Genome-wide Association Study of Long COVID

SummaryInfections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections1, 2. Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction3–5. The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative6, 7to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at theFOXP4locus.FOXP4has been previously associated with COVID-19 severity6, lung function8, and cancers9, suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in theFOXP4locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.</jats:p

Author Correction:Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article

Lymphatics at crossroads of angiogenesis and lymphangiogenesis

7noreservedThe lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies. This review highlights the recent insights and advances into the field of lymphatic vascular research, outlining the most important aspects of the embryo development, structure, specific markers and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms involved in the regulation of lymphangiogenesis are described. © Anatomical Society of Great Britain and Ireland 2004.mixedSCAVELLI, C.; WEBER, E.; AGLIANO', M.; CIRULLI, T.; NICO, B.; VACCA, A.; RIBATTI, D.Scavelli, C.; Weber, E.; Agliano', M.; Cirulli, T.; Nico, B.; Vacca, A.; Ribatti, D

Patients with Hereditary Hemorrhagic Telangectasia (HHT) exhibit a deficit of polymorphonuclear cell and monocyte oxidative burst and phagocytosis: A possible correlation with altered adaptive immune responsiveness in HHT

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disease characterized by mutations occurring in the endoglin and ALK-1, two receptors of transforming growth factor-beta 1. From a pathogenic point of view, a possible involvement of the immune system in HHT has been suggested since a mononuclear cell infiltrate was found around the area of telangiectascs. Up until now, no information has been available about the role played by leukocytes in HHT and the mechanisms elicited by secretion of their mediators. However, the fact that a deficit of adaptive immunity in HHT has been reported in a companion paper in this issue will represent a great contribution to the understanding of HHT pathogenesis. The purpose of this study was to evaluate whether patients with HHT manifest also alterations in the innate immune response. Therefore, the phenotype of T, B and natural killer lymphocytes, serum immunoglobulin levels, phagocytosis and oxidative burst activity exerted by polymorphonuclear cells (PMN) and monocytes (MO) were analyzed in 22 patients. Twenty individuals demonstrated single or multiple deficits of PMN and MO functions, while the immunophenotype of lymphocytes and serum concentrations of immunoglobulins were normal. To the best of our knowledge, this is the first demonstration of a reduction in IIMN and MO functions in HHT, thus suggesting a higher susceptibility to infectious complications in these patients. The relationship between innate immune deficits and T helper 1 and monocyte-derived cytokine dysfunction in HHT, as previously reported, is discussed

Endothelial differentiation of hematopoietic stem and progenitor cells from patients with multiple myeloma

Purpose: Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). In tumors, near angiogenesis, vasculogenesis contributes to the formation of the microvascular plexus that is important for diffusion. Here, we show that hematopoietic stem and progenitor cells (HSPC) of multiple myeloma (MM) patients are able to differentiate into cells with endothelial phenotype on exposure to angiogenic cytokines. Experimental Design: Circulating HSPCs were purified with an anti-CD133 antibody from patients with newly diagnosed MM before autologous transplantation and exposed to vascular endothelial growth factor (VEGF), fibroblast growth factor-2 and insulin-like growth factor in a 3-week culture. Results: HSPCs gradually lost CD133 expression and acquired VEGF receptor-2, factor VIII - related antigen, and vascular endothelial-cadherin expression. The expression pattern overlapped with paired MM endothelial cells (MMEC). During culture, cells adhered to fibronectin, spread, and acquired an endothelial cell shape. Differentiated HSPCs also became capillarogenic in the Matrigel assay with maximal activity at the third week of culture. Bone marrow biopsies revealed HSPCs inside the neovessel wall in patients with MM but not in those with monoclonal gammopathy of undetermined significance. Conclusions: In patients with MM, but not in those with monoclonal gammopathy of undetermined significance, HSPCs contribute to the neovessel wall building together with MMECs. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. Tentatively, we hypothesize that in HSPC cultures a multipotent cell population expressing low VEGF receptor-2 levels corresponds to the endothelial progenitor cell precursor and seems to be the MMEC precursor. ©2008 American Association for Cancer Research

Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: Preclinical efficacy of the novel, orally available inhibitor dasatinib

Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/ vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFRp) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRp kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRp/Src TK- inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor- tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRp/c-Src TKs in MM, providing a framework for future clinical trials. © 2008 by The American Society of Hematology

Depressive Anxiety Symptoms in Hospitalized Children with Chronic Illness during the First Italian COVID-19 Lockdown

COVID-19 is continuing to spread around the world, having a direct impact on people’s daily lives and health. Although the knowledge of the impact of the COVID-19 pandemic on mental health in the general population is now well established, there is less information on its effect on specific and vulnerable populations, such as children with chronic illness (CI). We conducted a multi-centered cross-sectional study among pediatric patients in six public children’s hospitals in Italy during the first lockdown, with the aim of assessing the proportion of children with CI presenting anxiety and depressive symptoms, and the clinical and demographic characteristics affecting such symptomatology. We included children with at least one chronic condition, with no cognitive delay, aged between 11 and 18 years. Brief standardized questionnaires were administered during medical scheduled visits to screen anxiety and depressive symptoms. We found a very high proportion of children showing mild to severe depressive and anxiety symptomatology (approximately 68% and 63%, respectively). Our results highlight the need of ensuring tailored psychological interventions to protect children with CI from the effect of the pandemic (and related restrictive measures such as quarantine and social distancing), with the final aim of promoting mental health and psychological well-being in this vulnerable population