Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks

The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease (n = 58) and in disease recovery in convalescent patients (n = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.

Recovery Plan for Scots Pine Blister Rust Caused by Cronartium pini

This Scots pine blister rust (caused by Cronartium pini) recovery plan is one of several plant disease-specific documents produced as part of the National Plant Disease Recovery System (NPDRS) requested by the Homeland Security Presidential Directive Number 9 (HSPD-9). The purpose of the NPDRS is to ensure that the tools, infrastructure, communication networks, and capacity required for mitigating impacts of high-consequence, plant-disease outbreaks are implemented so that a reasonable level of crop production is maintained. This recovery plan is intended to provide a brief summary of the disease, assess the status of critical recovery components, and identify disease management research, extension, and education needs. These documents are not intended to serve as stand-alone documents that address all of the many and varied aspects of plant disease outbreaks, all of the critical decisions that must be determined, or all of the actions needed to achieve effective response and recovery. These plans are, however, documents that will help the USDA to guide further efforts directed toward plant disease recovery.

Endothelial dysfunction determines severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks

The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 and disease recovery in convalescent patients, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. Core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.

Breast Cancer Prognosis: A Genetic Code for Personalized Therapy

Background: Breast cancer is distinguished in three different subtypes, based on clinical and molecular parameters: Luminal - HER2 - Basal type. Luminal carcinomas (which represent about 65% of the total) are distinguished by a particular heterogeneity of biological behaviour with disease recovery in about 40-50% and death in about two-thirds of these patients at 5 years from diagnosis, despite initial anatomopathological pictures of apparent low aggressiveness. Precisely, more biomolecular parameters are desirable for this diagnostic category which starting from an estimated disease recovery can guide therapeutic choices in a more articulated way that is modelled on the actual needs.Method: The aim of this work is to build a panel of genes that can be used to personalize therapy and consequently reduce mortality. Our kit is patented and includes 33 genes that best characterize neoplastic heterogeneity and sensitivity to drugs. The study involved the total transcriptome (RNA) sequencing of 40 patient samples carried out in the two-year period 1994/1995 with the aim of identifying a group of genes expressed differentially among patients with good prognosis and those with poor prognosis. Results: Total RNA extraction from formalin-fixed, paraffin-embedded samples and then Library preparation for RNA-Seq was achieved. The study highlighted some genes: CXCL13 life gene, IFITM10 death gene always present regardless of molecular subtype, and DSCAM-AS1 gene, specific for Luminal A subtype, that if present, let the patient avoid standard PBI and neoadjuvant therapy. Conclusion: The goal is to implement a different surgical and adjuvant personalized therapy for every single patient.

The Contribution of Macrophages in Old Mice to Periodontal Disease

The prevalence of periodontal disease increases with age. Systemic inflammatory dysregulation also increases with age and has been reported to contribute to the myriad of diseases and conditions that become more prevalent with advanced age. As periodontal disease involves a dysregulated host inflammatory response, the age-related inflammatory dysregulation may contribute to the pathogenesis of periodontal disease in aging populations. However, our understanding of what drives the age-related inflammatory dysregulation is limited. Here, we investigate the macrophage and its contribution to periodontal disease in old and young mice using a ligature-induced periodontal disease model. We demonstrate that control old mice present with an aged periodontal phenotype, characterized by increased alveolar bone loss and increased local inflammatory cytokine expression compared to young mice. Macrophages were demonstrated to be present in the periodontium of old and young mice in equal numbers in controls, during disease induction, and during disease recovery. However, it appears age may have a detrimental effect on macrophage activity during disease recovery. Depletion of macrophages during disease recovery in old mice resulted in decreased inflammatory cytokines within the gingiva and decreased bone loss as measured by micro–computed tomography. In young mice, macrophage depletion during disease recovery had no beneficial or detrimental effect. Macrophage depletion during disease induction resulted in decreased disease severity similarly in young and old mice. Findings from this work support the diverse roles of macrophages in disease induction as well as the active roles of disease recovery, including the resolution of inflammation. Here, we conclude that age-related changes to the macrophage appear to be detrimental to the recovery from disease and may explain, in part, the age-related increase in prevalence of periodontal disease. Future studies examining the specific intrinsic age-related changes to the macrophage will help identify therapeutic targets.

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin–kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin–kallikrein system in two markers that indicate improved disease recovery.