Key Points
Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant. Allogeneic stem cell transplantation after treatment with venetoclax in combination with HMA is associated with prolonged survival.
Unraveling the highly interconnected nature of complex biological systems is fundamental to a wide range of modern research questions. At the heart of any coordinated biological network is cell-cell communication, and researching the means by which different cell types communicate is an essential prerequisite to fully understanding many aspects of biology. One major mechanism of cell signaling is the regulated release of chemical messengers from preformed vesicles in the cytoplasm. The process of transporting these vesicles to the exterior of the cell and the subsequent release of vesicular contents via membrane fusion is known as exocytosis. In recent decades, carbon-fiber microelectrodes have become increasingly useful for the measurement and study of exocytosis in a variety of biological contexts. This article details the critical background concepts of carbon-fiber microelectrode amperometry (CFMA) and carbon-fiber microelectrode fast scan cyclic voltammetry (FSCV) and reviews a variety of applications for monitoring exocytosis from single in vitro cells. Although the authors recognize the importance of several other complimentary methods including various electron microscopy and patch-clamp techniques, the scope of this article will focus only on CFMA and FSCV and their contributions to the field of single cell exocytosis measurements.
As tissue-resident immune cells, mast cells are frequently found in close proximity to afferent neurons and are subjected to immunoactive mediators secreted by these neurons, including substance P (SP) and calcitonin gene-related peptide (CGRP). Neurogenic inflammation is thought to play an important role in the pathophysiology of many diseases. Unraveling the cellular mechanisms at the interface between the immune response and the peripheral nervous system is important for understanding how these diseases arise and progress. In this work, mast cell degranulation following direct exposure to CGRP and SP was studied both at the bulk and single-cell levels to characterize the mouse peritoneal mast cell response to neuropeptides and compare this response to well-studied mast cell activation pathways. Results show that mast cells secrete fewer chemical messenger-filled granules with increased IgE preincubation concentrations. The biophysical characteristics of mast cell degranulation in response to SP and CGRP is in many ways similar to calcium ionophore-induced mast cell degranulation; however, neuropeptide-stimulated mast cells secrete reduced chemical messenger content per secretion event, resulting in an overall relative decrease in secreted chemical messengers.
Determining triage activation levels in geriatric patients who fall (GF), and patients with penetrating wounds can be difficult and inaccurate, resulting in excessive overtriage (OT) and undertriage (UT) rates. We developed trauma activation prediction models using field data to predict with greater accuracy trauma activation level and triage rates consistent with the ACS recommendations. Using data from the 2014 National Trauma Data Bank, we created binary regression equations for each type of injury (GF and penetrating wounds). The 2014 data were randomized and divided into two halves. The first half for each injury type was used to generate prediction models, whereas the second half of the 2014 data were combined with 2013 and 2015 National Trauma Data Bank data for model verification. Binary regression equations were generated from vital signs collected by EMS. A Cribari grid with ISS ≥ 15 was used to determine the appropriateness of activation level. Chi-square analysis was used to determine significant differences between OT, UT, and accuracy predictions. Using our triage models, we were able to obtain UTrates of less than 4 per cent for GF with OT rates of less than 40 per cent, UT rates less than 4.1 per cent and OT of less than 50 per cent for patients with gunshot wounds, and UTrates less than 4 per cent and OT rates less than 25 per cent for patients who had stab wounds. Our developed trauma level prediction models enable health providers to predict trauma activation levels that can result in OT and UT rates in the recommended ranges by the ACS.
Sickle cell disease, caused by a mutation of hemoglobin, is characterized by a complex pathophysiology including an important inflammatory component. Mast cells are tissue-resident leukocytes known to influence a range of immune functions in a variety of different ways, largely through the secretion of biologically active mediators from preformed granules. However, it is not understood how mast cells influence the inflammatory environment in sickle cell disease. A notable consequence of sickle cell disease is severe pain. Therefore, morphine is often used to treat this disease. Because mast cells express opioid receptors, it is pertinent to understand how chronic morphine exposure influences mast cell function and inflammation in sickle cell disease. Herein, carbon-fiber microelectrode amperometry (CFMA) was used to monitor the secretion of immunoactive mediators from single mast cells. CFMA enabled the detection and quantification of discrete exocytotic events from single mast cells. Mast cells from two transgenic mouse models expressing human sickle hemoglobin (hBERK1 and BERK) and a control mouse expressing normal human hemoglobin (HbA-BERK) were monitored using CFMA to explore the impact of sickle cell-induced inflammation and chronic morphine exposure on mast cell function. This work, utilizing the unique mechanistic perspective provided by CFMA, describes how mast cell function is significantly altered in hBERK1 and BERK mice, including decreased serotonin released compared to HbA-BERK controls. Furthermore, morphine was shown to significantly increase the serotonin released from HbA-BERK mast cells and demonstrated the capacity to reverse the observed sickle cell-induced changes in mast cell function.
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