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Trends in Genetics : TIG Aug 2019The development of new technologies and experimental techniques is enabling researchers to see what was once unable to be seen. For example, the centromere was first... (Review)
Review
The development of new technologies and experimental techniques is enabling researchers to see what was once unable to be seen. For example, the centromere was first seen as the mediator between spindle fiber and chromosome during mitosis and meiosis. Although this continues to be its most prominent role, we now know that the centromere functions beyond cellular division with important roles in genome organization and chromatin regulation. Here we aim to share the structures and functions of centromeres in various organisms beginning with the diversity of their DNA sequence anatomies. We zoom out to describe their position in the nucleus and ultimately detail the different ways they contribute to genome organization and regulation at the spatial level.
Topics: Animals; Cell Nucleus; Centromere; Chromatin; Chromosomes; Eukaryota; Fungi; Genome; Meiosis; Microscopy; Mitosis; Plants
PubMed: 31200946
DOI: 10.1016/j.tig.2019.05.003 -
Biochimica Et Biophysica Acta Nov 2015Living cells are active mechanical systems that are able to generate forces. Their structure and shape are primarily determined by biopolymer filaments and molecular... (Review)
Review
Living cells are active mechanical systems that are able to generate forces. Their structure and shape are primarily determined by biopolymer filaments and molecular motors that form the cytoskeleton. Active force generation requires constant consumption of energy to maintain the nonequilibrium activity to drive organization and transport processes necessary for their function. To understand this activity it is necessary to develop new approaches to probe the underlying physical processes. Active cell mechanics incorporates active molecular-scale force generation into the traditional framework of mechanics of materials. This review highlights recent experimental and theoretical developments towards understanding active cell mechanics. We focus primarily on intracellular mechanical measurements and theoretical advances utilizing the Langevin framework. These developing approaches allow a quantitative understanding of nonequilibrium mechanical activity in living cells. This article is part of a Special Issue entitled: Mechanobiology.
Topics: Animals; Cytoskeleton; Energy Metabolism; Humans; Models, Biological
PubMed: 26025677
DOI: 10.1016/j.bbamcr.2015.05.022 -
Cell Reports Sep 2023Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical...
Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis using Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with the upregulation of PRAME, an independent prognostic biomarker in UM, and a potential therapeutic target. Our findings illustrate how multi-omics approaches can improve our understanding of tumorigenesis and reveal two distinct mechanisms of gene expression dysregulation in UM.
Topics: Humans; Multiomics; Melanoma; Melanocytes; DNA; Antigens, Neoplasm
PubMed: 37708024
DOI: 10.1016/j.celrep.2023.113132 -
Molecular Oncology Mar 2016Over the past decade, technically reliable circulating tumor cell (CTC) detection methods allowed the collection of large datasets of CTC counts in cancer patients.... (Review)
Review
Over the past decade, technically reliable circulating tumor cell (CTC) detection methods allowed the collection of large datasets of CTC counts in cancer patients. These data can be used either as a dynamic prognostic biomarker or as tumor material for "liquid biopsy". Breast cancer appears to be the cancer type in which CTC have been the most extensively studied so far, with level-of-evidence-1 studies supporting the clinical validity of CTC count in both early and metastatic stage. This review summarizes and discusses the clinical results obtained in breast cancer patients, the issues faced by the molecular characterization of CTC and the biological findings about cancer biology and metastasis that were obtained from CTC.
Topics: Animals; Biopsy; Breast Neoplasms; Female; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prognosis
PubMed: 26809472
DOI: 10.1016/j.molonc.2016.01.001 -
Journal For Immunotherapy of Cancer Aug 2022High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key...
BACKGROUND
High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies.
METHODS
We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays.
RESULTS
We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes.
CONCLUSIONS
Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment.
Topics: Animals; Child; Ecosystem; Humans; Mice; Neoplasm Recurrence, Local; Neuroblastoma; Transcriptome; Tumor Microenvironment
PubMed: 36054452
DOI: 10.1136/jitc-2022-004807 -
Heliyon Nov 2022Spectral analysis of the pole reduced magnetic anomaly data and inversion of complete Bouguer anomaly data are employed here as there is no previous published data...
Determination of Conrad and Curie point depth relationship with the variations in lithospheric structure, geothermal gradient and heat flow beneath the central main Ethiopian rift.
Spectral analysis of the pole reduced magnetic anomaly data and inversion of complete Bouguer anomaly data are employed here as there is no previous published data regarding for the determination of the Curie point depth (CPD), Conrad depth (CD) and lithospheric mantle thickness in the central main Ethiopian rift (CMER) and its environs. The results confirm that the CPD, range between 7.68 and 20.3 km, CD, range between 16 and 25 km and lithospheric mantle thickness, range between 13.4 and 27. 8 km. These results indicate that the CMER magnetic crust occur close to the CD and lithospheric mantle thickness, but below the Moho depth beneath the study area. Based on the results on CPD, we estimate the magnitude of the geothermal gradient and heat flow in the study area. The results confirm that the geothermal gradient, range between 32.4 and 65 °C km and heat flow, range between 80 and 160 mWm. These results are found to be inversely correlated with the CPD. It is a commonly known fact that shallow CPDs generate negative magnetization. Similarly, in this study, it is recorded low magnetic anomalies overlap with shallow (less than 13.1 km) CPDs in line with high (110-160 mWm) heat flow and high (48-64 °C km) geothermal gradient values are determined to occur beneath the CMER. These results associate with the presented geotectonic and geothermal signatures of the study area.
PubMed: 36439756
DOI: 10.1016/j.heliyon.2022.e11735 -
International Journal of Radiation... 2022This review is focused on radium and radionuclides in its decay chain in honor of Marie Curie, who discovered this element. (Review)
Review
PURPOSE
This review is focused on radium and radionuclides in its decay chain in honor of Marie Curie, who discovered this element.
MATERIALS AND METHODS
We conglomerated current knowledge regarding radium and its history predating our present understanding of this radionuclide.
RESULTS
An overview of the properties of radium and its dose assessment is shown followed by discussions about both the negative detrimental and positive therapeutic applications of radium with this history and its evolution reflecting current innovations in medical science.
CONCLUSIONS
We hope to remind all those who are interested in the progress of science about the vagaries of the process of scientific discovery. In addition, we raise the interesting question of whether Marie Curie's initial success was in part possible due to her tight alignment with her husband Pierre Curie who pushed the work along.
Topics: Female; France; History, 19th Century; History, 20th Century; Humans; Radiology; Radium
PubMed: 35030065
DOI: 10.1080/09553002.2022.2027542 -
Current Oncology (Toronto, Ont.) Apr 2007The year 2006 marked 100 years since the death of Pierre Curie. It is therefore appropriate that we remember his life and his work, which was cut short by his untimely...
The year 2006 marked 100 years since the death of Pierre Curie. It is therefore appropriate that we remember his life and his work, which was cut short by his untimely death from an accident on the Pont Neuf, Paris, on April 19, 1906. He had already accomplished much during his life, both before the discovery of radium with Marie Curie, in work co-authored with his brother Jacques on piezoelectricity, and afterwards, when he published the results of several experimental studies with radium and radon. He came from a medical family, and his grandfather Pierre Curie was a famous homeopathic physician. He has, in print, unfairly been relegated to the background-his own scientific contributions having been overtaken by the fame of Marie Curie, probably because she outlived him by 28 years.
PubMed: 17576470
DOI: 10.3747/co.2007.110 -
Cell Reports. Medicine Dec 2022Homologous recombination DNA-repair deficiency (HRD) is becoming a well-recognized marker of platinum salt and polyADP-ribose polymerase inhibitor chemotherapies in...
Homologous recombination DNA-repair deficiency (HRD) is becoming a well-recognized marker of platinum salt and polyADP-ribose polymerase inhibitor chemotherapies in ovarian and breast cancers. While large-scale screening for HRD using genomic markers is logistically and economically challenging, stained tissue slides are routinely acquired in clinical practice. With the objectives of providing a robust deep-learning method for HRD prediction from tissue slides and identifying related morphological phenotypes, we first show that digital pathology workflows are sensitive to potential biases in the training set, then we propose a method to overcome the influence of these biases, and we develop an interpretation method capable of identifying complex phenotypes. Application to our carefully curated in-house dataset allows us to predict HRD with high accuracy (area under the receiver-operator characteristics curve 0.86) and to identify morphological phenotypes related to HRD. In particular, the presence of laminated fibrosis and clear tumor cells associated with HRD open new hypotheses regarding its phenotypic impact.
Topics: Humans; Deep Learning; Neoplasms; Recombinational DNA Repair; Biomarkers, Tumor
PubMed: 36516847
DOI: 10.1016/j.xcrm.2022.100872 -
Molecular Cell Jul 2022Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that...
Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.
Topics: Carcinogenesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Silencing; Genome; Genomics; Humans; Oncogene Proteins, Fusion; Oncogenes; Proto-Oncogene Protein c-fli-1; Sarcoma, Ewing; Transcription Factors; Transcription, Genetic
PubMed: 35550257
DOI: 10.1016/j.molcel.2022.04.019