16858 results for "sec+and+unspecified+malignant+neoplasm"

in 26.43 milliseconds.

• TGF-β signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration

  Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia-myelin interactions are spatiotemporally regulated remains unexplored. By examining spinal cord white matter tracts, we found that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of TGF-β signaling. Disrupting TGF-β signaling in microglia led to unchecked microglial responses and myelin loss in the DC, accompanied by neurological deficits exacerbated with aging. snRNA-seq revealed the emergence of a TGF-β signaling-sensitive microglial subset and a disease-associated oligodendrocyte subset, both spatially restricted to the DC. We further discovered that microglia rely on a TGFβ autocrine mechanism to prevent damage of myelin in the DC. These findings demonstrate that TGF-β signaling is indispensable for maintaining microglial resilience to myelin degeneration in the DC during the aging process. This highlights a previously unresolved checkpoint mechanism of TGF-β signaling with regional specificity and spatially restricted microglia-oligodendrocyte interactions.

  Study EGAS50000001413

• Advancing fast in the analysis of circulating tumour DNA

  In cancer patients, solid tumours also release DNA fragments into the blood, and they are called Circulating Tumours DNA (ctDNA). Nowadays, the standard procedure for cancer monitoring is analysis of surgically obtained biopsies. They generate a big amount of material, but the operation is highly invasive and provide medical doctors with a single-time snapshot of the tumours, which are often highly changeable. Analysis of ctDNA, on the other hand, can provide continuous information regarding the tumour itself without the need of invasive procedures. This is why interest in this method is growing, and with it, the need for its technological optimization. Guanhua Zhu and colleagues, at the Genome Institute of Singapore, developed a methodology to quantify ctDNA burden, which means to estimate the amount of tumours derived circulating DNA among all cell-free DNA in the blood of individuals. Their work, published in Nature Communications in april 2021 and summarized in a sketch below, uses state-of-the art methods to analyse cfDNA degradation patterns at promoters and exon regions, to discern it from the DNA coming from the tumours. The bright point of their approach is that simultaneously enable for profiling of actionable cancer mutations and quantitative estimation of ctDNA burden. Their sequencing data of ctDNA has been deposited in the EGA under the accession number EGAS00001004657. This study sums up to a total of 37 of cfDNA and 36 about ctDNA present up to date in the EGA archive. The existence of cfDNA was firstly described back in 2002, while the use of ctDNA analysis in the oncological field exploded only after 2016. The approach is rapidly evolving, moving in parallel with the ever-improving sequencing technologies. Especially, the possibility to obtain high quality sequences from minimal amount of material is a crucial factor. Being able to alleviate cancer patients of disturbing and often slow-recovery procedures, while at the same time improving the quality of diagnosis and disease monitoring seems like a lot to ask. Thankfully, we are blessed with brilliant and dedicated scientists from all around the world who collaborate to make this a reality, sharing their results, knowledge and data.

  Blog advancing-fast-in-the-analysis-of-circulating-tumour-dna

• Youth-GEMs, the project using data to define the mental health trajectories of young people

  Mental health trajectories are shaped by genetic, cognitive, social, and environmental factors that are particularly influential during human development. How exactly the interplay between these factors is impacting mental health, however, is yet unknown. The project “Gene Environment interactions in Mental health trajectories of Youth (Youth-GEMs)”, funded by the European Commission under the Horizon Europe programme, aims to help reducing mental suffering among European youth. How do Youth-GEMs contribute to bettering mental health in young people? Youth-GEMs aims to identify specific neurological, (epi)genetic and environmental drivers on mental health trajectories of young people. To do so, the project is working on a public knowledge base on functional genomics of the developing human brain, between birth and 24 years old. Reliable predictive models for trajectories of onset and course of mental illness in young people of the general population in Europe will be developed. Additionally, a secure and FAIR data infrastructure in mental health is being produced. Engaging and empowering young people Youth-GEMs is also working on the engagement of young people in the scientific field of Psychiatry. For that, the project is developing initiatives such as Science Café, intended to create a learning community where ideas and stories are shared. The 10th Science Café will take place today, with the participation of Lauren Fromont from the EGA. How do the EGA contribute to Youth-GEMs? The contributions require careful data management and harmonisation: we are dealing with an extraordinary amount of data types, sources, and time points (since the studies are longitudinal). To analyse them together and to determine which factors and interactions are truly key to account for mental health trajectories, the variables need to be transformed in a common “language”, i.e., harmonised under a common data model. Further, to guarantee FAIRness of data storage and sharing for future projects that will further advance our knowledge in the mental health field, we are ensuring that data are processed securely but can also be discovered easily. Find out more information about the project in the Youth-GEMs website.

  Blog youth-gems-mental-health

• Passive and active DNA methylation and the interplay with genetic variation in gene regulation

  DNA methylation is an essential1 epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not yet fully understood2,3. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort4. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which more local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression.. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression.

  Study EGAS00001000446

• Development of a fully human glioblastoma-in-brain-spheroid model for accelerated translational research

  In glioblastoma (GBM) the intricate interplay between tumor cells and the surrounding microenvironment plays a crucial role in tumor progression, invasion, and therapeutic resistance. So far, studying these interactions in a controlled and representative model system has been challenging. Here, we report the development of hGliCS, a human glioma-cortical spheroid model that allows the elucidation of the biology of GBM cells and their interactions with a human-specific brain-like microenvironment and neurons. GBM cells efficiently invade the cortical spheroids, forming a well-connected network of communicating cells. The heterogeneous cellular states of the GBM cells within this model closely resembled findings previously observed in glioblastoma patients and in mouse xenografts. We observed a transition from predominantly mesenchymal-like cells to heterotopic states with a high diversity. In contrast to the substantial changes observed in the tumor cell population, the impact of the GBM cells on the neurons was minimal. We further demonstrate the suitability of hGliCS to test compounds targeting tumor-specific neurobiological features.

  Study EGAS50000000757

• Blood-based monitoring of relapsed/refractory cHL patients predict responses to PD-1 blockade treatment

  Hodgkin lymphoma (cHL) patients are uniquely susceptible to treatment with programmed cell death-1 (PD-1) treatment. However, monitoring with FDG-PET/CT, the current response detection standard, is challenging. Here, we address the potential applicability of tissue biomarkers and blood-based biomarkers in PD-1 treated cHL patients. We evaluated 9p24.1/PD-L1/PD-L2 alterations, and expression of PD-L1 and antigen presentation molecules (HLA class I/II) in 9 tissue biopsies of 4 patients. In addition, we assessed circulating tumor DNA (ctDNA), extracellular vesicle associated miRNAs (EV-miRNAs), soluble PD-L1 and serum TARC (sTARC) in 26 longitudinal blood samples of these patients during PD-1 treatment. We found that the predictive power of tissue biomarkers is dependent on the timing of the biopsy . The dynamics of blood-based biomarkers: sTARC, EV-miRNAs and ctDNA corresponded well immunotherapy treatment response. Therefore, blood-based biomarkers are promising monitoring strategies in PD-1 treated cHL patients and should be further explored in clinical trials or observational studies.

  Study EGAS00001005894

• Inferring tumor genomes from peripheral blood i.e. CTCs and plasma-DNA using deep sequencing and targeted enrichment

  In this study we tested whether complex tumor genomes can be inferred from the peripheral blood (plasma DNA /CTCs) of 32 patients with stage IV colorectal carcinoma (CRC). To establish the percentage of mutated plasma DNA fragments we used 8 patient samples with different plasma DNA size distributions and KRAS mutations in their corresponding primary tumors and employed ultra-deep pyrosequencing with 3 different sequencing reaction sizes (i.e., 119 bp, 168 bp, and 323 bp). Furthermore, we used massive parallel sequencing of a panel of 68 CRC-associated genes to establish the mutation spectrum of cancer driver genes in the primary tumors, metastases, and CTCs of two colorectal cancer patients. To investigate, whether mutations found in only one CTC (“private CTC mutations”) are true mutations occurring with allele frequencies below the resolution limits of current detection methods, or whether they are amplification or sequencing artifacts, we performed ultra-deep sequencing of the primary tumors, metastases, plasma DNAs and normal tissues.

  Study EGAS00001000337

• GDAP - Genome Diversity in Africa Project (2021-02-12)

  The Genomic Diversity in Africa Project (GDAP) started with the plan to develop a genomic resource from African populations, characterise genomic diversity and population history, and facilitate clinical studies in Africa. Currently, 25 individuals from 24 ethnolinguistic groups have been whole-genome sequenced at high depth totalling 585 individuals. An additional 41 individuals have been sequenced with 10X Genomics libraries. At this stage, the initial curation of this dataset has been finished and we are performing the analysis in coordination with our collaborators. The current state of the GDAP represents a very diverse panel of African populations that maximizes geographical and ethnic variation and represents a great starting point to achieve the aforementioned goals. However, southern sub-Saharan countries, Bantu speakers and hunter gatherer groups are currently underrepresented, despite being crucial to understand the evolutionary history of the continent. After extensive effort to collate studies documentation, we finally have the opportunity to sequence 600 new individuals from these groups, including countries as Gabon, Rwanda and Zambia, and address these deficiencies. We aim to proceed with the same strategy: to sequence at high depth 25 individuals with standard PCR free libraries, with 2 additional individuals with 10X Genomics Chromium libraries per ethnolinguistic group. The former allows a good representation of variants down to low frequency in any given population, and the latter allows accurate phasing and the analysis of structural variation. By including these new populations, we want to investigate three crucial questions in African history in addition to the initial objectives: the Bantu expansion, the evolutionary history of hunter gatherers and the transatlantic slave trade. Additionally, the expanded dataset will help us better discover the genetic variation present in Africa and characterize the African pangenome. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2021-02-12.

  Dataset EGAD00001006965

• Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution - WGS

  Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event.  Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F,  as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.

  Dataset EGAD00001007714

• Somatic pathogenic variants in the normal mammary gland of sporadic breast cancer patients.

  The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor and peripheral blood from 52 reportedly sporadic breast cancer patients, including breast-conserving surgery cases. Targeted resequencing of 542 cancer associated genes revealed mosaic somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3 and TSHR in the normal mammary gland, at considerable allelic frequencies (9x10-2 to 5.2x10-1) indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low level-mosaic (in 10-2 to 10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumor mammary gland tissue of breast-conserving surgery patients.

  Study EGAS00001005698