Current Medicinal Chemistry - Volume 27, Issue 17, 2020

Colorectal cancer represents the third most frequently occurring cancer worldwide. In the last decade, the survival of patients affected by metastatic colorectal cancer (mCRC) has improved through the introduction of biological drugs. However, in this new and dynamic therapeutic context, research about prognostic and predictive factors is important to guide the oncologists to effective therapies as well as to improve the understanding of colorectal cancer biology. Their identification is an intensive area of research and our future goal will be to depict tumour-specific "molecular signatures" in order to predict the clinical course of the disease and the best treatments. In this report, we describe clinical, pathological and molecular biomarkers that can play a role as prognostic or predictive factors in mCRC.

Background: A better understanding of prognostic factors and biomarkers that predict response to treatment is required in order to further improve survival rates in patients with melanoma. Prognostic Factors: The most important histopathological factors prognostic of worse outcomes in melanoma are sentinel lymph node involvement, increased tumor thickness, ulceration and higher mitotic rate. Poorer survival may also be related to several clinical factors, including male gender, older age, axial location of the melanoma, elevated serum levels of lactate dehydrogenase and S100B. Predictive Biomarkers: Several biomarkers have been investigated as being predictive of response to melanoma therapies. For anti-Programmed Death-1(PD-1)/Programmed Death-Ligand 1 (PD-L1) checkpoint inhibitors, PD-L1 tumor expression was initially proposed to have a predictive role in response to anti-PD-1/PD-L1 treatment. However, patients without PD-L1 expression also have a survival benefit with anti-PD-1/PD-L1 therapy, meaning it cannot be used alone to select patients for treatment, in order to affirm that it could be considered a correlative, but not a predictive marker. A range of other factors have shown an association with treatment outcomes and offer potential as predictive biomarkers for immunotherapy, including immune infiltration, chemokine signatures, and tumor mutational load. However, none of these have been clinically validated as a factor for patient selection. For combined targeted therapy (BRAF and MEK inhibition), lactate dehydrogenase level and tumor burden seem to have a role in patient outcomes. Conclusion: With increasing knowledge, the understanding of melanoma stage-specific prognostic features should further improve. Moreover, ongoing trials should provide increasing evidence on the best use of biomarkers to help select the most appropriate patients for tailored treatment with immunotherapies and targeted therapies.

Glioblastoma multiforme (GBM) is characterized by poor prognosis despite an aggressive therapeutic strategy. In recent years, many advances have been achieved in the field of glioblastoma biology. Here we try to summarize the main clinical and biological factors impacting clinical prognostication and therapy of GBM patients. From that standpoint, hopefully, in the near future, personalized therapies will be available.

The addition of adjuvant chemotherapy to hormonal therapy is often considered questionable in patients with estrogen receptor-positive early breast cancer. Low risk of disease relapse after endocrine treatment alone and/or a low sensitivity to chemotherapy are reasons behind not all patients benefit from chemotherapy. Most of the patients could be exposed to unnecessary treatment- related adverse events and health care costs when treatment decision-making is based only on classical clinical histological features. Gene expression profile has been developed to refine physician’s decision-making process and to tailor personalized treatment to patients. In particular, these tests are designed to spare patients the side effects of unnecessary treatment, and ensure that adjuvant chemotherapy is correctly recommended to patients with early breast cancer. In this review, we will discuss the main diagnostic tests and their potential clinical applications (Oncotype DX, MammaPrint, PAM50/Prosigna, EndoPredict, MapQuant Dx, IHC4, and Theros-Breast Cancer Gene Expression Ratio Assay).

For decades, neutrophils were generally regarded as the cells of innate immunity with proinflammatory and phagocytic properties involved in a dual activity, beneficial (antimicrobial) and detrimental (tissue damage). Importantly, until the discovery of toll-like receptors (TLRs), a role of neutrophils in adaptive immunity was limited to the effector stage of humoral response and phagocytosis of opsonized antigens. Moreover, in common opinion, neutrophils, as well as the entire innate immune system, were not functionally associated with adaptive immunity. At the time we demonstrated protein chlorination by HOCl, the major product of neutrophil MPO-halide system enhances protein immunogenicity. Based on this discovery, we proposed, as the first, a new role for neutrophils as APC-accessory cells involved in the induction stage of adaptive immunity. Thereafter, we developed our theory concerning the role of neutrophils as the cells which link innate and adaptive immunity. We proposed that protein modification by HOCl may act as a neutrophildependent molecular tagging system, by which sentinel dendritic cells can faster recognise pathogen- derived antigens. Contemporaneously, it was demonstrated that taurine, the most abundant free amino acid in neutrophil cytosol and the major scavenger of HOCl, is a part of the oxidantantioxidant network and is responsible for the regulation and termination of acute inflammation. Moreover, it has been described, that taurine chloramine (TauCl), the physiological products of the reaction of HOCl with taurine, show anti-microbial and anti-inflammatory properties. In this review, the role of HOCl, taurine and TauCl in innate and adaptive immunity will be discussed.

Diagnosis of vasculitis is based on the presence of histologic features and serological testing for antineutrophil cytoplasmic antibodies (ANCA). In patients with vasculitis, two types of ANCA have been identified: ANCA directed against the neutrophil serine protease proteinase-3 (PR3) which results in a cytoplasmic immunofluorescence pattern (c-ANCA) and ANCA directed against the neutrophil enzyme myeloperoxidase (MPO), which results in a perinuclear immunofluorescence pattern (p-ANCA). Question is if the presence of ANCA is the consequence of abnormal neutrophil adhesion, activation, and apoptosis. Or is it, through mechanisms which are not totally clear for the moment, the cause of vasculitis. In the latter case it has to be postulated that ANCA autoantigens are expressed on the cell surface of viable, or activated, or early-apoptotic neutrophils.

Autoantibiodies against aminoacyl-tRNA synthetases are found in patients suffering from a wide range of autoimmune and inflammatory disorders. Recent data indicate that these antibodies are directed against splice-variants of synthetase genes, the so-called catalytic nulls. Latter molecules have cytokine-like functions and are involved in the regulation of the activation of lymphocytes, monocytes and granulocytes. The potential role of anti-synthetase antibodies as a diagnostic tool and a target for therapeutic interventions is discussed.

The electrospraying technique, which consists of electrohydrodynamic atomization of polymeric fluids, can be used to generate dry nano- and microparticles by subjecting a polymer solution, suspension or melt to a high voltage (typically in the range of 7-20 kV) electric field. This potential can be exploited for developing nano- and microencapsulation structures under mild temperature conditions. Thus, it constitutes a promising alternative to conventional microencapsulation techniques for sensitive ingredients, like most plant-derived bioactive compounds, especially for their application in the food sector. Given the importance of plants as one of the major sources of dietary bioactive compounds, significant attention has been recently paid to research the encapsulation of phytochemicals through novel techniques such as electrospraying, aiming to provide new tools for the development of innovative functional food products and nutraceuticals. In this review, the latest advances in the application of electrospraying for nano- and microencapsulation of phytochemicals are discussed, with a focus on their potential use in the food sector.

Background: Innate immune system plays an important role in pathogen detection and the recognition of vaccines, mainly through pattern recognition receptors (PRRs) that identify pathogen components (danger signals). One of the typically recognised bacterial components are lipids in conjugation with peptides, proteins and saccharides. Lipidic compounds are readily recognised by the immune system, and thus are ideal candidates for peptide- based vaccine delivery. Thus, bacterial or synthetic lipids mixed with, or conjugated to, antigens have shown adjuvant properties. These systems have many advantages over traditional adjuvants, including low toxicity and good efficacy for stimulating mucosal and systemic immune responses. Methods: The most recent literature on the role of lipids in stimulation of immune responses was selected for this review. The vast majority of reviewed papers were published in the last decade. Older but significant findings are also cited. Results: This review focuses on the development of lipopeptide vaccine systems including application of palmitic acid, bacterial lipopeptides, glycolipids and the lipid core peptide and their routes of administration. The use of liposomes as a delivery system that incorporates lipopeptides is discussed. The review also includes a brief description of immune system in relation to vaccinology and discussion on vaccine delivery routes. Conclusion: Lipids and their conjugates are an ideal frontrunner in the development of safe and efficient vaccines for different immunisation routes.

The introduction of antibiotics to treat bacterial infections either by killing or blocking their growth has been accompanied by the studies of mechanism that allows the drugs to kill the bacteria or to stop their proliferation. In such a scenario, the emergence of antibacterial agents active on the bacterial cell wall has been of fundamental importance in the fight against bacterial agents responsible for severe diseases. As a matter of fact, the cell wall, which plays many roles during the lifecycle, is an essential constituent of most bacteria. This overview focuses on the intracellular steps of peptidoglycan biosynthesis and the research of new antibacterial agents based on the enzymes involved in these early steps of the formation of cell membrane components.