Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

• Publication type
• Journal Article MeSH

The last 2 decades have attended a dynamic evolution in the nosology of poorly differentiated sinonasal tract malignancies, with several new molecularly defined entities having been described in addition to delineation of the genetic driver/s of some established older entities. These discoveries, however, mostly concerned epithelial-derived neoplasms (carcinomas). Adamantinoma-like Ewing sarcoma and biphenotypic sinonasal sarcoma are the major representatives of the newly defined mesenchymal categories. The colorectal cancer associated 2 (COLCA2) has been discovered recently as a colorectal cancer risk gene locus, but fusions involving this gene have not been well characterized. We, herein, describe clinicopathologic and molecular features of a novel sinonasal sarcoma characterized by undifferentiated spindle/round cell morphology and defined by recurrent EWSR1::COLCA2 fusions. All patients (n=5) were adults (3 female and 2 male) with a median age of 46 years (range, 23 to 60 y). The tumors originated in different subsites of the sinonasal tract with frequent multisite involvement. Original diagnoses were undifferentiated or unclassified round cell/spindle cell neoplasm/sarcoma (n=4) and neuroendocrine carcinoma (n=1). Surgery with or without adjuvant chemoradiation was the treatment in all cases. At the last follow-up, 1 patient developed multiple local recurrences over 21 years and another developed local recurrence and distant metastasis to bone 27 months after diagnosis. A third patient developed local recurrence 11 months later. Two patients were disease-free at 23, and 24 months. Histology showed nondescript highly cellular neoplasms with an admixture of spindled and round cells disposed into solid sheets and fascicles with brisk mitotic activity. Immunohistochemistry was negative for all lineage-specific markers with only limited focal membranous CD99 (4 of 5 cases) and weak pankeratin (1 of 5 cases) expression. Targeted RNA sequencing revealed an EWSR1::COLCA2 fusion, verified by EWSR1 fluorescence in situ hybridization, in all cases. This series identifies a novel member in the undifferentiated spindle/round cell sarcoma category with strong predilection for the sinonasal tract. None of >10,000 epithelial and mesenchymal neoplasms tested at the authors' centers during the same period showed this fusion, highlighting rarity of tumors carrying this gene fusion. Accordingly, molecular testing of unclassified sinonasal malignancies/sarcomas showing round and spindle cell morphology is recommended to enhance the identification and further characterization of this entity.

• MeSH
• Adult MeSH
• Sarcoma, Ewing * genetics   MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Colorectal Neoplasms * MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   MeSH
• Neoplasm Proteins genetics   MeSH
• Soft Tissue Neoplasms * MeSH
• Paranasal Sinus Neoplasms * MeSH
• Paranasal Sinuses * pathology   MeSH
• RNA-Binding Protein EWS genetics   MeSH
• Sarcoma * genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The loss of control of cell proliferation, apoptosis regulation and contact inhibition leads to tumor development. While benign tumors are restricted to their primary space, i.e. where these tumors first originate, the metastatic tumors not only disseminate- facilitated by hypoxia-driven neovascularization- to distant secondary sites but also show substantial changes in metabolism, tissue architectures, gene expression profiles and immune phenotypes. All these alterations result in radio-, chemo- and immune-resistance rendering these metastatic tumor cells refractory to therapy. Since the beginning of the transformation, these factors- which influence each other- are incorporated to the developing and metastasizing tumor. As a result, the complexities in the heterogeneity of tumor progressively increase. This space-time function in the heterogeneity of tumors is generated by various conditions and factors at the genetic as well as microenvironmental levels, for example, endogenous retroviruses, methylation and epigenetic dysregulation that may be etiology-specific, cancer associated inflammation, remodeling of the extracellular matrix and mesenchymal cell shifted functions. On the one hand, these factors may cause de-differentiation of the tumor cells leading to cancer stem cells that contribute to radio-, chemo- and immune-resistance and recurrence of tumors. On the other hand, they may also enhance the heterogeneity under specific microenvironment-driven proliferation. In this editorial, we intend to underline the importance of heterogeneity in cancer progress, its evaluation and its use in correlation with the tumor evolution in a specific patient as a field of research for achieving precise patient-tailored treatments and amelioration of diagnostic (monitoring) tools and prognostic capacity.

• MeSH
• Extracellular Matrix MeSH
• Humans MeSH
• Neoplastic Stem Cells MeSH
• Tumor Microenvironment genetics   MeSH
• Neoplasms * genetics   MeSH
• Neovascularization, Pathologic MeSH
• Cell Proliferation genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Editorial MeSH

• MeSH
• Genome, Human * MeSH
• Molecular Biology MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Biochemie. Molekulární biologie. Biofyzika
• NML Fields
• molekulární biologie, molekulární medicína

Compartmentalization was likely essential for primitive chemical systems during the emergence of life, both for preventing leakage of important components, i.e., genetic materials, and for enhancing chemical reactions. Although life as we know it uses lipid bilayer-based compartments, the diversity of prebiotic chemistry may have enabled primitive living systems to start from other types of boundary systems. Here, we demonstrate membraneless compartmentalization based on prebiotically available organic compounds, α-hydroxy acids (αHAs), which are generally coproduced along with α-amino acids in prebiotic settings. Facile polymerization of αHAs provides a model pathway for the assembly of combinatorially diverse primitive compartments on early Earth. We characterized membraneless microdroplets generated from homo- and heteropolyesters synthesized from drying solutions of αHAs endowed with various side chains. These compartments can preferentially and differentially segregate and compartmentalize fluorescent dyes and fluorescently tagged RNA, providing readily available compartments that could have facilitated chemical evolution by protecting, exchanging, and encapsulating primitive components. Protein function within and RNA function in the presence of certain droplets is also preserved, suggesting the potential relevance of such droplets to various origins of life models. As a lipid amphiphile can also assemble around certain droplets, this further shows the droplets' potential compatibility with and scaffolding ability for nascent biomolecular systems that could have coexisted in complex chemical systems. These model compartments could have been more accessible in a "messy" prebiotic environment, enabling the localization of a variety of protometabolic and replication processes that could be subjected to further chemical evolution before the advent of the Last Universal Common Ancestor.

• MeSH
• Fluorescent Dyes chemistry   MeSH
• Fluorescence Recovery After Photobleaching MeSH
• Hydrogen-Ion Concentration MeSH
• Carboxylic Acids chemistry   MeSH
• Membranes, Artificial * MeSH
• Polyesters chemical synthesis   chemistry   MeSH
• Origin of Life * MeSH
• RNA chemistry   MeSH
• Particle Size MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Since aging seems omnipresent, many authors regard it as an inevitable consequence of the laws of physics. However, recent research has conclusively shown that some organisms do not age, or at least do not age on a scale comparable with other aging organisms. This begets the question why aging evolved in some organisms yet not in others. Here we present a simulation model of competition between aging and non-aging individuals in a sexually reproducing population. We find that the aging individuals may outcompete the non-aging ones if they have a sufficiently but not excessively higher initial fecundity or if individuals mate assortatively with respect to their own phenotype. Furthermore, the aging phenotype outcompetes the non-aging one or resists dominance of the latter for a longer period in populations composed of genuine males and females compared to populations of simultaneous hermaphrodites. Finally, whereas sterilizing parasites promote non-aging, the effect of mortality-enhancing parasites is to enable longer persistence of the aging phenotype relative to when parasites are absent. Since the aging individuals replace the non-aging ones in diverse scenarios commonly found in nature, our study provides important insights into why aging has evolved in most, but not all organisms.

• MeSH
• Biological Evolution * MeSH
• Phenotype MeSH
• Fertility genetics   physiology   MeSH
• Sex Characteristics MeSH
• Genetics, Population MeSH
• Reproduction genetics   MeSH
• Mating Preference, Animal physiology   MeSH
• Aging genetics   physiology   MeSH
• Models, Theoretical MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.

• MeSH
• Biomarkers MeSH
• Epigenesis, Genetic MeSH
• Lymphoma, Follicular etiology   metabolism   pathology   MeSH
• Humans MeSH
• RNA, Untranslated genetics   MeSH
• Proto-Oncogene Proteins c-bcl-2 genetics   metabolism   MeSH
• Receptors, Antigen, B-Cell metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Neoplasms MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• onkologie
• NML Publication type
• kolektivní monografie

KEY MESSAGE: This work discusses several selected topics of plant genetics and breeding in relation to the 150th anniversary of the seminal work of Gregor Johann Mendel. In 2015, we celebrated the 150th anniversary of the presentation of the seminal work of Gregor Johann Mendel. While Darwin's theory of evolution was based on differential survival and differential reproductive success, Mendel's theory of heredity relies on equality and stability throughout all stages of the life cycle. Darwin's concepts were continuous variation and "soft" heredity; Mendel espoused discontinuous variation and "hard" heredity. Thus, the combination of Mendelian genetics with Darwin's theory of natural selection was the process that resulted in the modern synthesis of evolutionary biology. Although biology, genetics, and genomics have been revolutionized in recent years, modern genetics will forever rely on simple principles founded on pea breeding using seven single gene characters. Purposeful use of mutants to study gene function is one of the essential tools of modern genetics. Today, over 100 plant species genomes have been sequenced. Mapping populations and their use in segregation of molecular markers and marker-trait association to map and isolate genes, were developed on the basis of Mendel's work. Genome-wide or genomic selection is a recent approach for the development of improved breeding lines. The analysis of complex traits has been enhanced by high-throughput phenotyping and developments in statistical and modeling methods for the analysis of phenotypic data. Introgression of novel alleles from landraces and wild relatives widens genetic diversity and improves traits; transgenic methodologies allow for the introduction of novel genes from diverse sources, and gene editing approaches offer possibilities to manipulate gene in a precise manner.

• MeSH
• History, 19th Century MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Phenotype MeSH
• Genetic Variation MeSH
• Plants, Genetically Modified genetics   MeSH
• Genetics history   MeSH
• Genome, Plant MeSH
• Genomics MeSH
• Pisum sativum genetics   MeSH
• Quantitative Trait Loci MeSH
• Chromosome Mapping MeSH
• Selection, Genetic MeSH
• Plant Breeding * MeSH
• Check Tag
• History, 19th Century MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Publication type
• Biography MeSH
• Journal Article MeSH
• Historical Article MeSH
• Review MeSH

• About
• Mendel, Johann Gregor, 1822-1884 Authority

Geographical isolation, habitat variation and trophic specialization have contributed to a large extent to the astonishing diversity of cichlid fishes in the Great East African lakes. Because parasite communities often vary across space and environments, parasites can accompany and potentially enhance cichlid species diversification. However, host dispersal may reduce opportunities for parasite-driven evolution by homogenizing parasite communities and allele frequencies of immunity genes. To test for the relationships between parasite community variation, host dispersal and parasite-induced host evolution, we studied two sympatric cichlid species with contrasting dispersal capacities along the shores of southern Lake Tanganyika. Whereas the philopatric Tropheus moorii evolved into several genetically differentiated colour morphs, Simochromis diagramma is phenotypically rather uniform across its distribution range and shows only weak population structure. Populations of both species were infected with divergent parasite communities and harbour differentiated variant pools of an important set of immune genes, the major histocompatibility complex (MHC). The overall extent of geographical variation of parasites and MHC genes was similar between host species. This indicates that immunogenetic divergence among populations of Lake Tanganyika cichlids can occur even in species that are strongly dispersing. However, because this also includes species that are phenotypically uniform, parasite-induced evolution may not represent a key factor underlying species diversification in this system.

• MeSH
• Cichlids genetics   immunology   parasitology   MeSH
• Phenotype MeSH
• Major Histocompatibility Complex genetics   MeSH
• Immunogenetics * MeSH
• Parasites MeSH
• Genetics, Population MeSH
• Animal Distribution * MeSH
• Sympatry * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Tanzania MeSH