Publications by authors named "Alessandro Allegra"

107 Publications

Antiproliferative Effects of St. John's Wort, Its Derivatives, and Other Species in Hematologic Malignancies.

Int J Mol Sci 2020 Dec 25;22(1). Epub 2020 Dec 25.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

is a widely present plant, and extracts of its leaves, flowers, and aerial elements have been employed for many years as therapeutic cures for depression, skin wounds, and respiratory and inflammatory disorders. also displays an ample variety of other biological actions, such as hypotensive, analgesic, anti-infective, anti-oxidant, and spasmolytic abilities. However, recent investigations highlighted that this species could be advantageous for the cure of other pathological situations, such as trigeminal neuralgia, as well as in the treatment of cancer. This review focuses on the in vitro and in vivo antitumor effects of St. John's Wort ( its derivatives, and other species in hematologic malignancies. induces apoptosis in both myeloid and lymphoid cells. Other targets include matrix metalloproteinase-2, vascular endothelial growth factor, and matrix metalloproteinase-9, which are mediators of cell migration and angiogenesis. also downregulates the expression of proteins that are involved in the resistance of leukemia cells to chemotherapeutic agents. Finally, and its derivatives appear to have photodynamic effects and are candidates for applications in tumor photodynamic therapy. Although the in vitro studies appear promising, controlled in vivo studies are necessary before we can hypothesize the introduction of and its derivatives into clinical practice for the treatment of hematologic malignancies.
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http://dx.doi.org/10.3390/ijms22010146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795730PMC
December 2020

The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients.

Biomedicines 2020 Dec 22;9(1). Epub 2020 Dec 22.

School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Although pruritus may sometimes be a consequential situation to neoplasms, it more frequently emerges after commencing chemotherapy. In this review, we present our analysis of the chemotherapy treatments that most often induce skin changes and itching. After discussing conventional chemotherapies capable of inducing pruritus, we present our evaluation of new drugs such as immunological checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and monoclonal antibodies. Although ICIs and targeted therapy are thought to damage tumor cells, these therapies can modify homeostatic events of the epidermis and dermis, causing the occurrence of cutaneous toxicities in treated subjects. In the face of greater efficacy, greater skin toxicity has been reported for most of these drugs. A remarkable aspect of some reports is the presence of a probable correlation between cutaneous toxicity and treatment effectiveness in tumor patients who were treated with novel drugs such as nivolumab or pembrolizumab. Findings from these experiments demonstrate that the occurrence of any grade of skin side effects can be considered as a predictor of a better outcome. In the near future, studies on the relationship between the onset of skin alterations and outcomes could open new perspectives on the treatment of neoplasms through specific target therapy.
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http://dx.doi.org/10.3390/biomedicines9010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822170PMC
December 2020

Quantitative polymerase Chain reaction profiling of microRNAs in peripheral lymph-monocytes from MGUS subjects.

Pathol Res Pract 2021 Feb 13;218:153317. Epub 2020 Dec 13.

Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, Località Gazzi, Via Consolare Valeria, Messina, Italy.

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant abnormality of plasma cells, with increased serum levels of immunoglobulins. Patients with MGUS may evolve to multiple myeloma through a multistep process including deregulated gene expression. microRNAs are small non-coding RNA molecules involved in post-transcriptional regulation of crucial biological processes, such as morphogenesis, cell differentiation, apoptosis, and cancer. This study aimed to evaluate microRNA expression on peripheral lymph-monocytes from MGUS subjects compared with healthy controls using qPCR arrays. Blood samples were collected by venipuncture from fifteen, newly diagnosed MGUS patients and fifteen healthy subjects. A further group (validation group) of six newly diagnosed MGUS patients and five healthy control were enrolled for the validation of miRNAs and their mRNAs target. The study was conducted performing miProfile miRNA qPCR arrays, followed by validation of miRNAs and related mRNA targets through RT-qPCR. The functional interaction between microRNAs and target gene were obtained by Ingenuity Pathways Analysis (IPA). IPA network analysis identified only molecules and relationships experimentally observed in peripheral lymphomonocytes. The following miRNAs :133a-3p, 16-5p, 291-3p, 23a-3p, 205-5p, 17-5p, 7a-5p, 221-3p, 30c-5p, 126a-3p,155-5p, let-7a-5p and 26a-5p, involved in the regulation of genes with a role in lymphocyte homeostasis, cell proliferation, apoptosis, and multiple myeloma (MM) progression, were differently expressed in MGUS with respect to healthy subjects. This miRNA signature and its relative targets could be considered for the formulation of new therapeutic strategies in the prophylaxis or treatment of monoclonal gammopathies.
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http://dx.doi.org/10.1016/j.prp.2020.153317DOI Listing
February 2021

New Frontiers about the Role of Human Microbiota in Immunotherapy: The Immune Checkpoint Inhibitors and CAR T-Cell Therapy Era.

Int J Mol Sci 2020 Nov 24;21(23). Epub 2020 Nov 24.

Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98122 Messina, Italy.

Microbiota is considered an independent organ with the capability to modulate tumor growth and response to therapies. In the chemo-free era, the use of new immunotherapies, more selective and effective and less toxic, led to the extension of overall survival of patients, subject to their ability to not stop treatment. This has focused scientists' attention to optimize responses by understanding and changing microbiota composition. While we have obtained abundant data from studies in oncologic and hematologic patients receiving conventional chemotherapy, we have less data about alterations in intestinal flora in those undergoing immunotherapy, especially based on Chimeric Antigen Receptor (CAR) T-cells. Actually, we know that the efficacy of Programmed Cell Death 1 (PD-1), PD-1 ligand, and Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is improved by probiotics rich in spp., while compounds of and protect from the development of the anti-CTLA-4-induced colitis in mouse models. CAR T-cell therapy seems to not be interfering with microbiota; however, the numerous previous therapies may have caused permanent damage, thus obscuring the data we might have obtained. Therefore, this review opens a new chapter to transfer known acquisitions to a typology of patients destined to grow.
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http://dx.doi.org/10.3390/ijms21238902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727716PMC
November 2020

The Osteoporosis/Microbiota Linkage: The Role of miRNA.

Int J Mol Sci 2020 Nov 24;21(23). Epub 2020 Nov 24.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Hundreds of trillions of bacteria are present in the human body in a mutually beneficial symbiotic relationship with the host. A stable dynamic equilibrium exists in healthy individuals between the microbiota, host organism, and environment. Imbalances of the intestinal microbiota contribute to the determinism of various diseases. Recent research suggests that the microbiota is also involved in the regulation of the bone metabolism, and its alteration may induce osteoporosis. Due to modern molecular biotechnology, various mechanisms regulating the relationship between bone and microbiota are emerging. Understanding the role of microbiota imbalances in the development of osteoporosis is essential for the development of potential osteoporosis prevention and treatment strategies through microbiota targeting. A relevant complementary mechanism could be also constituted by the permanent relationships occurring between microbiota and microRNAs (miRNAs). miRNAs are a set of small non-coding RNAs able to regulate gene expression. In this review, we recapitulate the physiological and pathological meanings of the microbiota on osteoporosis onset by governing miRNA production. An improved comprehension of the relations between microbiota and miRNAs could furnish novel markers for the identification and monitoring of osteoporosis, and this appears to be an encouraging method for antagomir-guided tactics as therapeutic agents.
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http://dx.doi.org/10.3390/ijms21238887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727697PMC
November 2020

Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies.

Antioxidants (Basel) 2020 Nov 12;9(11). Epub 2020 Nov 12.

Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", Division of Haematology, University of Messina, 98125 Messina, Italy.

Radiation therapy plays a critical role in the management of a wide range of hematologic malignancies. It is well known that the post-irradiation damages both in the bone marrow and in other organs are the main causes of post-irradiation morbidity and mortality. Tumor control without producing extensive damage to the surrounding normal cells, through the use of radioprotectors, is of special clinical relevance in radiotherapy. An increasing amount of data is helping to clarify the role of oxidative stress in toxicity and therapy response. Radioprotective agents are substances that moderate the oxidative effects of radiation on healthy normal tissues while preserving the sensitivity to radiation damage in tumor cells. As well as the substances capable of carrying out a protective action against the oxidative damage caused by radiotherapy, other substances have been identified as possible enhancers of the radiotherapy and cytotoxic activity via an oxidative effect. The purpose of this review was to examine the data in the literature on the possible use of old and new substances to increase the efficacy of radiation treatment in hematological diseases and to reduce the harmful effects of the treatment.
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http://dx.doi.org/10.3390/antiox9111116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696711PMC
November 2020

Drug repositioning for the treatment of hematologic disease: limits, challenges and future perspectives.

Curr Med Chem 2020 Aug 16. Epub 2020 Aug 16.

Department of Chemical, Biological, Pharmaceutical and Environmental Chemistry, University of Messina, Messina. Italy.

Drug repositioning is a strategy to identify new uses for approved or investigational drugs that are used off-label outside the scope of the original medical indication. In this review we report the most relevant studies about drug repositioning in hematology, reporting the signalling pathways and molecular targets of these drugs, and describing the biological mechanisms which are responsible for anticancer effects. Although the majority of studies on drug repositioning in hematology concern acute myeloid leukemia and multiple myeloma, numerous studies are present in the literature on the possibility to use these drugs also in other hematological diseases, such as acute lymphoblastic leukemia, chronic myeloid leukemia, and lymphomas. Numerous anti-infectious drugs, chemical entities used for the therapy of neurological or endocrine diseases, oral antidiabetics, statins, medications used to treat high blood pressure and heart failure, bisphosphonate, natural substance such as artemisin and curcumin, have found a place in hematological diseases treatment. Moreover, seve.
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http://dx.doi.org/10.2174/0929867327999200817102154DOI Listing
August 2020

Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR-ABL-Negative Myeloproliferative Neoplasm.

Antioxidants (Basel) 2020 Oct 23;9(11). Epub 2020 Oct 23.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In --negative MPNs, the driver mutations include , , and . Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.
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http://dx.doi.org/10.3390/antiox9111037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690801PMC
October 2020

Immune checkpoint inhibitors in multiple myeloma: A review of the literature.

Pathol Res Pract 2020 Oct 13;216(10):153114. Epub 2020 Jul 13.

Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, Via Consolare Valeria 98125 Messina, Italy. Electronic address:

The human immune system has structures called checkpoints controlling the intensity and the duration of immune responses. In the last years, studies and research have been concentrating on creating new drugs recognized as Immune Checkpoint Inhibitors that have been launched in clinical practice to treat patients with several types of cancer, including multiple myeloma. Multiple myeloma is characterized by dysfunctions in humoral and cellular immunity altering immune surveillance and support tumor advancement to escape: in particular, the disease causes the inactivation of T-cells because of their bond with antigens shown in cancer cells. It can be stated that checkpoint inhibitors "inhibit the inhibition" of cell-mediated immunity and induce tumor cells apoptosis. In this review we have focused our attention on summarizing current information about Immune Checkpoint Inhibitors which have been developed in the last years to treat multiple myeloma; particular consideration will be dedicated to describing their mechanism of action and their potential use in therapy. Further investigations are necessary in this field to define the possibility of an effective and safe inclusion of these drugs in clinical practice.
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http://dx.doi.org/10.1016/j.prp.2020.153114DOI Listing
October 2020

Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw.

Biomed Res Int 2020 2;2020:9879876. Epub 2020 Jul 2.

Department of Biochemical and Dental Sciences and Morphofunctional Images, University of Messina, Messina, Italy.

Bisphosphonates (BPs) are inhibitors of osteoclast-mediated bone resorption used for the treatment of multiple myeloma (MM) patients with osteolytic lesions. Bisphosphonate-induced osteonecrosis of the jaw (BONJ) is an infrequent drug-caused adverse event of these agents. Long noncoding RNAs (lncRNAs) are a set of more than 200 base pairs, noncoding RNA molecules, which are critical posttranscriptional regulators of gene expression. Our study was aimed at evaluating 17 lncRNAs, whose targets were previously validated as key elements in MM, bone metabolism, and angiogenesis in MM subjects without BONJ (MM group), in MM subjects with BONJ (BONJ group), and a group of healthy controls (CTRL group). Our results demonstrated a different lncRNA profile in BONJ patients compared to MM patients and controls. Two lncRNAs (DANCR and MALAT1) were both downregulated compared to controls and MM, twelve (HOTAIR, MEG3, TP73-AS1, HOTTIP, HIF1A-AS2, MANTIS, CTD-2201E18, CTD1-2003C8, R-471B22, RP1-43E13, RP11-553L6.5, and RP1-286D6) were overexpressed in MM with BONJ, and one (H19) was upregulated compared with only MM. Two lncRNAs (JHDMD1 and MTMR9LP) had higher expression, but these differences were not statistically significant. The examined lncRNAs target several genes and metabolic pathways. An altered lncRNA signature could contribute to the onset of BONJ or have a protective action. Targeting these lncRNAs could offer a possibility for the prevention or therapy of BONJ.
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http://dx.doi.org/10.1155/2020/9879876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354644PMC
July 2020

Coagulopathy and thromboembolic events in patients with SARS-CoV-2 infection: pathogenesis and management strategies.

Ann Hematol 2020 Sep 15;99(9):1953-1965. Epub 2020 Jul 15.

Division of Haematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125, Messina, Italy.

In October 2019, a viral infectious disease appeared in the city of Wuhan in China. A new betacoronavirus, SARS-CoV-2, has been recognized as the responsible pathogen in this infection. Although coronavirus disease is principally expressed as a pulmonary infection, critical SARS-CoV-2 infection is frequently complicated with coagulopathy, and thromboembolic events are recognizable in several patients. Dehydration, acute inflammatory condition, protracted immobilization during disease, existence of multiple cardiovascular risk factors such as diabetes, obesity or hypertension, previous coronary artery disease, ischemic stroke, peripheral artery disease are frequent comorbidities in SARS-CoV-2 hospitalized subjects, which possibly augment thrombo-embolic risk. However, other causal factors can still be identified such as unrestricted angiotensin II action, the use of immunoglobulins, an increased production of adhesion molecules able to induce vascular inflammation and endothelial activation, complement stimulation, excessive production of neutrophil extracellular traps (NETs), and increased platelet count. Low-molecular-weight heparin should be chosen as early treatment because of its anti-inflammatory action and its ability to antagonize histones and so defend the endothelium. However, several therapeutic possibilities have also been proposed such as fibrinolytic treatment, drugs that target NETs, and complement inhibition. Nevertheless, although the violence of the pandemic may suggest the use of heroic treatments to reduce the frightening mortality that accompanies SARS-CoV-2 infection, we believe that experimental treatments should only be used within approved and controlled protocols, the only ones that can provide useful and specify information on the validity of the treatments.
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http://dx.doi.org/10.1007/s00277-020-04182-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363407PMC
September 2020

Immunopathology of SARS-CoV-2 Infection: Immune Cells and Mediators, Prognostic Factors, and Immune-Therapeutic Implications.

Int J Mol Sci 2020 Jul 6;21(13). Epub 2020 Jul 6.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

The present is a comprehensive review of the immunopathology of Covid-19. The immune reaction to SARS-CoV-2 infection is characterized by differentiation and proliferation of a variety of immune cells with immune mediator production and release, and activation of other pathogen resistance mechanisms. We fully address the humoral and cellular immune changes induced by the virus, with particular emphasis on the role of the "cytokine storm" in the evolution of the disease. Moreover, we also propose some immune alterations (i.e., inflammatory parameters, cytokines, leukocytes and lymphocyte subpopulations) as prognostic markers of the disease. Furthermore, we discuss how immune modifying drugs, such as tocilizumab, chloroquine, glucocorticoids and immunoglobulins, and blood purification therapy, can constitute a fundamental moment in the therapy of the infection. Finally, we made a critical analysis of a number of substances, not yet utilized, but potentially useful in SARS-CoV-2 patients, such as IFN lambda, TNF blockers, ulinastatin, siponimod, tacrolimus, mesenchymal stem cells, inhibitors of mononuclear macrophage recruitment, IL-1 family antagonists, JAK-2 or STAT-3 inhibitors.
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http://dx.doi.org/10.3390/ijms21134782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370171PMC
July 2020

Cancer and SARS-CoV-2 Infection: Diagnostic and Therapeutic Challenges.

Cancers (Basel) 2020 Jun 15;12(6). Epub 2020 Jun 15.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

In late December 2019, a new infectious viral disease appeared. A new betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), has been recognized as the pathogen responsible for this infection. Patients affected by tumors are more vulnerable to infection owing to poor health status, concomitant chronic diseases, and immunosuppressive conditions provoked by both the cancer and antitumor therapies. In this review, we have analyzed some lesser known aspects of the relationship between neoplasms and SARS-CoV-2 infection, starting from the different expression of the ACE2 receptor of the virus in the various neoplastic pathologies, and the roles that different cytokine patterns could have in vulnerability to infection and the appearance of complications. This review also reports the rationale for a possible use of drugs commonly employed in neoplastic therapy, such as bevacizumab, ibrutinib, selinexor, thalidomide, carfilzomib, and PD-1 inhibitors, for the treatment of SARS-CoV-2 infection. Finally, we have highlighted some diagnostic challenges in the recognition of SARS-CoV-2 infection in cancer-infected patients. The combination of these two health problems-tumors and a pandemic virus-could become a catastrophe if not correctly handled. Careful and judicious management of cancer patients with SARS-Cov-2 could support a better outcome for these patients during the current pandemic.
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http://dx.doi.org/10.3390/cancers12061581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352319PMC
June 2020

Anticancer Activity of L.: Mechanisms of Action and Therapeutic Potentials.

Nutrients 2020 Jun 10;12(6). Epub 2020 Jun 10.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Alternative treatments for neoplastic diseases with new drugs are necessary because the clinical effectiveness of chemotherapy is often reduced by collateral effects. Several natural substances of plant origin have been demonstrated to be successful in the prevention and treatment of numerous tumors. L. is a herb that is cultivated in diverse areas of the world. There is increasing attention being directed towards the pharmaceutical capacities of rosemary, utilized for its anti-inflammatory, anti-infective or anticancer action. The antitumor effect of rosemary has been related to diverse mechanisms, such as the antioxidant effect, antiangiogenic properties, epigenetic actions, regulation of the immune response and anti-inflammatory response, modification of specific metabolic pathways, and increased expression of onco-suppressor genes. In this review, we aim to report the results of preclinical studies dealing with the anticancer effects of rosemary, the molecular mechanisms related to these actions, and the interactions between rosemary and anticancer drugs. The prospect of utilizing rosemary as an agent in the treatment of different neoplastic diseases is discussed. However, although the use of rosemary in the therapy of neoplasms constitutes a fascinating field of study, large and controlled studies must be conducted to definitively clarify the real impact of this substance in clinical practice.
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http://dx.doi.org/10.3390/nu12061739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352773PMC
June 2020

Oxidative Stress and Photodynamic Therapy of Skin Cancers: Mechanisms, Challenges and Promising Developments.

Antioxidants (Basel) 2020 May 22;9(5). Epub 2020 May 22.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Ultraviolet radiation is one of the most pervasive environmental interactions with humans. Chronic ultraviolet irradiation increases the danger of skin carcinogenesis. Probably, oxidative stress is the most important mechanism by which ultraviolet radiation implements its damaging effects on normal cells. However, notwithstanding the data referring to the negative effects exerted by light radiation and oxidative stress on carcinogenesis, both factors are used in the treatment of skin cancer. Photodynamic therapy (PDT) consists of the administration of a photosensitiser, which undergoes excitation after suitable irradiation emitted from a light source and generates reactive oxygen species. Oxidative stress causes a condition in which cellular components, including DNA, proteins, and lipids, are oxidised and injured. Antitumor effects result from the combination of direct tumour cell photodamage, the destruction of tumour vasculature and the activation of an immune response. In this review, we report the data present in literature dealing with the main signalling molecular pathways modified by oxidative stress after photodynamic therapy to target skin cancer cells. Moreover, we describe the progress made in the design of anti-skin cancer photosensitisers, and the new possibilities of increasing the efficacy of PDT via the use of molecules capable of developing a synergistic antineoplastic action.
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http://dx.doi.org/10.3390/antiox9050448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278813PMC
May 2020

Myeloma cells induce the accumulation of activated CD94low NK cells by cell-to-cell contacts involving CD56 molecules.

Blood Adv 2020 05;4(10):2297-2307

Laboratory of Immunology and Biotherapy and.

Natural killer (NK) cells represent innate effector cells potentially able to play a role during the immune response against multiple myeloma (MM). To better define the distribution and the specific properties of NK cell subsets during MM disease, we analyzed their features in the bone marrow and peripheral blood of newly diagnosed MM patients. Our findings revealed that, in both compartments, NK cells were more abundant than in healthy donors. Among total MM-NK cells, a significant increase of CD94lowCD56dim NK cell subset was observed, which already appears in clinical precursor conditions leading to MM, namely monoclonal gammopathy of undetermined significance and smoldering MM, and eventually accumulates with disease progression. Moreover, a consistent fraction of CD94lowCD56dim NK cells was in a proliferation phase. When analyzed for their killing abilities, they represented the main cytotoxic NK cell subset against autologous MM cells. In vitro, MM cells could rapidly induce the expansion of the CD94lowCD56dim NK cell subset, thus reminiscent of that observed in MM patients. Mechanistically, this accumulation relied on cell to cell contacts between MM and NK cells and required both activation via DNAM-1 and homophilic interaction with CD56 expressed on MM cells. Considering the growing variety of combination treatments aimed at enhancing NK cell-mediated cytotoxicity against MM, these results may also be informative for optimizing current immunotherapeutic approaches.
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http://dx.doi.org/10.1182/bloodadvances.2019000953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252548PMC
May 2020

Drug Synergism: Studies of Combination of RK-52 and Curcumin against Rhodesain of .

ACS Med Chem Lett 2020 May 15;11(5):806-810. Epub 2020 Jan 15.

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy.

Rhodesain is an enzyme essential for the life of a parasite causing a rapid-onset form of Human African Trypanosomiasis. is a synthetic inhibitor of rhodesain, characterized by an impressive value ( = 67000 × 10 M min) and by a picomolar affinity toward the trypanosomal protease ( = 38 pM). Differently, curcumin, the golden multitarget nutraceutical obtained from L., was proven to inhibit rhodesain noncompetitively with an IC of 7.75 μM. In the present study, we carried out studies of a combination of RK-52 and curcumin toward rhodesain, by applying the Chou and Talalay approach, which led us to obtain a combination index <1 for the most relevant f values, which means a potent synergistic effect for the reduction of rhodesain activity from 40% to 99%.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236278PMC
May 2020

Interactions between the MicroRNAs and Microbiota in Cancer Development: Roles and Therapeutic Opportunities.

Cancers (Basel) 2020 Mar 27;12(4). Epub 2020 Mar 27.

Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

The human microbiota is made up of the fungi, bacteria, protozoa and viruses cohabiting within the human body. An altered microbiota can provoke diseases such as cancer. The mechanisms by which a modified microbiota can intervene in the onset and progression of neoplastic diseases are manifold. For instance, these include the effects on the immune system and the onset of obesity. A different mechanism seems to be constituted by the continuous and bidirectional relationships existing between microbiota and miRNAs. MiRNAs emerged as a novel group of small endogenous non-coding RNAs from that control gene expression. Several works seem to confirm the presence of a close connection between microbiota and miRNAs. Although the main literature data concern the correlations between microbiota, miRNAs and colon cancer, several researches have revealed the presence of connections with other types of tumour, including the ovarian tumour, cervical carcinoma, hepatic carcinoma, neoplastic pathologies of the central nervous system and the possible implication of the microbiota-miRNAs system on the response to the treatment of neoplastic pathologies. In this review, we summarise the physiological and pathological functions of the microbiota on cancer onset by governing miRNA production. A better knowledge of the bidirectional relationships existing between microbiota and miRNAs could provide new markers for the diagnosis, staging and monitoring of cancer and seems to be a promising approach for antagomir-guided approaches as therapeutic agents.
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http://dx.doi.org/10.3390/cancers12040805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225936PMC
March 2020

Changes in Serum Interleukin-8 and sRAGE Levels in Multiple Myeloma Patients.

Anticancer Res 2020 Mar;40(3):1443-1449

School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Messina, Italy.

Background/aim: Although numerous cytokines influence proliferation and progression of multiple myeloma (MM), a relevant action in the onset of the disease also seems to be played by the oxidative state.

Patients And Methods: In the present study we evaluated the concentrations of interleukin-8 (IL-8) and soluble receptor of advanced glycation end products (sRAGE) in patients with MM, assessing the existing variations with respect to a control group and the possible existence of correlations between these molecules and the biological variables or the presence of a correlation between IL-8 and sRAGE. The study was conducted on 33 patients affected by MM compared to 39 healthy subjects.

Results: IL-8 and sRAGE levels were significantly higher in MM patients compared to healthy subjects. sRAGE and IL-8 evidence no significant linear correlation. Furthermore, IL-8 was significantly increased in both sexes, but we found a slight variation for females compared to males.

Conclusion: IL-8 could play an important role in the onset of MM and the progression of bone disease, while the increased sRAGE values would seem to have a protective action in MM patients. Further studies on animal models may clarify the real impact of introducing modulation of IL-8 and sRAGE levels.
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http://dx.doi.org/10.21873/anticanres.14086DOI Listing
March 2020

Post-chemotherapy cognitive impairment in hematological patients: current understanding of chemobrain in hematology.

Expert Rev Hematol 2020 04 10;13(4):393-404. Epub 2020 Mar 10.

Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy.

: Cognitive impairment caused by chemotherapies, a condition known as chemobrain, is a possible side effect that affects alertness, learning, memory, and concentration.: Chemobrain has been principally investigated as a possible side-effect among cancer patients. However, numerous drugs used to treat hematological malignancies can determine the appearance of chemobrain. In this review, we have examined some commonly used drugs for the treatment of hematological malignancies which are known to have a deleterious action on cognitive functions.Numerous mechanisms have been suggested, comprising the direct neurotoxicity of chemotherapeutic drugs, oxidative stress, genetic predisposition, cytokine-provoked damage, histone modifications, immune alteration, and the action of chemotherapeutic on trophic factors and structural proteins of brain cells.: Cognitive dysfunction provoked by the treatment of hematological diseases is an actual challenge in clinical practice. Actually, there are no totally efficient and innocuous treatments for this syndrome. It is important that further investigations specify the existence of predictors and gravity factors to pre- and post-therapy cognitive change and identify the influence of tumor treatments on the cognitive alterations in long-term, cancer survivors. Moreover, future studies are needed to analyze the interactions between genetic risk, amyloid accumulation, intrinsic brain networks, and chemotherapy.
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http://dx.doi.org/10.1080/17474086.2020.1738213DOI Listing
April 2020

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role.

Cancers (Basel) 2020 Feb 24;12(2). Epub 2020 Feb 24.

Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

B-cell chronic lymphocytic leukemia (B-CLL) is the main cause of mortality among hematologic diseases in Western nations. B-CLL is correlated with an intense alteration of the immune system. The altered functions of innate immune elements and adaptive immune factors are interconnected in B-CLL and are decisive for its onset, evolution, and therapeutic response. Modifications in the cytokine balance could support the growth of the leukemic clone via a modulation of cellular proliferation and apoptosis, as some cytokines have been reported to be able to affect the life of B-CLL cells in vivo. In this review, we will examine the role played by cytokines in the cellular dynamics of B-CLL patients, interpret the contradictions sometimes present in the literature regarding their action, and evaluate the possibility of manipulating their production in order to intervene in the natural history of the disease.
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http://dx.doi.org/10.3390/cancers12020524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072434PMC
February 2020

Therapeutic potential of antagomiRs in haematological and oncological neoplasms.

Eur J Cancer Care (Engl) 2020 Mar 3;29(2):e13208. Epub 2020 Jan 3.

Division of Hematology, Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva "Gaetano Barresi", University of Messina, Messina, Italy.

Background: The importance of the role of MicroRNAs (or miRNAs) has been emphasised by the large number of studies in human tumour cells, underlining the high impact of post-transcriptional processes in cancer onset, progression, invasion and metastatisation. Currently known as oncomiR, real databases are collecting all the smaller fragments of RNA capable of participating in the oncogenesis.

Aims: With the aim to collect for the first time the most important acquisitions in literature about antagomiRs in oncology, our narrative review is born with the purpose of showing that specific antisense oligonucleotides, capable to bind and antagonise single or multiple miRNAs, are effective as therapeutic compounds.

Results: Peptide or locked nucleic acids, miRNA sponges or antagomiRs attached to plasmid or lentiviral vectors carrying miRNA sequences to its target are objects of our analysis, demonstrating their effectiveness in a large number and types of tumours. We have also tried how to overcome their high immunogenicity, which remains its greatest limit for clinical use.

Conclusions: They are ambitious but fascinating promise to alter the promotion of the tumour growth by binding specific molecular targets, with high precision and low toxicity, leaving the scientists the chance of development as anti-cancer drugs and not just.
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http://dx.doi.org/10.1111/ecc.13208DOI Listing
March 2020

The ST2/Interleukin-33 Axis in Hematologic Malignancies: The IL-33 Paradox.

Int J Mol Sci 2019 Oct 22;20(20). Epub 2019 Oct 22.

School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria SNC, 98125 Messina, Italy.

Interleukin (IL)-33 is a chromatin-related nuclear interleukin that is a component of IL-1 family. IL-33 production augments the course of inflammation after cell damage or death. It is discharged into the extracellular space. IL-33 is regarded as an "alarmin" able to stimulate several effectors of the immune system, regulating numerous immune responses comprising cancer immune reactions. IL-33 has been demonstrated to influence tumorigenesis. However, as far as this cytokine is concerned, we are faced with what has sometimes been defined as the IL-33 paradox. Several studies have demonstrated a relevant role of IL-33 to numerous malignancies, where it may have pro- and-less frequently-antitumorigenic actions. In the field of hematological malignancies, the role of IL-33 seems even more complex. Although we can affirm the existence of a negative role of IL-33 in Chronic myelogenos leukemia (CML) and in lymphoproliferative diseases and a positive role in pathologies such as Acute myeloid leukemia (AML), the action of IL-33 seems to be multiple and sometimes contradictory within the same pathology. In the future, we will have to learn to govern the negative aspects of activating the IL-33/ST2 axis and exploit the positive ones.
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http://dx.doi.org/10.3390/ijms20205226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834139PMC
October 2019

Formaldehyde Exposure and Acute Myeloid Leukemia: A Review of the Literature.

Medicina (Kaunas) 2019 Sep 25;55(10). Epub 2019 Sep 25.

Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98122 Messina, Italy.

The aim of the present study was to evaluate associations between cumulative and peak formaldehyde exposure and occurrence of acute myeloid leukemia. A comprehensive search was performed using the PubMed and Embase databases. We included studies presenting information about the role of formaldehyde in leukemic occurrence and mortality risk. Then, full texts of the selected references were assessed, and references of included studies were checked to identify additional articles. The information was then summarized and organized in the present review. A total of 81 articles were obtained from the search. Findings from the review of the literature do not support the hypothesis that formaldehyde is a cause of acute myeloid leukemia.
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http://dx.doi.org/10.3390/medicina55100638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843642PMC
September 2019

Selective Inhibitors of Nuclear Export in the Treatment of Hematologic Malignancies.

Clin Lymphoma Myeloma Leuk 2019 11 29;19(11):689-698. Epub 2019 Aug 29.

Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi," University of Messina, Messina, Italy.

The correct localization of molecules between nucleus and cytoplasm is fundamental for cellular homeostasis and is controlled by a bidirectional transport system. Exportin 1 (XPO1) regulates the passage of numerous cancer-related proteins. In this review, we summarize the development of a novel class of antitumor agents, known as selective inhibitors of nuclear export (SINEs). We report results of preclinical studies and clinical trials, and discuss the mechanism of action of SINEs and their effects in multiple myeloma, non-Hodgkin lymphomas, lymphoblastic leukemia, and acute and chronic myeloid leukemia. In the future, the numerous experimental studies currently underway will allow us to define the role of SINEs and will possibly permit these substances to be introduced into daily clinical practice.
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http://dx.doi.org/10.1016/j.clml.2019.08.011DOI Listing
November 2019

[Efficacy of conventional chemotherapy in a primary double-refractory IgM multiple myeloma.]

Recenti Prog Med 2019 Jul-Aug;110(7):364-367

Divisione di Ematologia, Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva "Gaetano Barresi", Università di Messina, Italia.

We report the case of a young man and good PS, diagnosed with a stage II A Durie-Salmon, II ISS and II Revised-ISS IgM kappa Multiple Myeloma. After refractoriety to the I and II-line induction therapies, including novel and novel novel agents, we decided to treat the patient with conventional high dose chemotherapy, with dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP), achieving a very good partial response (VGPR). Furthermore, we discuss histopathologic patterns, to make a correct differential diagnosis with others IgM-correlated disorders. Analyzing the literature, we demonstrated that more intensive therapy correlates with better therapeutic goals, therefore, empathizing that today IgM Multiple Myeloma is still a difficult pathological subtype to treat.
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http://dx.doi.org/10.1701/3197.31749DOI Listing
January 2020

Mitochondria-Targeted Antioxidant SkQ1 for Gammopathy-Related Corneal Damage.

Am J Ther 2020 May/Jun;27(3):e309-e310

Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi," University of Messina, Messina, Italy.

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http://dx.doi.org/10.1097/MJT.0000000000001010DOI Listing
July 2019

Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma.

Int J Mol Sci 2019 Jun 10;20(11). Epub 2019 Jun 10.

School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria SNC, 98125 Messina, Italy.

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs.
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http://dx.doi.org/10.3390/ijms20112822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600674PMC
June 2019

Antiresorptive Agents and Anti-Angiogenesis Drugs in the Development of Osteonecrosis of the Jaw.

Tohoku J Exp Med 2019 05;248(1):27-29

Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina.

Medication-related osteonecrosis of the jaw (MRONJ) is a condition of exposed bone in the maxillofacial region, which occurs among subjects treated with antiresorptive agents or anti-angiogenesis drugs, despite the lack of a history of head or neck radiation treatment. Although there are still many points to be clarified about the mechanism of MRONJ, it is possible to hypothesize a common pathogenetic mechanism for two different classes of drugs: antiresorptive and anti-angiogenetic drugs. These drugs can inhibit angiogenesis by interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis. This hypothesis could be of immediate translational interest. Targeting the anti-angiogenetic effect of the antiresorptive agents could provide a new possibility for the prevention of treatment of MRONJ.
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http://dx.doi.org/10.1620/tjem.248.27DOI Listing
May 2019