Identification of a Consolidation Phase in Immunological Memory

Long lasting antibody responses and immunological memory are the desired outcomes of vaccination. In general, multiple vaccine doses result in enhanced immune responses, a notable exception being booster-induced hyporesponsiveness, which has been observed with polysaccharide and glycoconjugate vaccines. In this study, we analyzed the effect of early booster doses of multimeric protein vaccine (1-11)E2 on recall memory to B epitope 1-11 of β-amyloid. Mice immunized with a single dose of (1-11)E2 stochastically display, when immunized with a recall dose 9 months later, either memory, i.e., an enhanced response to epitope 1-11, or hyporesponsiveness, i.e., a reduced response. Memory is the most common outcome, achieved by 80% of mice. We observed that a booster dose of vaccine (1-11)E2 at day 15 significantly reduced the ratio between the magnitude of the secondary and primary response, causing an increase of hyporesponsive mice. This booster-dependent disruption of recall memory only occurred in a limited time window: a booster dose at day 21 had no significant effect on the ratio between the secondary and primary response magnitude. Thus, this study identifies a consolidation phase in immunological memory, that is a time window during which the formation of memory is vulnerable, and a disrupting stimulus reduces the probability that memory is achieved

Proteomic Analysis of Sera from Common Variable Immunodeficiency Patients Undergoing Replacement Intravenous Immunoglobulin Therapy

Common variable immunodeficiency is the most common form of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment of these patients. By using a differential proteomic approach based on 2D-DIGE, we examined serum samples from normal donors and from matched, naive, and immunoglobulin-treated patients. The results highlighted regulated expression of serum proteins in naive patients. Among the identified proteins, clusterin/ApoJ serum levels were lower in naive patients, compared to normal subjects. This finding was validated in a wider collection of samples from newly enrolled patients. The establishment of a cellular system, based on a human hepatocyte cell line HuH7, allowed to ascertain a potential role in the regulation of CLU gene expression by immunoglobulins

High-Resolution Conformational Analysis of RGDechi-Derived Peptides Based on a Combination of NMR Spectroscopy and MD Simulations

The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvβ3 without cross reacting with αvβ5 and αIIbβ3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvβ3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions

Metabolic syndrome-breast cancer link varies by intrinsic molecular subtype

Metabolic syndrome (MS) has been shown to increase the risk of breast cancer. Existing data suggest that the strength of metabolic syndrome-breast cancer link varies by intrinsic molecular subtype, but results from worldwide literature are controversial. Primary endpoint of the study was to assess whether MS is a predictor of specific breast cancer (BC) subtype. Secondary endpoint was to determine whether components of MS can individually increase the risk of specific breast cancer subtype

Vaccination with (1-11)E2 in alum efficiently induces an antibody response to β-amyloid without affecting brain β-amyloid load and microglia activation in 3xTg mice.

peer reviewedImmunization against β-amyloid (Aβ) is pursued as a possible strategy for the prevention of Alzheimer's disease (AD). In clinical trials, Aβ 1-42 proved poorly immunogenic and caused severe adverse effects; therefore, safer and more immunogenic candidate vaccines are needed. Multimeric protein (1-11)E2 is able to induce an antibody response to Aβ, immunological memory, and IL-4 production, with no concomitant anti-Aβ T cell response. Antisera recognize Aβ oligomers, protofibrils, and fibrils. In this study, we evaluated the effect of prophylactic immunization with three doses of (1-11)E2 in alum in the 3xTg mouse model of AD. Immunization with (1-11)E2 efficiently induced anti-Aβ antibodies, but afforded no protection against Aβ accumulation and neuroinflammation. The identification of the features of the anti-Aβ immune response that correlate with the ability to prevent Aβ accumulation remains an open problem that deserves further investigation

Costs of clinical trials with anticancer biological agents in an Oncologic Italian Cancer Center using the activity-based costing methodology

The aim of the present study was to assess the estimated "per patient" total cost for a single Oncologic Italian Cancer Center participating in a multicenter clinical trial with new anticancer biological agents using the activity-based costing (ABC) methodology

Impact of the COVID-19 pandemic on paediatric otolaryngology: a nationwide study

Objective: The COVID-19 pandemic profoundly modified the work routine in healthcare; however, its impact on the field of paediatric otorhinolaryngology (ORL) has been rarely investigated. The aim of this study was to assess the impact of COVID-19 on paediatric ORL. Methods: A questionnaire was developed by the Young Otolaryngologists of the Italian Society of ORL-Head and Neck Surgery (GOS). The questionnaire consisted of 26 questions related to workplace and personal paediatric ORL activities. The link was advertised on the official social media platforms and sent by e-mail to 469 Italian otolaryngologists. Results: The questionnaire was completed by 118 responders. During the pandemic, the main reduction was observed for surgical activity (78.8%), followed by outpatient service (16.9%). The conditions that were mostly impacted by a delayed diagnosis were respiratory infections in 45.8% of cases and sensorineural hearing loss in 37.3% of cases. Conclusions: Paediatric ORL was highly impacted by the COVID-19 pandemic, with a significant reduction of surgical and outpatient activities and a delay in time-sensitive diagnosis. Therefore, the implementation of new strategies, such as telemedicine, is recommended

Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007?1.038 and OR = 1.025, 95%CI 1.001?1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061?0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively). Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration