The Malignant Role of Exosomes as Nanocarriers of Rare RNA Species

Publisher's version (útgefin grein)Nowadays, advancements in the oncology sector regarding diagnosis methods allow us to specifically detect an increased number of cancer patients, some of them in incipient stages. However, one of the main issues consists of the invasive character of most of the diagnosis protocols or complex medical procedures associated with it, that impedes part of the patients to undergo routine checkups. Therefore, in order to increase the number of cancer cases diagnosed in incipient stages, other minimally invasive alternatives must be considered. The current review paper presents the value of rare RNA species isolated from circulatory exosomes as biomarkers of diagnosis, prognosis or even therapeutic intervention. Rare RNAs are most of the time overlooked in current research in favor of the more abundant RNA species like microRNAs. However, their high degree of stability, low variability and, for most of them, conservation across species could shift the interest toward these types of RNAs. Moreover, due to their low abundance, the variation interval in terms of the number of sequences with differential expression between samples from healthy individuals and cancer patients is significantly diminished and probably easier to interpret in a clinical context.This research was funded by three national research grants from the Romanian Government: the first one awarded for Frontiers Research Projects 2018-2022 (grant number PN-III-P4-ID-PCCF-2016-112) to Babes Bolyai University, Cluj-Napoca, in collaboration with the Ion Chiricuta Oncology Institute, Cluj-Napoca; the second one awarded for Young Research Teams 2020-2022 (grant number PN-III-P1-1.1-TE2019-0271) to Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, and the third one awarded for Postdoctoral Research Projects 2020-2022 (grant number PN-III-P1-1.1-PD-2019-0805) to Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca. The APC was funded by an international collaborative grant from the European Economic Space between Romania and Iceland 2020-2022 (grant number 19-COP-0031)."Peer Reviewed

Overview of the Side-Effects of FDA- and/or EMA-Approved Targeted Therapies for the Treatment of Hematological Malignancies.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadIn the last decade there has been tremendous effort in offering better therapeutic management strategies to patients with hematologic malignancies. These efforts have ranged from biological to clinical approaches and resulted in the rapid development of new approaches. The main "problem" that comes with the high influx of newly approved drugs, which not only influences hematologists that frequently work with these drugs but also affects other healthcare professionals that work with hematologists in patient management, including intensive care unit (ICU) physicians, is they have to keep up within their specialty and, in addition, with the side-effects that can occur when encountering hematology-specific therapies. Nonetheless, there are few people that have an in-depth understanding of a specialty outside theirs. Thus, this manuscript offers an overview of the most common side-effects caused by therapies used in hematology nowadays, or that are currently being investigated in clinical trials, with the purpose to serve as an aid to other specialties. Nevertheless, because of the high amount of information on this subject, each chapter will offer an overview of the side-effects of a drug class with each reference of the section being intended as further reading. Keywords: hematological malignancies; life-threatening side-effects; novel therapies.MDPI A

RNA sequencing suggests that non-coding RNAs play a role in the development of acquired haemophilia

Funding Information: Adrian Bogdan Tigu and Ionut Hotea contributed equally to the current manuscript and are both considered first author. The authors also gratefully acknowledge the support of Sergiu Pasca, M.D. – Johns Hopkins University School of Medicine, Baltimore, United States, for his contribution on the statistical analysis. Funding Information: IH is funded by an internal grant of the Iuliu Hatieganu University – School of Doctoral Studies. BT is supported by a national grant of the Romanian Academy of Scientists (Academia Oamenilor de Stiinta din Romania) 2023–2024. ABT, DG, JTB and VG are supported by an international collaborative grant of the European Economic Space between Romania and Iceland 2021–2023: ‘Cooperation strategy for knowledge transfer, internationalization and curricula innovation in the field of research education at the 3rd level of study –AURORA.’. The experiments were funded by an international grant awarded by the Novo Nordisk Haemophilia Foundation to the Romanian Haematology Society—Romania 4. CT is supported by a grant by grants awarded by the Romanian National Ministry of 350 Research, Innovation, and Digitalisation: Project PN‐III‐P4‐ID‐PCE‐2020‐1118. Publisher Copyright: © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings.Peer reviewe

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMalignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman. Keywords: B lymphocytes; T lymphocytes; lymphocyte inter-talk; malignant lymphomas; tumor microenvironment.Iuliu Hatieganu University, School of Doctoral Studies RomanianMinistry of Research and Innovation, CCCDI-UEFISCDI within PNCDI III European Economic Spac

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

Publisher's version (útgefin grein)Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman.The research on the lymphoma microenvironment was funded by an internal grant of the Iuliu Hatieganu University, School of Doctoral Studies (PCD 2018-2021) (Minodora Desmirean), under the frame of European Social Found, Human Capital Operational Program 2014-2020, project no. POCU/380/6/13/125171 (Minodora Desmirean) and the Romanian Ministry of Research and Innovation, CCCDI-UEFISCDI, Project No. PN-III-P4-ID-PCCF-2016-0112 within PNCDI III, by an award for Young Research Teams 2020-2022 (Grant No. PN-III-P1-1.1-TE-2019-0271) (both Ciprian Tomuleasa) as well as by an international collaborative grant of the European Economic Space between Romania and Iceland 2020-2022 (Grant No. 19-COP-0031) (Ciprian Tomuleasa)."Peer Reviewed

A narrative review of central nervous system involvement in acute leukemias.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadAcute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia. Keywords: Acute leukemias; central nervous system involvement (CNS involvement); clinical management; pathophysiology.Iuliu Hatieganu University-School of Doctoral Studies (PCD 2019-2021) Romanian Government Ion Chiricuta Oncology Institute Cluj Napoca European Economic Spac

Transforming growth factor β-mediated micromechanics modulates disease progression in primary myelofibrosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadPrimary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor-β (TGF-β) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF-β signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF-derived fibroblast cell lines and transforming growth factor-β receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2. Keywords: TGF-β; fibroblast activation; invasion; micromechanics; myelofibrosis; proliferation.School of Doctoral Studies-Iuliu Hatieganu University Romanian Government Ion Chiricuta Oncology Institute Cluj Napoca international collaborative grant of the European Economic Space between Romania and Iceland 2020-2022 1

The Role of Angiogenesis and Pro-Angiogenic Exosomes in Regenerative Dentistry

Dental surgeries can result in traumatic wounds that provoke major discomfort and have a high risk of infection. In recent years, density research has taken a keen interest in finding answers to this problem by looking at the latest results made in regenerative medicine and adapting them to the specificities of oral tissue. One of the undertaken directions is the study of angiogenesis as an integrative part of oral tissue regeneration. The stimulation of this process is intended to enhance the local availability of stem cells, oxygen levels, nutrient supply, and evacuation of toxic waste. For a successful stimulation of local angiogenesis, two major cellular components must be considered: the stem cells and the vascular endothelial cells. The exosomes are extracellular vesicles, which mediate the communication between two cell types. In regenerative dentistry, the analysis of exosome miRNA content taps into the extended communication between these cell types with the purpose of improving the regenerative potential of oral tissue. This review analyzes the stem cells available for the dentistry, the molecular cargo of their exosomes, and the possible implications these may have for a future therapeutic induction of angiogenesis in the oral wounds

Molecular Links between Central Obesity and Breast Cancer

Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs

The Potential of Different Origin Stem Cells in Modulating Oral Bone Regeneration Processes

Tissue engineering has gained much momentum since the implementation of stem cell isolation and manipulation for regenerative purposes. Despite significant technical improvements, researchers still have to decide which strategy (which type of stem cell) is the most suitable for their specific purpose. Therefore, this short review discusses the advantages and disadvantages of the three main categories of stem cells: embryonic stem cells, mesenchymal stem cells and induced pluripotent stem cells in the context of bone regeneration for dentistry-associated conditions. Importantly, when deciding upon the right strategy, the selection needs to be made in concordance with the morbidity and the life-threatening level of the condition in discussion. Therefore, even when a specific type of stem cell holds several advantages over others, their availability, invasiveness of the collection method and ethical standards become deciding parameters