Opportunities for organoids as new models of aging.

The biology of aging is challenging to study, particularly in humans. As a result, model organisms are used to approximate the physiological context of aging in humans. However, the best model organisms remain expensive and time-consuming to use. More importantly, they may not reflect directly on the process of aging in people. Human cell culture provides an alternative, but many functional signs of aging occur at the level of tissues rather than cells and are therefore not readily apparent in traditional cell culture models. Organoids have the potential to effectively balance between the strengths and weaknesses of traditional models of aging. They have sufficient complexity to capture relevant signs of aging at the molecular, cellular, and tissue levels, while presenting an experimentally tractable alternative to animal studies. Organoid systems have been developed to model many human tissues and diseases. Here we provide a perspective on the potential for organoids to serve as models for aging and describe how current organoid techniques could be applied to aging research

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.RCUK Cancer Research UK ERC H2020 Wellcome Trus

Lymphocyte traffic changes induced by monolateral vagal denervation in mouse thymus and peripheral lymphoid organs

In this report we show that after monolateral vagal denervation (vagotomy), performed at the cervical level, a transient effect, lasting about 24 h, was produced on lymphocyte release from mouse thymus to peripheral lymphoid organs (spleen and lymph nodes). Labelling thymocytes in situ with fluorescein isothiocyanate (FITC) we note that the export of immature cells, CD4+CD8+, double positive (DP), and double negative, CD4-CD8- (DN), from the thymus was consistently increased 24 and 48 h after vagotomy. Double staining with anti-L3T4 (CD4) and anti-mouse CD8α showed that the number of DP and DN cells was significantly higher in both spleen and lymph nodes of vagotomized mice compared to controls (sham-operated), whereas the percentage of CD4+CD8- and CD8+CD4-, single positives (SP), was decreased. Considering thymic cellularity and apoptotic values, we exclude the non-specific effect of stress and suggest that this phenomenon could be in part due to a transient lack of the facilitating influence exerted by vagal efferent fibers on lymphocyte traffic at the cortico-medullary junction of the thymic gland, where mature cells, SP, leave the thymus to enter systemic circulation

A large asymptomatic portal vein aneurysm in an old man

Ultrasound (US) is a useful tool in diagnosis and follow-up of portal vein aneurysms (PVA). In the absence of international surgical guidelines on PVAs, US can be effectively used in follow-up of asymptomatic patients not suitable for surgery

Vimentin-typing in diagnostic surgical pathology: a comparative study using four antibodies after different fixations

Vimentin-typing was carried out on various normal and neoplastic tissues using four anti-vimentin antibodies in order to evaluate the effect of different fixation treatments on tissue reactivity in comparison to the results obtained on frozen sections. All antisera were reactive on frozen material; on paraffin embedded material staining of tissues depended on the type of fixation method applied (formalin, methacarn or absolute alcohol) and each antibody behaved differently in relation to the fixative used. Only mesenchymal normal structures were revealed on frozen material whilst on paraffin embedded material three of the four antibodies reacted also with non-mesenchymal normal structures (epithelia, central and peripheral nervous system cells). All four antibodies decorated, regardless of treatment, neoplastic cells of mesenchymal and non-mesenchymal derivation, but not germ cells or germ cell tumors. The reactivity of vimentin to its specific antibodies depends on the fixative used: therefore, in routine pathology more than one antiserum should be available for testing. Furthermore, given the variety of non-mesenchymal structures stained by the anti-vimentin antibodies, the differential diagnosis of undifferentiated tumors must not be based on vimentin positivity alone. The expression of vimentin by non-mesenchymal neoplastic cells seems to parallel that of normal tissues during embryogenesis; therefore, this intermediate filament appears to be not only a marker of mesenchymal cells but also of many immature elements

Neuron-specific enolase (gamma enolase, gamma-gamma dimer) expression in Hodgkin's disease and large cell lymphomas

BACKGROUND: The presence of gamma-enolase, gamma gamma dimer, or neuron-specific enolase (NSE) has been demonstrated in miscellaneous tumors, including malignant lymphomas. Up to now these results have been interpreted as non-specific, although NSE can be expressed by normal B and T lymphoid cells at a particular stage of differentiation. The aim of the present study was to investigate the expression of NSE in a large series of malignant lymphomas, including Hodgkin's disease, in relation to morphology and immunophenotype. MATERIALS AND METHODS: Frozen and paraffin embedded sections from 16 cases of Hodgkin's disease (4 lymphocyte predominance, nodular; 4 mixed cellularity; 6 nodular sclerosis; 2 lymphocyte depletion) and 35 cases of non-Hodgkin's lymphomas were investigated in order to evaluate the expression of NSE, its specificity and correlation to immunophenotype or other immunological cell markers. Among the non-Hodgkin's lymphomas, there were 9 Anaplastic Large Cell (CD30+) Lymphomas; 2 Peripheral Large T-Cell Lymphomas; 22 Diffuse Large B-Cell Lymphomas and 2 Primary Mediastinal Large B-Cell Lymphomas. RESULTS: In Hodgkin's disease, NSE showed a diffuse cytoplasmic reaction in CD30+ Reed-Sternberg cells, whereas the "popcorn" (L&H) cells of lymphocyte predominance, nodular variant cases, were always negative. Among the non-Hodgkin's lymphomas, NSE positivity was found only in lymphomas expressing CD30. All the other cases were negative. No relationship was found between NSE and B- or T-immunophenotype. CONCLUSIONS: Our results suggest that a link between NSE and CD30 expression exists in malignant lymphomas. However, at the moment this has not been sufficiently investigated and is subject to speculation

Bone marrow uptake of 18F-FDG PET/CT and bone marrow biopsy in initial staging of diffuse large B-cell lymphoma patients

Objective: To develop a method to fuse lymphoscintigraphic images with an adaptable anatomical vector profile and to evaluate its role in the clinical practice. Methods: We used Adobe Illustrator CS6 to create different vector profiles, we fused those profiles, using Adobe Photoshop CS6, with lymphoscintigraphic images of the patient. We processed 197 lymphoscintigraphies performed in patients with cutaneous melanomas, breast cancer or delayed lymph drainage. Results: Our models can be adapted to every patient attitude or position and contain different levels of anatomical details ranging from external body profiles to the internal anatomical structures like bones, muscles, vessels, and lymph nodes. If needed, more new anatomical details can be added and embedded in the profile without redrawing them, saving a lot of time. Details can also be easily hidden, allowing the physician to view only relevant information and structures. Fusion times are about 85 s. The diagnostic confidence of the observers increased significantly. The validation process showed a slight shift (mean 4.9 mm). Conclusions: We have created a new, practical, inexpensive digital technique based on commercial software for fusing lymphoscintigraphic images with built-in anatomical reference profiles. It is easily reproducible and does not alter the original scintigraphic image. Our method allows a more meaningful interpretation of lymphoscintigraphies, an easier recognition of the anatomical site and better lymph node dissection planning. © 2013 The Japanese Society of Nuclear Medicine