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- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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- Alström, Per, et al.
(författare)
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Integrative taxonomy of the Russet Bush Warbler Locustella mandelli complex reveals a new species from central China
- 2015
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Ingår i: Avian Research. - : Elsevier BV. - 2053-7166. ; 6:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Russet Bush Warbler Locustella (previously Bradypterus) mandelli complex occurs in mountains in the eastern Himalayas, southern China, Vietnam, the Philippines, and Indonesia. The taxonomy has been debated, with one (L. seebohmi) to four (L. seebohmi, L. mandelli, L. montis and L. timorensis) species having been recognised. Methods: We used an integrative approach, incorporating analyses of morphology, vocalizations and a molecular marker, to re-evaluate species limits in the L. mandelli complex. Results: We found that central Chinese L. mandelli differed from those from India through northern Southeast Asia to southeast China in plumage, morphometrics and song. All were easily classified by song, and (wing + culmen)/tail ratio overlapped only marginally. Both groups were reciprocally monophyletic in a mitochondrial cytochrome b (cytb) gene tree, with a mean divergence of 1.0 +/- 0.2%. They were sympatric and mostly altitudinally segregated in the breeding season in southern Sichuan province. We found that the Mt Victoria (western Myanmar) population differed vocally from other L. mandelli, but no specimens are available. Taiwan Bush Warbler L. alishanensis was sister to the L. mandelli complex, with the most divergent song. Plumage, vocal and cytb evidence supported the distinctness of the south Vietnamese L. mandelli idonea. The Timor Bush Warbler L. timorensis, Javan Bush Warbler L. montis and Benguet Bush Warbler L. seebohmi differed distinctly in plumage, but among-population song variation in L. montis exceeded the differences between some populations of these taxa, and mean pairwise cytb divergences were only 0.5-0.9%. We also found that some L. montis populations differed morphologically. Conclusions: We conclude that the central Chinese population of Russet Bush Warbler represents a new species, which we describe herein, breeding at mid elevations in Sichuan, Shaanxi, Hubei, Hunan and Guizhou provinces. The taxonomic status of the other allopatric populations is less clear. However, as they differ to a degree comparable with that of the sympatric L. mandelli and the new species, we elevate L. idonea to species status, and retain L. seebohmi and L. montis as separate species, the latter with timorensis as a subspecies. Further research should focus on different populations of L. montis and the Mt Victoria population of L. mandelli.
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- Khan, RMM, et al.
(författare)
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From Pre-Diabetes to Diabetes: Diagnosis, Treatments and Translational Research
- 2019
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Ingår i: Medicina (Kaunas, Lithuania). - : MDPI AG. - 1648-9144. ; 55:9
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes, a silent killer, is one of the most widely prevalent conditions of the present time. According to the 2017 International Diabetes Federation (IDF) statistics, the global prevalence of diabetes among the age group of 20–79 years is 8.8%. In addition, 1 in every 2 persons is unaware of the condition. This unawareness and ignorance lead to further complications. Pre-diabetes is the preceding condition of diabetes, and in most of the cases, this ultimately leads to the development of diabetes. Diabetes can be classified into three types, namely type 1 diabetes, type 2 diabetes mellitus (T2DM) and gestational diabetes. The diagnosis of both pre-diabetes and diabetes is based on glucose criteria; the common modalities used are fasting plasma glucose (FPG) test and oral glucose tolerance test (OGTT). A glucometer is commonly used by diabetic patients to measure blood glucose levels with fast and rather accurate measurements. A few of the more advanced and minimally invasive modalities include the glucose-sensing patch, SwEatch, eyeglass biosensor, breath analysis, etc. Despite a considerable amount of data being collected and analyzed regarding diabetes, the actual molecular mechanism of developing type 2 diabetes mellitus (T2DM) is still unknown. Both genetic and epigenetic factors are associated with T2DM. The complications of diabetes can predominantly be classified into two categories: microvascular and macrovascular. Retinopathy, nephropathy, and neuropathy are grouped under microvascular complications, whereas stroke, cardiovascular disease, and peripheral artery disease (PAD) belong to macrovascular complications. Unfortunately, until now, no complete cure for diabetes has been found. However, the treatment of pre-diabetes has shown significant success in preventing the further progression of diabetes. To prevent pre-diabetes from developing into T2DM, lifestyle intervention has been found to be very promising. Various aspects of diabetes, including the aforementioned topics, have been reviewed in this paper.
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- Kupers, LK, et al.
(författare)
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Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1893-
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Tidskriftsartikel (refereegranskat)abstract
- Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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- Wu, K, et al.
(författare)
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Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 10131-
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Tidskriftsartikel (refereegranskat)abstract
- The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.
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