic dysfunction, but otherwise hemodynamically stable. This was recently challenged, so disagreement still exists. Objectives: This study sought to provide additional evidence on the outcome of FM and to ascertain whether patient stratification based on the main histologic subtypes can provide additional prognostic information. Methods: A total of 220 patients (median age 42 years, 46.3% female) with histologically proven acute myocarditis (onset of symptoms <30 days) all presenting with left ventricular systolic dysfunction were included in a retrospective, international registry comprising 16 tertiary hospitals in the United States, Europe, and Japan. The main endpoint was the occurrence of cardiac death or heart transplantation within 60 days from admission and at long-term follow-up. Results: Patients with FM (n = 165) had significantly higher rates of cardiac death and heart transplantation compared with those with NFM (n = 55), both at 60 days (28.0% vs. 1.8%, p = 0.0001) and at 7-year follow-up (47.7% vs. 10.4%, p < 0.0001). Using Cox multivariate analysis, the histologic subtype emerged as a further variable affecting the outcome in FM patients, with giant cell myocarditis having a significantly worse prognosis compared with eosinophilic and lymphocytic myocarditis. In a subanalysis including only adults with lymphocytic myocarditis, the main endpoints occurred more frequently in FM compared with in NFM both at 60 days (19.5% vs. 0%, p = 0.005) and at 7-year follow up (41.4% vs. 3.1%, p = 0.0004). Conclusions: This international registry confirms that patients with FM have higher rates of cardiac death and heart transplantation both in the short- and long-term compared with patients with NFM. Furthermore, we provide evidence that the histologic subtype of FM carries independent prognostic value, highlighting the need for timely endomyocardial biopsy in this condition.
|
|
| 6. |
- Ghadri, J. R., et al.
(författare)
-
International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology
- 2018
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:22, s. 2032-2046
-
Tidskriftsartikel (refereegranskat)abstract
- Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.
|
|
| 7. |
- Ghadri, J. R., et al.
(författare)
-
International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management
- 2018
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:22, s. 2047-2062
-
Tidskriftsartikel (refereegranskat)abstract
- The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.
|
|
| 8. |
- Kato, Norihiro, et al.
(författare)
-
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
-
Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
|
|
| 9. |
|
|
| 10. |
|
|
