Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral ...remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.
The term “biobanking” is often misapplied to any collection of human biological materials (biospecimens) regardless of requirements related to ethical and legal issues or the standardization of ...different processes involved in tissue collection. A proper definition of biobanks is large collections of biospecimens linked to relevant personal and health information (health records, family history, lifestyle, genetic information) that are held predominantly for use in health and medical research. In addition, the International Organization for Standardization, in illustrating the requirements for biobanking (ISO 20387:2018), stresses the concept of biobanks being legal entities driving the process of acquisition and storage together with some or all of the activities related to collection, preparation, preservation, testing, analysing and distributing defined biological material as well as related information and data. In this review article, we aim to discuss the basic principles of biobanking, spanning from definitions to classification systems, standardization processes and documents, sustainability and ethical and legal requirements. We also deal with emerging specimens that are currently being generated and shaping the so-called next-generation biobanking, and we provide pragmatic examples of cancer-associated biobanking by discussing the process behind the construction of a biobank and the infrastructures supporting the implementation of biobanking in scientific research.
Safety and immunogenicity of BNT162b2 mRNA vaccine are unknown in hematological patients; both were evaluated prospectively in 42 patients with multiple myeloma (MM) and 50 with myeloproliferative ...malignancies (MPM) (20 chronic myeloid leukemias and 30 myeloproliferative neoplasms), all of them on active anti-cancer treatment, in comparison with 36 elderly controls not suffering from cancer. Subjects serologically and/or molecularly (by nasal/throat swab) positives at basal for SARS-CoV-2 were excluded. Primary endpoint was to compare titers of neutralizing anti-SARS-CoV-2 IgG and seroprotection rates among the cohorts at 3 and 5 weeks from first dose.
Titration was done using LIAISON® SARS-CoV-2 S1/S2 IgG test, a quantitative chemiluminescent immunoassay approved by FDA on the basis of robust evidences of concordance (94.4%) between the test at cutoff of 15 AU/mL and the Plaque Reduction Neutralization Test 90% at 1:40 ratio. Cutoff of 15 AU/mL was assumed to discriminate responders to vaccination with a protective titer. Cohorts were compared using Fisher' exact test and the Mann-Whitney test as appropriated. Geometric mean concentrations (GMCs), geometric mean ratios and response rates after 1st and 2nd dose were compared in each cohort by Wilcoxon and McNemar tests, respectively.
At 5 weeks, GMC of IgG in elderly controls was 353.3 AU/mL versus 106.7 in MM (p = 0.003) and 172.9 in MPM patients (p = 0.049). Seroprotection rate at cutoff of 15 AU/mL was 100% in controls compared to 78.6% in MM (p = 0.003) and 88% in MPM patients (p = 0.038). In terms of logarithm of IgG titer, in a generalized multivariate linear model, no gender effect was observed (p = 0.913), while there was a significant trend toward lower titers by increasing age (p < 0.001) and in disease cohorts with respect to controls (MM: p < 0.001 and MPM: p < 0.001). An ongoing treatment without daratumumab was associated with higher likelihood of response in MM patients (p = 0.003). No swabs resulted positive on each time point. No safety concerns were observed.
BNT162b2 has demonstrated to be immunogenic at different extent among the cohorts. Response was 88% and robust in MPM patients. MM patients responded significantly less, particularly those on anti-CD38-based treatment. These latter patients should be advised to maintain masks and social distancing regardless of vaccination status, and their cohabiting family members need to be vaccinated in order to reduce the risk of contagion from the family. Additional boosters and titer monitoring could be considered. Trial registration Study was formally approved by the IRCCS Central Ethical Committee of Regione Lazio in January 2021 (Prot. N-1463/21).
Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, ...N‐acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti‐inflammatory therapy, the lipid‐like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole–piperazine derivatives that inhibit NAAA in a potent and selective manner by a non‐covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non‐covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.
Treating neuroinflammation: The cysteine amidase N‐acyl ethanolamine acid amidase (NAAA) promotes inflammation by degrading endogenous anti‐ inflammatory lipid amides such as palmitoylethanolamide (PEA). A new class of non‐covalent, orally available NAAA inhibitors (see example) interrupt NAAA‐mediated lipid amide degradation in the brain, and are strongly protective in a mouse model of neuroinflammation.
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of ...monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.
Display omitted
•Hybridoma library screening highlights integrin α7 as a glioblastoma antigen•Knockdown of integrin α7 impairs growth and survival of glioblastoma stem cells•High integrin α7 expression correlates with poor prognostic outcomes in patients•An antibody against integrin α7 suppresses tumor growth and invasion
Haas et al. identify integrin α7 as a functional marker of glioblastoma stem cells by screening a monoclonal antibody library generated against primary glioblastoma (GBM) cells. Functional experiments in culture and in vivo show that the targeting of integrin α7 has potential as a therapeutic avenue for treating this aggressive disease.
Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. ...Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.
Cancer stem cells (CSCs) are a subpopulation with the properties of extensive self‐renewal, capability to generate differentiated cancer cells and resistance to therapies. We have previously shown ...that malignant pleural effusions (MPEs) from patients with non‐small‐cell lung cancer (NSCLC) represent a valuable source of cancer cells that can be grown as three‐dimensional (3D) spheroids enriched for stem‐like features, which depend on the activation of the Yes‐associated protein‐transcriptional coactivator with PDZ‐binding motif (YAP‐TAZ)/Wnt‐βcatenin/stearoyl‐CoA desaturase 1 (SCD1) axis. Here, we describe a novel support, called CytoMatrix, for the characterization of limited amounts of cancer cells isolated from MPEs of patients with NSCLC. Our results show that this synthetic matrix allows an easy and fast characterization of several epithelial cellular markers. The use of CytoMatrix to study CSCs subpopulation confirms that SCD1 protein expression is enhanced in 3D spheroids when compared with 2D adherent cell cultures. YAP/TAZ nuclear‐cytoplasmic distribution analysed by CytoMatrix in 3D spheroids is highly heterogeneous and faithfully reproduces what is observed in tumour biopsies. Our results confirm and extend the robustness of our workflow for the isolation and phenotypic characterization of primary cancer cells derived from the lung MPEs and underscore the role of SCD1.
Malignant pleural effusions (MPEs) are a good source of lung cancer cells and represent an excellent model to investigate tumour heterogeneity. MPE‐derived tumour cells can be grown as three‐dimensional (3D) spheroids enriched for stem‐like properties. CytoMatrix is a reliable support for the characterization of primary 2D and 3D MPE‐derived cell cultures using minimum amount of biological material.
The evolution of the foot and the attainment of the bipedia represent a distinctive characteristic of the human species. The force of gravity is dissipated through the tibial astragalic joints, and ...the movement of the ankle is manifested on a sagittal plane. However, this is in contrast with other studies that analyze the straight station in bipodalic support of the body. According to these studies, the oscillations of the body dissipated by the articulation of the ankle are greater on a frontal plane than on a sagittal plane. Probably, this can be deduced by analyzing the concept of “cone of economy (COE) and equilibrium;” a cone that has its base with the oscillations described by the 360° movement performed by the head and has its apex that supports polygon defined by the tibio-astragalic articulation. The purpose of this study was to evaluate a kind of communication between the oscillations of the COE and equilibrium and the main sphere of somatic dysfunction (structural, visceral, or cranial sacral), assessing the reliability of the “fascial compression test.” The implications of this connection have been considered, while grounding the hypothesis in the ability of the human body to maintain its center of mass (COM) with minimum energy expenditure and with minimum postural influence. At the same time, the fascial compression test provides a dominant direction of fascial compartments in restriction of mobility.
PDF
