Purpose
To describe the use of hydroxychloroquine (HCQ), azithromycin (AZI) and low‐molecular‐weight‐heparins (LMWH) by sex among elderly residents in nursing homes (NHs) of Tuscany region (Italy) ...during the first pandemic peak.
Methods
A population‐based drug utilization study was performed linking the Tuscany Administrative Databases (TAD) to the regional COVID‐19 registry. Among elderly patients (≥ 65 years old) registered in TAD on 1st December 2019, new users of HCQ, AZI and LMWH that started the treatment during NHs stay (i.e., no dispensing of the same drug during the previous 6 months) were respectively identified in each month of observation period (December 2019–May 2020). The percentage of subjects diagnosed with COVID‐19 (COVID‐19+) on, or before, the date of first dispensing of the drug of interest was described. Results were stratified by sex (male = M; female = F).
Results
New users of HCQ, AZI and LMWH were 62, 300, and 1215, respectively. About 95% of HCQ new users received the drug in April (M = 20; F = 40) of which 11 of men (55%) and 25 of women (62%) were COVID‐19+; AZI new users in April (M = 32; F = 83) were two‐fold compared to February, of which 10 of men (31%) and 30 of women (36%) were COVID‐19+; LMWH new users showed a peak in April (M = 74; F = 142), when 31% of men and 34% of women were COVID‐19 + .
Conclusions
New users showed a peak during the first pandemic wave and females were over two‐fold compared to men. HCQ was often prescribed in absence of COVID‐19 diagnosis. During future global emergencies drug prescriptions should better be monitored in frail populations, especially in case of drugs with uncertain efficacy and safety.
Background
Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for ...studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class‐specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans.
Methods
We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour‐associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE‐FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies.
Results
In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a “cytokine storm” or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE‐mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour‐bearing lungs.
Conclusion
Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.
To study IgE class‐specific functions and safety, we designed a surrogate rat tumour model and rat equivalent antibodies of a human/chimeric IgE therapeutic candidate recognising a tumour associated antigen. IgE restricted tumour growth, elevated intratumoural immune cell infiltration and enhanced immune pathway activation, without clinical, histopathological or metabolic toxicity signs, nor immunological evidence of allergic response or cytokine storm. This model may inform translation of anti‐tumour IgE antibodies to clinical study, and help to dissect IgE functions in AllergoOncology, allergic inflammation, allergen immunotherapy and anti‐parasitic responses.
Purpose
Skeletal muscle (Skm) plays a key role in regulating energetic metabolism through glucose homeostasis. Several hormones such as Testosterone (T) and Vitamin D (VD) have been shown to affect ...energy-dependent cell trafficking by determining Insulin (I)-like effects.
Aim
To elucidate possible hormone-related differences on muscular metabolic control, we analyzed and compared the effects of T and elocalcitol (elo), a VD analogue, on the activation of energy-dependent cell trafficking, metabolism-related-signal transduction pathways and transcription of gene downstream targets.
Methods
Human fetal skeletal muscle cells (Hfsmc) treated with T or elo were analyzed for GLUT4 localization, phosphorylation/activation status of AKT, ERK1/2, IRS-1 signaling and c-MYC protein expression.
Results
T, similar to elo, induced GLUT4 protein translocation likely in lipid raft microdomains. While both T and elo induced a rapid IRS-1 phosphorylation, the following dynamic in phosphorylation/activation of AKT and ERK1/2 signaling was different. Moreover, T but not elo increased c-MYC protein expression.
Conclusions
All together, our evidence indicates that whether both T and elo are able to affect upstream I-like pathway, they differently determine downstream effects in I-dependent cascade, suggesting diverse physiological roles in mediating I-like response in human skeletal muscle.
B cells participate in immune surveillance in human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses in cutaneous immunity is underappreciated. ...We report circulating skin-homing CD22+CLA+B cells in healthy volunteers and melanoma patients (n = 73) and CD22+ cells in melanoma and normal skin samples (n = 189). Normal and malignant skin featured mature IgG and CD22 mRNA, alongside mRNA for the transiently-expressed enzyme Activation-induced cytidine Deaminase (AID). Gene expression analyses of publically-available data (n = 234 GEO, n = 384 TCGA) confirmed heightened humoral responses (CD20, CD22, AID) in melanoma. Analyses of 51 melanoma-associated and 29 normal skin-derived IgG sequence repertoires revealed lower IgG1/IgGtotal representation compared with antibodies from circulating B cells. Consistent with AID, comparable somatic hypermutation frequencies and class-switching indicated affinity-matured antibodies in normal and malignant skin. A melanoma-associated antibody subset featured shorter complementarity-determining (CDR3) regions relative to those from circulating B cells. Clonal amplification in melanoma-associated antibodies and homology modeling indicated differential potential antigen recognition profiles between normal skin and melanoma sequences, suggesting distinct antibody repertoires. Evidence for IgG-expressing B cells, class switching and antibody maturation in normal and malignant skin and clonally-expanded antibodies in melanoma, support the involvement of mature B cells in cutaneous immunity.
T-helper 1 (Th1) cell-mediated inflammatory responses predominate in the early pathogenesis of Graves’ disease (GD), whereas Th2 cell-mediated immunity may play a role in later stages. The chemokine ...CXCL10 and its receptor CXCR3 are expressed in most thyroid glands of early GD patients. Circulating CXCL10 levels inversely correlate with disease duration; CXCL10 maximal expression also correlates with interferon (IFN)γ levels in recent GD onset. Methimazole (MMI) reduces CXCL10 secretion by isolated thyrocytes, decreases serum CXCL10 levels, and promotes a transition from Th1 to Th2 dominance in patients in GD active phase. Vitamin D receptor agonists exhibit antiinflammatory properties and promote tolerance induction. We investigated the effects and the mechanism of action of a nonhypercalcemic vitamin D receptor agonist, elocalcitol (BXL-628), compared with MMI on CXCL10 secretion induced by proinflammatory cytokines. Furthermore, we studied the effects of both drugs on Th1, Th17, and Th2 cytokine secretion in CD4+ T cells. ELISA, cytometry, immunocytochemistry, Western blot, and quantitative real-time PCR were used for protein and gene analysis. In human thyrocytes, elocalcitol inhibited IFNγ and TNFα-induced CXCL10 protein secretion more potently than MMI. Elocalcitol impaired both cytokine intracellular pathways, whereas MMI was effective only on the IFNγ pathway. In CD4+ T cells, elocalcitol decreased Th1- and Th17-type cytokines, and promoted Th2-type cytokine secretion. Elocalcitol and MMI inhibited Th1 cytokine-mediated responses in thyrocytes and CD4+ T cells. In addition, elocalcitol promoted a shift toward a Th2 response. In conclusion, elocalcitol could represent a novel pharmacological tool in the treatment of autoimmune thyroid diseases.
The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to ...enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.
Purpose
Testosterone by promoting different metabolic pathways contributes to short-term homeostasis of skeletal muscle, the largest insulin-sensitive tissue and the primary site for ...insulin-stimulated glucose utilization. Despite evidences indicate a close relationship between testosterone and glucose metabolism, the molecular mechanisms responsible for a possible testosterone-mediated insulin-like effects on skeletal muscle are still unknown.
Methods
Here we used undifferentiated proliferating or differentiated human fetal skeletal muscle cells (Hfsmc) to investigate the short-term effects of testosterone on the insulin-mediated biomolecular metabolic machinery. GLUT4 cell expression, localization and the phosphorylation/activation of AKT, ERK, mTOR and GSK3β insulin-related pathways at different time points after treatment with testosterone were analyzed.
Results
Independently from cells differentiation status, testosterone, with an insulin-like effect, induced Glut4-mRNA expression, GLUT4 protein translocation to the cytoplasmic membrane, while no effect was observed on GLUT4 protein expression levels. Furthermore, testosterone treatment modulated the insulin-dependent signal transduction pathways inducing a rapid and persistent activation of AKT, ERK and mTOR, and a transient inhibition of GSK3β. T-related effects were shown to be androgen receptor dependent.
Conclusion
All together our data indicate that testosterone through the activation of non-genomic pathways, participates in skeletal muscle glucose metabolism by inducing insulin-related effects.
The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. Previous ...reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non-allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE-mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE-FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues.The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. Previous reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non-allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE-mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE-FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues.
Abstract The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. ...Previous reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non‐allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE‐mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE‐FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues.
Objective: According to American clinical guidelines, allopurinol and febuxostat may be prescribed as first-line therapy to treat hyperuricemia. However, the Italian Medicines Agency directive, ...called Nota 91, allows the reimbursement of second-line febuxostat in the case of failure and/or intolerance of a previous allopurinol therapy, so partially embracing European League Against Rheumatism recommendations and the British Society for Rheumatology Guideline. Such inconsistency might lead to heterogeneity among General Practitioners (GPs) in treatment of hyperuricemia. This study, therefore, aimed to evaluate the prescribing behavior of GPs in terms of compliance with Nota 91 and/or official guidelines.
Methods: Using the Health Search Database, a retrospective cohort study was conducted to evaluate the patterns of use of allopurinol and febuxostat between 2011 and 2016.
Results: In total, 44,257 and 5837 patients were prescribed with allopurinol and febuxostat, respectively. Among febuxostat users, 4321 (74%) had a previous allopurinol treatment; 92% of switches to febuxostat were related to hyperuricemia, whereas 9% of switchers presented intolerance to allopurinol; 26% of patients were prescribed with febuxostat as first-line therapy. The presence of diabetes and/or moderate/severe renal disease were statistically significant determinants of febuxostat use as first-line therapy.
Conclusion: Prescriptions of febuxostat were highly compliant to Nota 91. Only a sub-group of frontline prescriptions of febuxostat were mainly driven by the presence of renal dysfunction, which is able to increase the risk of allopurinol intolerance and/or inefficacy. These findings indicate that GPs' prescribing behavior for hyperuricemia is highly compliant with both regulatory directives and clinical guidelines.
PDF
