Background
Immune system conditions of the patient is a key factor in COVID-19 infection survival. A growing number of studies have focused on immunological determinants to develop better biomarkers ...for therapies.
Aim
Studies of the insurgence of immunity is at the core of both SARS-CoV-2 vaccine development and therapies. This paper attempts to describe the insurgence (and the span) of immunity in COVID-19 at the population level by developing an in-silico model. We simulate the immune response to SARS-CoV-2 and analyze the impact of infecting viral load, affinity to the ACE2 receptor, and age in an artificially infected population on the course of the disease.
Methods
We use a stochastic agent-based immune simulation platform to construct a virtual cohort of infected individuals with age-dependent varying degrees of immune competence. We use a parameter set to reproduce known inter-patient variability and general epidemiological statistics.
Results
By assuming the viremia at day 30 of the infection to be the proxy for lethality, we reproduce in-silico several clinical observations and identify critical factors in the statistical evolution of the infection. In particular, we evidence the importance of the humoral response over the cytotoxic response and find that the antibody titers measured after day 25 from the infection are a prognostic factor for determining the clinical outcome of the infection. Our modeling framework uses COVID-19 infection to demonstrate the actionable effectiveness of modeling the immune response at individual and population levels. The model developed can explain and interpret observed patterns of infection and makes verifiable temporal predictions. Within the limitations imposed by the simulated environment, this work proposes quantitatively that the great variability observed in the patient outcomes in real life can be the mere result of subtle variability in the infecting viral load and immune competence in the population. In this work, we exemplify how computational modeling of immune response provides an important view to discuss hypothesis and design new experiments, in particular paving the way to further investigations about the duration of vaccine-elicited immunity especially in the view of the blundering effect of immunosenescence.
The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, ...current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the maintenance of cellular homeostasis, and plays a pivotal role in viral replication processes. In this review, we discuss several aspects of the UPS and the effects of its inhibition with particular regard to the life cycle of the coronaviruses (CoVs). In fact, proteasome inhibition by various chemical compounds, such as MG132, epoxomycin and bortezomib, may reduce the virus entry into the eucariotic cell, the synthesis of RNA, and the subsequent protein expression necessary for CoVs. Importantly, since UPS inhibitors reduce the cytokine storm associated with various inflammatory conditions, it is reasonable to assume that they might be repurposed for SARS-CoV-2, thus providing an additional tool to counteract both virus replication as well as its most deleterious consequences triggered by abnormal immunological response.
BRAF mutations in hairy-cell leukemia Tiacci, Enrico; Trifonov, Vladimir; Schiavoni, Gianluca ...
The New England journal of medicine,
06/2011, Letnik:
364, Številka:
24
Journal Article
Recenzirano
Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure.
We searched for HCL-associated mutations by performing massively parallel ...sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.
Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
Insulin-like growth factors binding protein-6 (IGFBP-6) is involved in a relevant number of cellular activities and represents an important factor in the immune response, particularly in human ...dendritic cells (DCs). Over the past several years, significant insights into the IGF-independent effects of IGFBP-6 were discovered, such as the induction of chemotaxis, capacity to increase oxidative burst and neutrophils degranulation, ability to induce metabolic changes in DCs, and, more recently, the regulation of the Sonic Hedgehog (SHH) signaling pathway during fibrosis. IGFBP-6 has been implicated in different human diseases, and it plays a rather controversial role in the biology of tumors. Notably, well established relationships between immunity, stroma activity, and fibrosis are prognostic and predictive of response to cancer immunotherapy. This review aims at describing the current understanding of mechanisms that link IGFBP-6 and fibrosis development and at highlighting the multiple roles of IGFBP-6 to provide an insight into evolutionarily conserved mechanisms that can be relevant for inflammation, tumor immunity, and immunological diseases.
Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause ...cytoplasmic dislocation of the NPM protein.
We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease.
Cytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells.
Cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy.
Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene ...expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
Antimicrobial resistance (AMR) poses several issues concerning the management of hospital-acquired infections, leading to increasing morbidity and mortality rates and higher costs of care. ...Multidrug-resistant (MDR) bacteria can spread in the healthcare setting by different ways. The most important are direct contact transmission occurring when an individual comes into physical contact with an infected or colonized patient (which can involve healthcare workers, patients, or visitors) and indirect contact transmission occurring when a person touches contaminated objects or surfaces in the hospital environment. Furthermore, in recent years, toilets in hospital settings have been increasingly recognised as a hidden source of MDR bacteria. Different sites in restrooms, from toilets and hoppers to drains and siphons, can become contaminated with MDR bacteria that can persist there for long time periods. Therefore, shared toilets may play an important role in the transmission of nosocomial infections since they could represent a reservoir for MDR bacteria. Such pathogens can be further disseminated by bioaerosol and/or droplets potentially produced during toilet use or flushing and be transmitted by inhalation and contact with contaminated fomites. In this review, we summarize available evidence regarding the molecular features of MDR bacteria contaminating toilets of healthcare environments, with a particular focus on plumbing components and sanitary installation. The presence of bacteria with specific molecular traits in different toilet sites should be considered when adopting effective managing and containing interventions against nosocomial infections potentially due to environmental contamination. Finally, here we provide an overview of traditional and new approaches to reduce the spreading of such infections.
The lung is an accomplished organ for gas exchanges and directly faces the external environment, consequently exposing its large epithelial surface. It is also the putative determinant organ for ...inducing potent immune responses, holding both innate and adaptive immune cells. The maintenance of lung homeostasis requires a crucial balance between inflammation and anti-inflammation factors, and perturbations of this stability are frequently associated with progressive and fatal respiratory diseases. Several data demonstrate the involvement of the insulin-like growth factor (IGF) system and their binding proteins (IGFBPs) in pulmonary growth, as they are specifically expressed in different lung compartments. As we will discuss extensively in the text, IGFs and IGFBPs are implicated in normal pulmonary development but also in the pathogenesis of various airway diseases and lung tumors. Among the known IGFBPs, IGFBP-6 shows an emerging role as a mediator of airway inflammation and tumor-suppressing activity in different lung tumors. In this review, we assess the current state of IGFBP-6's multiple roles in respiratory diseases, focusing on its function in the inflammation and fibrosis in respiratory tissues, together with its role in controlling different types of lung cancer.
This study proposes to exploit the in vivo metabolism of two probiotics (
subsp.
and
)
which, upon adhesion on a solid surface, form a biofilm able to control the growth of pathogenic and food ...spoilage bacteria. The results showed that pathogenic cell loads were always lower in presence of biofilm (6.5-7 log CFU/cm
) compared to those observed in its absence. For
O157:H7, a significant decrease (>1-2 logarithmic cycles) was recorded; for
,
and
, cell load reductions ranged from 0.5 to 1.5 logarithmic cycles. When tested as active packaging, the biofilm was successfully formed on polypropylene, polyvinyl chloride, greaseproof paper, polyethylene and ceramic; the sessile cellular load ranged from 5.77 log CFU/cm
(grease-proof paper) to 6.94 log CFU/cm
(polyethylene, PE). To test the potential for controlling the growth of spoilage microorganisms in food, soft cheeses were produced, inoculated with
and
wrapped in PE pellicles with pre-formed biofim, packed both in air and under vacuum, and stored at 4 and 15 °C: an effective effect of biofilms in slowing the decay of the microbiological quality was recorded.
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