Project description:Lymphatic vessels are essential for the uptake of fluid, immune cells, macromolecules, and lipids from the interstitial space. During lung transplant surgery, the pulmonary lymphatic vessel continuum is completely disrupted, and, as a result, lymphatic drainage function is severely compromised. After transplantation, the regeneration of an effective lymphatic drainage system plays a crucial role in maintaining interstitial fluid balance in the lung allograft. In the meantime, these newly formed lymphatic vessels are commonly held responsible for the development of immune responses leading to graft rejection, because they are potentially capable of transporting antigen-presenting cells loaded with allogeneic antigens to the draining lymph nodes. However, despite remarkable progress in the understanding of lymphatic biology, there is still a paucity of consistent evidence that demonstrates the exact impacts of lymphatic vessels on lung graft function. In this review, we examine the current literature related to roles of lymphatic vessels in the pathogenesis of lung transplant rejection.
Project description:Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.
Project description:Robotic microsurgery has emerged as a new technology with potential benefits for reconstructive surgery. We report the first-in-human use of the Symani surgical system to perform lympho-venous and arterial anastomosis for lymphatic reconstruction. In five patients, 10 robot-assisted anastomoses were performed. Next to lympho-venous anastomoses, two patients received a free vascularized lymph node transfer. Motion scaling was set to 10×. Visualization was either achieved with a 3D system or an optical microscope. All anastomoses were patent as confirmed by ICG. Despite a longer time to perform the first anastomoses with the robot, we observed a decline in duration of anastomosis. Among the advantages of the system were a high accuracy in placing the stitches even in very small and fragile vessels or when performing anastomoses with size mismatches. The challenges encountered included the lack of a touch sensation and the necessity to develop a "see-feel." This could be achieved surprisingly well because the force necessary to close dilator and needle holder via the manipulators was perceived as comparable to using conventional micro instruments. Our data confirm feasibility and safety of the robotic system to perform lymphatic surgery. Larger patient cohorts and inclusion of surgeons at different training levels will be necessary to investigate the true potential of robotics in microsurgery. In addition, robot-assisted surgery shows a promising potential in opening up new frontiers in reconstructive microsurgery (eg, the reliable performance of anastomoses on even smaller blood and lymphatic vessels or on structures deeper within the body cavities-eg, the thoracic duct).
Project description:Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.
Project description:Purpose of reviewThis review summarizes current immunotherapies in breast cancer, with an emphasis on immune checkpoint inhibitors and vaccines.Recent findingsCombination immunotherapy with checkpoint inhibitors and cytotoxic therapies have shown promising results. Active clinical trials are ongoing in both early stage and metastatic settings for triple negative, HER2+, and hormone-positive breast cancer patients.SummaryOngoing challenges remain in defining biomarkers that predict response to immunotherapy, determining the optimal combination immunotherapies, and enhancing the immunogenicity of breast cancer subtypes.
Project description:Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics. Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse or the components of the ovary that are not ovarian follicles. The ovarian stroma includes more general components such as immune cells, blood vessels, nerves, and lymphatic vessels, as well as ovary-specific components including ovarian surface epithelium, tunica albuginea, intraovarian rete ovarii, hilar cells, stem cells, and a majority of incompletely characterized stromal cells including the fibroblast-like, spindle-shaped, and interstitial cells. The stroma also includes ovarian extracellular matrix components. This review combines foundational and emerging scholarship regarding the structures and roles of the different components of the ovarian stroma in normal physiology. This is followed by a discussion of key areas for further research regarding the ovarian stroma, including elucidating theca cell origins, understanding stromal cell hormone production and responsiveness, investigating pathological conditions such as polycystic ovary syndrome (PCOS), developing artificial ovary technology, and using technological advances to further delineate the multiple stromal cell types.
Project description:Volcanic CO2 emissions play a key role in the geological carbon cycle, and monitoring of volcanic CO2 fluxes helps to forecast eruptions. The quantification of CO2 fluxes is challenging due to rapid dilution of magmatic CO2 in CO2-rich ambient air and the diffuse nature of many emissions, leading to large uncertainties in the global magmatic CO2 flux inventory. Here, we report measurements using a new DIAL laser remote sensing system for volcanic CO2 (CO2DIAL). Two sites in the volcanic zone of Campi Flegrei (Italy) were scanned, yielding CO2 path-amount profiles used to compute fluxes. Our results reveal a relatively high CO2 flux from Campi Flegrei, consistent with an increasing trend. Unlike previous methods, the CO2DIAL is able to measure integrated CO2 path-amounts at distances up to 2000 m using virtually any solid surface as a reflector, whilst also being highly portable. This opens a new frontier in quantification of geological and anthropogenic CO2 fluxes.
Project description:Mast cells are unique tissue-resident immune cells of the myeloid lineage that have long been implicated in the pathogenesis of allergic and autoimmune disorders. More recently, mast cells have been recognized as key orchestrators of anti-tumor immunity, modulators of the cancer stroma, and have also been implicated in cancer cell intrinsic properties. As such, mast cells are an underrecognized but very promising target for cancer immunotherapy. In this review, we discuss the role of mast cells in shaping cancer and its microenvironment, the interaction between mast cells and cancer therapies, and strategies to target mast cells to improve cancer outcomes. Specifically, we address (1) decreasing cell numbers through c-KIT inhibition, (2) modulating mast cell activation and phenotype (through mast cell stabilizers, FcεR1 signaling pathway activators/inhibitors, antibodies targeting inhibitory receptors and ligands, toll like receptor agonists), and (3) altering secreted mast cell mediators and their downstream effects. Finally, we discuss the importance of translational research using patient samples to advance the field of mast cell targeting to optimally improve patient outcomes. As we aim to expand the successes of existing cancer immunotherapies, focused clinical and translational studies targeting mast cells in different cancer contexts are now warranted.
Project description:Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.