644 research outputs found

    Immunomorphological Patterns of Chaperone System Components in Rare Thyroid Tumors with Promise as Biomarkers for Differential Diagnosis and Providing Clues on Molecular Mechanisms of Carcinogenesis

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    Hurthle cell (HC), anaplastic (AC), and medullary (MC) carcinomas are low frequency thyroid tumors that pose several challenges for physicians and pathologists due to the scarcity of cases, information, and histopathological images, especially in the many areas around the world in which sophisticated molecular and genetic diagnostic facilities are unavailable. It is, therefore, cogent to provide tools for microscopists to achieve accurate diagnosis, such as histopathological images with reliable biomarkers, which can help them to reach a differential diagnosis. We are investigating whether components of the chaperone system (CS), such as the molecular chaperones, can be considered dependable biomarkers, whose levels and distribution inside and outside cells in the tumor tissue could present a distinctive histopathological pattern for each tumor type. Here, we report data on the chaperones Hsp27, Hsp60, and Hsp90. They presented quantitative levels and distribution patterns that were different for each tumor and differed from those of a benign thyroid pathology, goiter (BG). Therefore, the reported methodology can be beneficial when the microscopist must differentiate between HC, AC, MC, and BG

    Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies

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    : Mutations in genes encoding molecular chaperones, for instance the genes encoding the subunits of the chaperonin CCT (chaperonin containing TCP-1, also known as TRiC), are associated with rare neurodegenerative disorders. Using a classical molecular dynamics approach, we investigated the occurrence of conformational changes and differences in physicochemical properties of the CCT5 mutations His147Arg and Leu224Val associated with a sensory and a motor distal neuropathy, respectively. The apical domain of both variants was substantially but differently affected by the mutations, although these were in other domains. The distribution of hydrogen bonds and electrostatic potentials on the surface of the mutant subunits differed from the wild-type molecule. Structural and dynamic analyses, together with our previous experimental data, suggest that genetic mutations may cause different changes in the protein-binding capacity of CCT5 variants, presumably within both hetero- and/or homo-oligomeric complexes. Further investigations are necessary to elucidate the molecular pathogenic pathways of the two variants that produce the two distinct phenotypes. The data and clinical observations by us and others indicate that CCT chaperonopathies are more frequent than currently believed and should be investigated in patients with neuropathies

    Immunohistochemistry of Human Hsp60 in Health and Disease: Recent Advances in Immunomorphology and Methods for Assessing the Chaperonin in Extracellular Vesicles

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    The subject matter of this chapter is defined by the title of its two previous editions, "Immunohistochemistry of human Hsp60 in health and disease: From autoimmunity to cancer," the latest of which appeared in 2018. Since then, considerable advances have been made in the fields of autoimmunity and cancer and some of them are closely linked to progress in the understanding of the chaperone system (CS). This is a physiological system composed of molecular chaperones, co-chaperones, chaperone cofactors, and chaperone interactors and receptors. The molecular chaperones are the chief members of the CS, and here we focus on one of them, Hsp60. Since extracellular vesicles (EVs) have also emerged as key factors in the functioning of the CS and in carcinogenesis, we have incorporated a detailed section about them. This chapter explains how to assess Hsp60 in tissues and in EVs for application in diagnosis, prognostication, and patient monitoring and, eventually, for developing methods using them as therapeutic targets and tools. We describe immunohistochemical techniques, immunofluorescence and double immunofluorescence-confocal microscopy, and methods for collecting and isolating EVs from blood plasma and for assessing their contents in Hsp60 and related microRNAs (miRNAs). All these procedures have proven to be reliable and useful in the study and management of various types of cancer and inflammatory and autoimmune conditions

    BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

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    International audienceAbstract Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance

    La simulazione

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    Il contributo costituisce la seconda edizione, totalmente riveduta ed aggiornata, della trattazione dell'intera disciplina legale in materia di simulazione del contratto e degli atti unilaterali, unitamente ad una compiuta analisi delle ipotesi applicative esaminate alla luce della giurisprudenza più recente della Corte di Cassazione

    Forest fire history in Amazonia inferred from intensive soil charcoal sampling and radiocarbon dating

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    This study was supported by funding from the UK Natural Environment Research Council (NERC, NE/N011570/1 and NE/R017980/1) and a radiocarbon dating allocation (allocation 2122.0818) from the NERC-funded NEIF Radiocarbon Laboratory.Fire has a historical role in tropical forests related to past climate and ancient land use spanning the Holocene; however, it is unclear from charcoal records how fire varied at different spatiotemporal scales and what sampling strategies are required to determine fire history and their effects. We evaluated fire variation in structurally intact, terra-firme Amazon forests, by intensive soil charcoal sampling from three replicate soil pits in sites in Guyana and northern and southern Peru. We used radiocarbon (14C) measurement to assess (1) locally, how the timing of fires represented in our sample varied across the surface of forest plots and with soil depth, (2) basin-wide, how the age of fires varies across climate and environmental gradients, and (3) how many samples are appropriate when applying the 14C approach to assess the date of last fire. Considering all 14C dates (n = 33), the most recent fires occurred at a similar time at each of the three sites (median ages: 728–851 cal years BP), indicating that in terms of fire disturbance at least, these forests could be considered old-growth. The number of unique fire events ranged from 1 to 4 per pit and from 4 to 6 per site. Based upon our sampling strategy, the N-Peru site—with the highest annual precipitation—had the most fire events. Median fire return intervals varied from 455 to 2,950 cal years BP among sites. Based on available dates, at least three samples (1 from the top of each of 3 pits) are required for the sampling to have a reasonable likelihood of capturing the most recent fire for forests with no history of a recent fire. The maximum fire return interval for two sites was shorter than the time since the last fire, suggesting that over the past ∼800 years these forests have undergone a longer fire-free period than the past 2,000–3,500 years. Our analysis from terra-firme forest soils helps to improve understanding of changes in fire regime, information necessary to evaluate post-fire legacies on modern vegetation and soil and to calibrate models to predict forest response to fire under climate change.Publisher PDFPeer reviewe

    Late Holocene mangrove dynamics of the Doce River delta, southeastern Brazil: implications for the understanding of mangrove resilience to sea-level changes and channel dynamics

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    This work aims to understand mangrove resilience to changes in a wave-influenced delta in southeastern Brazil during the late Holocene using an integrated analysis of palynology, sedimentology, and geochemistry (δ13C, δ15N, C:N and C:S ratio), and radiocarbon dating on two sediment cores. The data indicated three mangrove succession phases: 1) an estuarine point bar/tidal flat occupied by a mixture of mangrove species (~2660 - ~2050 cal yr BP); 2) a tidal flat dominated by Laguncularia mangroves (~2050 - ~900 cal yr BP); and 3) tidal flats with Laguncularia mangroves upstream and establishment of Rhizophora/Avicennia mangrove at the river mouth (~900 cal yr BP until present). The geochemical results suggest a dominance of C3 terrestrial plants with a mixture of C4 plants and organic matter of marine/estuarine origin throughout the late Holocene. Laguncularia and Rhizophora trees were established since ~2660 cal yr BP as pioneers, followed thereafter by Avicennia. Currently, tidal flats upstream are occupied by mangroves mainly represented by Laguncularia. Rhizophora/Avicennia mangroves occur at the mouth of the river. The relative sea-level fall during the late Holocene, as well as the channel dynamics, caused the development of tidal flats and mangrove succession inland. The succession of Rhizophora, Laguncularia, and Avicennia, followed by the permanence of only Laguncularia, is likely related to the resilience of each mangrove genus to habitat disturbance (e.g., salinity and sediment grain size fractions) caused by sea-level changes and channel dynamics. Our results show that mangroves may be resilient to the effects of Atlantic sea-level fluctuations, but the floristic structure in the past is different from that of today
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