Background: T cell lymphoma, comprising 15% of diagnosed US lymphomas, currently has no standard of care in the relapsed setting. Exposure to molds diminishes the numbers of T-helpers cells in ...peripheral blood. Aspergillus and Penicillium are known to produce small molecules called mycotoxins. Mycotoxins have previously been associated with immunosuppressive effects (Sutton et al., 1994, 1995), and a reduction of cytokine secretion (Rossano et al., 1999.) This study investigates the effects of two of these mycotoxins, Gliotoxin and Patulin, on the cellular components of mononuclear cells in peripheral blood of normal donors and T-cell lymphoma cells, examining viability and apoptotic damage in CD3+ (T cells), CD4+ (cytotoxic t cells), CD8+ (t helper cells), and CD16+ (NK cells), BDCA1+ and BDCA2+ (dendritic cells), CD14+ (monocytes), and CD19+ (B cells).
Methods: Two mycotoxins, Gliotoxin and Patulin were solubilized into methanol or ethanol and cultured with either normal ficolled blood samples, T-cell lymphoma or T-cell leukemic cells. We plated cells at a concentration of 1x 106 cells per well, treated them with concentrations of 0, 1, 10, 100, 1,000, or 10,000 ng/mL, and incubated for 24 hours. After incubation the cells were removed and washed, and stained with fluorescent antibodies. Cellular content was determined by flow cytometry (FACS). Prior to acquisition by FACS, counting beads were added to each sample to determine absolute counts of each population of cells. Populations of interest were CD3+, CD4+, CD8+, and CD16+, BDCA1+ and BDCA2+, CD14+, and CD19+. Annexin and Propidium Iodide (PI) were added to evaluate apoptotic and non-viable cells. FloJo software was used to analyze the FACS data. Absolute count of viable cells was then converted to percentages using solvent only control as 100% viable.
Results:
Cell Viability after 24 hr Incubation with MycotoxinsConcentrationNormal Peripheral Blood (n=9)T Cell Lymphoma (n=2)Gliotoxin (ng/mL)CD3+/CD4+CD3+/CD8+DC1DC2NKBCD3+01001001001001001001001127128219143104127961012612936691091178210015153252181101,000233331113113710,0004746631326274Patulin (ng/mL)01001001001001001001001666874866081931094100101114848833310084101791411101381521,000393822635276910,000534503439781Median Percent Viable when 0 ng/mL = 100% Viable
The dose of Gliotoxin, most effective for inducing apoptosis and cell death in normal donor T cells is 100 ng/mL, whereas the most effective dose of Patulin was 1,000 ng/mL. In the cell line, the lowest dose of both mycotoxins that produced significant apoptosis and cell death was 1,000 ng/mL.
Conclusion: Our results demonstrate that the mycotoxins, Patulin and Gliotoxin kill PBMC, and confirm the results found by Stanzani et al that Gliotoxin is most cytotoxic against the antigen presenting cells (APC), which impairs T cell response. Our experiment showed that Patulin had the same effect against APC. T cell viability itself was greatly influenced by the addition of Gliotoxin or Patulin, which supports previous evidence that mycotoxins suppress some populations of T cells. Certain issues, such as a less toxic solvent must be addressed; the data, however, shows that mycotoxins do have the ability to kill both normal and T cell leukemic/lymphoma cells.
Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately ...suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers.
Workplace technologies are more central to working in organisations than ever before. These technologies began as instrumental aids to support office work of individuals but have since also become ...the basis for social interactions and community building in organisations and more recently become able to perform managerial roles with the use of advanced AI capabilities. Our call for papers to this special issue invited original studies to go further and advance our thinking on the strategic implications of this layered evolution of workplace technologies on work and the structure of organisations. In this introduction, we synthesise the main themes from the special issue, and also ongoing dialogues with the growing community at the regular AIS / IFIP 9.1 workshop on the Changing Nature of Work. A key observation is that the work involved in configuring emergent Digital/Human configurations, is vastly under-reported and poorly understood. Paradoxically, this configuring work is the most demanding and critical in the shaping of modern organisations. We suggest that this type of largely invisible work requires engagement beyond the level of execution or even the meaning of work, it requires intervening with third order effects that get to the core of what an organisation is. We highlight the challenges for organisations in dealing with third order change, particularly because these effects are beyond existing frames of reference and require more dynamic and supple responses based on the values, purpose andintent dominantin the organisation – we describe this as structural digital work. Leaders that are unable or unwilling to engage with effects at this level, and this type of work, will miss identifying core opportunities and risks associated with digital transformation in organisations. We also reflect on the value of current theories and methods used to research this important and emergent phenomenon.
Abstract
As advances in oncology therapies lead to significant improvement in life expectancy of many cancer entities, short-, and long-term cardiac side effects of oncology treatments gain ...increasing importance. In search of new screening modalities, echocardiography currently presents the best established and clinically easily feasible tool to detect cardiotoxicity in patients undergoing cancer therapy. This review focusses on the most commonly used oncology therapies and aims to give a practical approach to guide clinicians caring for this growing number of patients.
Understanding the antibody response to HIV-1 in humans that show broad neutralizing serologic activity is a crucial step in trying to reproduce such responses by vaccination. Investigating antibodies ...with cross clade reactivity is particularly important as these antibodies may target conserved epitopes on the HIV envelope gp160 protein. To this end we have used a clade B YU-2 gp140 trimeric antigen and single-cell antibody cloning methods to obtain 189 new anti-gp140 antibodies representing 51 independent B cell clones from the IgG memory B cells of 3 patients infected with HIV-1 clade A or B viruses and exhibiting broad neutralizing serologic activity. Our results support previous findings showing a diverse antibody response to HIV gp140 envelope protein, characterized by differentially expanded B-cell clones producing highly hypermutated antibodies with heterogenous gp140-specificity and neutralizing activity. In addition to their high-affinity binding to the HIV spike, the vast majority of the new anti-gp140 antibodies are also polyreactive. Although none of the new antibodies are as broad or potent as VRC01 or PG9, two clonally-related antibodies isolated from a clade A HIV-1 infected donor, directed against the gp120 variable loop 3, rank in the top 5% of the neutralizers identified in our large collection of 185 unique gp140-specific antibodies in terms of breadth and potency.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly ...neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.
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