Donor selection for allogenic hemopoietic stem cell transplantation: clinical and ethical considerations

Allogenic hematopoietic progenitor cell transplantation (allo-HSCT) is an established treatment for many diseases. Stem cells may be obtained from different sources: mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The progress in transplantation procedures, the establishment of experienced transplant centres, and the creation of unrelated adult donor registries and cord blood banks gave those without an human leucocyte antigen- (HLA-) identical sibling donor the opportunity to find a donor and cord blood units worldwide. HSCT imposes operative cautions so that the entire donation/transplantation procedure is safe for both donors and recipients; it carries with it significant clinical, moral, and ethical concerns, mostly when donors are minors. The following points have been stressed: the donation should be excluded when excessive risks for the donor are reasonable, donors must receive an accurate information regarding eventual adverse events and health burden for the donors themselves, a valid consent is required, and the recipient’s risks must be outweighed by the expected benefits. The issue of conflict of interest, when the same physician has the responsibility for both donor selection and recipient care, is highlighted as well as the need of an adequate insurance protection for all the parties involved

From Infection to Immunity: Understanding the Response to SARS-CoV2 Through In-Silico Modeling.

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

Insulin-Like Growth Factor Binding Protein (IGFBP-6) as a Novel Regulator of Inflammatory Response in Cystic Fibrosis Airway Cells

Cystic Fibrosis (CF) patients are prone to contracting bacterial lung infections with opportunistic pathogens, especially Pseudomonas aeruginosa. Prolonged P. aeruginosa infections have been linked to chronic inflammation in the CF lung, whose hallmarks are increased levels of cytokines (i.e., TNF-alpha, IL-1 beta, IL-6) and neutrophil attraction by chemokines, like IL-8. Recently, insulin-like growth factor binding protein 6 (IGFBP-6) has been shown to play a putative role in the immune system and was found at higher levels in the sera and synovial tissue of rheumatoid arthritis patients. Moreover, it has been demonstrated that IGFBP-6 has chemoattractant properties towards cells of the innate (neutrophils, monocytes) and adaptive (T cells) immunity. However, it is not known whether IGFBP-6 expression is dysregulated in airway epithelial cells under infection/inflammatory conditions. Therefore, we first measured the basal IGFBP-6 mRNA and protein levels in bronchial epithelial cells lines (Wt and F508del-CFTR CFBE), finding they both are upregulated in F508del-CFTR CFBE cells. Interestingly, LPS and IL-1 beta+TNF alpha treatments increased the IGFBP-6 mRNA level, that was reduced after treatment with an anti-inflammatory (Dimethyl Fumarate) in CFBE cell line and in patient-derived nasal epithelial cultures. Lastly, we demonstrated that IGFBP-6 reduced the level of pro-inflammatory cytokines in both CFBE and primary nasal epithelial cells, without affecting rescued CFTR expression and function. The addition of a neutralizing antibody to IGFBP-6 increased pro-inflammatory cytokines expression under challenge with LPS. Together, these data suggest that IGFBP-6 may play a direct role in the CF-associated inflammation

Gene Expression Profiling of Hairy Cell Leukemia Reveals a Phenotype Related to Memory B Cells with Altered Expression of Chemokine and Adhesion Receptors

Hairy cell leukemia (HCL) is a chronic B cell malignancy characterized by the diffuse infiltration of bone marrow and spleen by cells displaying a typical “hairy” morphology. However, the nature of the HCL phenotype and its relationship to normal B cells and to other lymphoma subtypes remains unclear. Using gene expression profiling, we show here that HCL displays a homogeneous pattern of gene expression, which is clearly distinct from that of other B cell non-Hodgkin lymphomas. Comparison with the gene expression profiles of purified normal B cell subpopulations, including germinal center (GC), pre-GC (naive), and post-GC (memory) B cells, shows that HCL cells are more related to memory cells, suggesting a derivation from this B cell population. Notably, when compared with memory cells, HCL cells displayed a remarkable conservation in proliferation, apoptosis, and DNA metabolism programs, whereas they appeared significantly altered in the expression of genes controlling cell adhesion and response to chemokines. Finally, these analyses have identified several genes that are specifically expressed in HCL and whose expression was confirmed at the protein level by immunocytochemical analysis of primary HCL cases. These results have biological implications relevant to the pathogenesis of this malignancy as well as clinical implications for its diagnosis and therapy

Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling

Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy

A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1).

Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.</p

USE OF ANTI-PLAC1 PROTEIN ANTIBODIES AS BIOMARKERS OF INFERTILITY, DIAGNOSTIC KIT FOR THE DETECTION OF THE IMMUNE RESPONSE AGAINST PLAC1 AND USE OF PLAC1 PROTEIN IN THERAPEUTIC AND CONTRACEPTIVE FIELDS

(EN)Use of antibodies against PLAC1 protein as biomarkers of infertility, diagnostic kit for the detection of immune response against PLAC1 and use of PLAC1 protein in therapeutic and contraceptive fields The present invention concerns the use of antibodies against PLAC1 protein as biomarkers of infertility, diagnostic kit for the detection of immune response against PLAC1 and use of PLAC1 protein in tolerogenic or immunogenic form in the therapy for infertility or as contraceptive or post-coital interception means, respectively. (FR)L'invention concerne l'utilisation d'anticorps dirigés contre la protéine PLAC-1 en tant que biomarqueurs de l'infertilité, une trousse de diagnostic servant à détecter une réponse immunitaire envers PLAC1 et l'utilisation de la protéine PLAC1 sous forme tolérogène ou immunogène respectivement dans le traitement de l'infertilité ou en tant que moyen de contraception ou d'interception post-coïtale