Publications by authors named "Ioana Berindan-Neagoe"

285 Publications

MicroRNA expression profiling with a Droplet Digital PCR assay enables molecular diagnosis and prognosis of cancers of unknown primary (CUPs).

Mol Oncol 2021 Jun 2. Epub 2021 Jun 2.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Metastasis is responsible for the majority of cancer-related deaths. Particularly challenging is the management of metastatic cancer of unknown primary site (CUP), whose tissue of origin (TOO) remains undetermined even after extensive investigations and whose therapy is rather unspecific and poorly effective. Molecular approaches to identify the most probable TOO of CUPs can overcome some of these issues. In this study, we applied a pre-determined set of 89 microRNAs (miRNAs) to infer the TOO of 53 metastatic cancers of unknown or uncertain origin. The miRNA expression was assessed with Droplet Digital PCR in 159 samples, including primary tumors from 17 tumor classes (reference set), and metastases of known and unknown origin (test set). We combined two different statistical models for class prediction to obtain the most probable TOOs: the nearest shrunken centroids approach of Prediction Analysis of Microarrays (PAMR) and the Least Absolute Shrinkage and Selection Operator (LASSO) models. The molecular test was successful for all formalin-fixed paraffin-embedded samples and provided a TOO identification within 1 week from the biopsy procedure. The most frequently predicted origins were gastrointestinal, pancreas, breast, lung and bile duct. The assay was applied also to multiple metastases from the same CUP, collected from different metastatic sites: the predictions showed a strong agreement, intrinsically validating our assay. The final CUPs' TOO prediction was compared with the clinico-pathological hypothesis of primary site. Moreover, a panel of 13 miRNAs proved to have prognostic value and be associated with overall survival in CUP patients. Our study demonstrated that miRNA expression profiling in CUP samples could be employed as diagnostic and prognostic test. Our molecular analysis can be performed on request, concomitantly with standard diagnostic workup and in association with genetic profiling, to offer valuable indications about the possible primary site, thereby supporting treatment decisions.
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http://dx.doi.org/10.1002/1878-0261.13026DOI Listing
June 2021

Epithelial-Mesenchymal Transition Gene Signature Related to Prognostic in Colon Adenocarcinoma.

J Pers Med 2021 May 26;11(6). Epub 2021 May 26.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.

Colon adenocarcinoma (COAD) remains an important cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) is a key mechanism, promoting not only the invasive or metastatic phenotype but also resistance to therapy. Using bioinformatics approaches, we studied the alteration on EMT related genes and its implication on COAD prognostic based on public datasets. For the EMT mechanisms, two overexpressed genes were identified (NOX4 and IGF2BP3), as well as five downregulated genes (BMP5, DACT3, EEF1A2, GCNT2 and SFRP1) that were related to prognosis in COAD. A qRT-PCR validation step was conducted in a COAD patient cohort comprising of 29 tumor tissues and 29 normal adjacent tissues, endorsing the expression level for BMP5, as well as for two of the miRNAs targeting key EMT related genes, revealing upregulation of miR-27a-5p and miR-146a-5p. The EMT signature can be used to develop a panel of biomarkers for recurrence prediction in COAD patients, which may contribute to the improvement of risk stratification for the patients.
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http://dx.doi.org/10.3390/jpm11060476DOI Listing
May 2021

Hsa-miR-125b Therapeutic Role in Colon Cancer Is Dependent on the Mutation Status of the TP53 Gene.

Pharmaceutics 2021 May 6;13(5). Epub 2021 May 6.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.

Colon cancer is the third most common cancer type worldwide and is highly dependent on DNA mutations that progressively appear and accumulate in the normal colon epithelium. Mutations in the gene appear in approximately half of these patients and have significant implications in disease progression and response to therapy. miR-125b-5p is a controversial microRNA with a dual role in cancer that has been reported to target specifically in colon adenocarcinomas. Our study investigated the differential therapeutic effect of miR-125b-5p replacement in colon cancer based on the mutation status of colon cancer cell lines. In mutated models, miR-125b-5p overexpression slows cancer cells' malignant behavior by inhibiting the invasion/migration and colony formation capacity via direct downregulation of mutated . In wild type cells, the exogenous modulation of miR-125b-5p did not significantly affect the molecular and phenotypic profile. In conclusion, our data show that miR-125b-5p has an anti-cancer effect only in mutated colon cancer cells, explaining partially the dual behavior of this microRNA in malignant pathologies.
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http://dx.doi.org/10.3390/pharmaceutics13050664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148199PMC
May 2021

EBUS in optimizing non-small cell lung cancer diagnosis and treatment.

Med Pharm Rep 2021 Apr 29;94(2):176-184. Epub 2021 Apr 29.

Leon Daniello Pulmonology Hospital, Cluj-Napoca, Romania.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a commonly used minimally invasive method for the diagnosis and staging of lung cancer. In order to improve its diagnostic accuracy, rapid on-site cytologic evaluation (ROSE) is being utilized in some institutions. ROSE, performed by a cytopathologist in the examination room, allows the assessment of the adequacy of the collected samples, identifies malignant cells and sometimes establishes diagnosis on the spot, thus improving diagnostic sensitivity. As non-small cell lung carcinomas (NSCLC) require not only pathological subtyping, but also molecular characterization, obtaining the adequate amount of tissue is crucial. Only a limited number of studies have analyzed the suitability of EBUS-TBNA samples for assessment of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and programmed death-ligand 1 (PD-L1) status.

Aim: We intended to examine the diagnostic yield of ROSE in NSCLC and the results and feasibility of molecular analysis performed on EBUS-TBNA small samples.

Methods: 100 patients with lung tumors and hilar and/or mediastinal lymphadenopathy on CT or PET/CT scans were retrospectively identified over a 3-year period, from a prospectively maintained EBUS-TBNA database. All examinations were accompanied by on-site cytological exam - ROSE, histopathological exam (HPE) and, in the case of NSCLC, molecular testing. After the sampling of the lymph nodes, specimens were Diff-Quik stained and a rapid preliminary diagnosis was established. Immunohistochemistry and mutational testing were performed using cell blocks.

Results: Adenocarcinoma was the most frequent diagnosis in both ROSE (34%) and histopathology (53%). Overall sensitivity and positive predictive value of ROSE in NSCLC, considering HPE the gold standard, were 92.18% and 93.65%, respectively, with a specificity and negative predictive value of 75% and 70.58%, respectively. All samples that were tested for EGFR mutation and ALK rearrangement were adequate for analysis. The adequacy ratio for PD-L1 was 91.66%; 37.5% of patients showed a high PD-L1 expression level, with a tumor proportion score TPS ≥50%.

Conclusion: EBUS-TBNA is a valuable method for lung cancer diagnosis. ROSE proved to have a moderate prediction of the final diagnosis in NSCLC. Molecular analysis of EGFR, ALK and PD-L1 can be successfully accomplished on EBUS-TBNA small tissue samples.
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http://dx.doi.org/10.15386/mpr-1725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118210PMC
April 2021

The shifting landscape of genetic alterations separating endometriosis and ovarian endometrioid carcinoma.

Am J Cancer Res 2021 15;11(4):1754-1769. Epub 2021 Apr 15.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj 400337, Romania.

Ovarian cancer is one of the most common cancers worldwide, and is associated with a prior diagnosis of endometriosis in several cases. Our aim was to correlate genetic and methylation profile of ovarian endometrioid ovarian cancer and endometriosis patients. We evaluated the genetic profile of 50 ovarian endometriosis and 20 ovarian endometrioid carcinoma samples using next generation sequencing technology. In addition, the DNA methylation profile was evaluated for both cohorts of patients. We observed several mutated genes that were common for both types of patients, but we also identified mutated genes that were characteristic for each group: and for endometriosis; and and for ovarian endometrioid cancer. Also we idenfied genes that are highly methylated only in endometriosis samples ( and CDH13) and MLH3 gene was methylated only in endometrioid ovarian carcinoma samples. Also, and genes are mainly methylated in endometrioid ovarian carcinoma patients. We identified a correlation for the cancer group between tumor stage, copy number aberrations and the presence of metastases; more specifically, the presence of pathogenic variants was correlated with tumor differentiation degree, variants and copy number aberrations. This study was able to demonstrate the presence of similar pathways being altered in both endometriosis and ovarian endometrioid carcinoma, which could mean that a diagnosis of endometriosis could be an early marker for cancer diagnosis. In addition, we showed that hypomethylation, hypermethylation, hypomethylation, higher tumor differentiation degree or higher tumor stage is associated with a poor prognosis in patients with ovarian endometrioid carcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085850PMC
April 2021

Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival.

NPJ Precis Oncol 2021 Apr 28;5(1):33. Epub 2021 Apr 28.

American Society of Clinical Oncology (ASCO), Alexandria, VA, USA.

The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E-05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E-04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients' treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).
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http://dx.doi.org/10.1038/s41698-021-00171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080819PMC
April 2021

Game of "crowning" season 8: RAS and reproductive hormones in COVID-19 - can we end this viral series?

Arch Med Sci 2021 27;17(2):275-284. Epub 2020 Jun 27.

Applied Biotechnology Research Centre, Baqiyatallah University of Medical Sciences, Tehran, Iran.

The outbreak of a newly identified coronavirus, the SARS-CoV-2 (alternative name 2019-nCoV), capable of jumping across species causing zoonosis with severe acute respiratory syndromes (SARS), has alerted authorities worldwide. Soon after the epidemic was first detected in the city of Wuhan in the Hubei Province of China, starting in late December 2019, the virus spread over multiple countries in different continents, being declared a pandemic by March 2020. The demographic characteristics of the infected patients suggest that age, sex, and comorbidities are predictive factors for the fatality of the infection. The mechanisms of viral entry into the human host cells seem to be in a close relationship with the mechanisms of regulating the renin-angiotensin system (RAS), which may explain the pathogenesis associated with the infection. This brings new insights into the possibilities of exploiting viral entry mechanisms to limit associated complications by means of enhancing the resistance of the infected patients using methods of regulating the RAS and strategies of modulating ACE2 expression. In this perspective article we exploit the mechanisms of COVID-19 pathogenesis based on the demographic characteristics of the infected patients reported in the recent literature and explore several approaches of limiting the initial steps of viral entry and pathogenesis based on viral interactions with ACE2 and RAS. We further discuss the implications of reproductive hormones in the regulation of the RAS and investigate the premise of using endocrine therapy against COVID-19.
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http://dx.doi.org/10.5114/aoms.2020.96604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959061PMC
June 2020

Comprehensive Analysis of the Expression of Key Genes Related to Hippo Signaling and Their Prognosis Impact in Ovarian Cancer.

Diagnostics (Basel) 2021 Feb 19;11(2). Epub 2021 Feb 19.

Department of Surgery, Institute of Oncology "Prof. Dr. Ion Chiricuta", 400015 Cluj-Napoca, Romania.

The Hippo signaling pathway, one of the most conserved in humans, controlling dimensions of organs and tumor growth, is frequently deregulated in several human malignancies, including ovarian cancer (OC). The alteration of Hippo signaling has been reported to contribute to ovarian carcinogenesis and progression. However, the prognostic roles of individual Hippo genes in OC patients remain elusive. Herein we investigated the expression level and prognostic value of key Hippo genes in OC using online databases, followed by a qRT-PCR validation step in an additional patient cohort. Using the GEPIA database, we observed an increased level for TP53 and reduced expression level for LATS1, LATS2, MST1, TAZ, and TEF in tumor tissue versus normal adjacent tissue. Moreover, LATS1, LATS2, TP53, TAZ, and TEF expression levels have prognostic significance correlated with progression-free survival. The qRT-PCR validation step was conducted in an OC patient cohort comprising 29 tumor tissues and 20 normal adjacent tissues, endorsing the expression level for LATS1, LATS2, and TP53, as well as for two of the miRNAs targeting the TP53 gene, revealing miR-25-3p upregulation and miR-181c-5p downregulation. These results display that there are critical prognostic value dysregulations of the Hippo genes in OC. Our data demonstrate the major role the conserved Hippo pathway presents in tumor control, underlying potential therapeutic strategies and controlling several steps modulated by miRNAs and their target genes that could limit ovarian cancer progression.
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http://dx.doi.org/10.3390/diagnostics11020344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922135PMC
February 2021

'De Novo' Brain AVMs-Hypotheses for Development and a Systematic Review of Reported Cases.

Medicina (Kaunas) 2021 Feb 26;57(3). Epub 2021 Feb 26.

Research Center for Functional Genomics, Biomedicine, and Translational Medicine, Institute of Doctoral Studies, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.

Brain arteriovenous malformations AVMs have been consistently regarded as congenital malformations of the cerebral vasculature. However, recent case reports describing "de novo AVMs" have sparked a growing debate on the nature of these lesions. We have performed a systematic review of the literature concerning de novo AVMs utilizing the PubMed and Google Academic databases. Termes used in the search were "AVM," "arteriovenous," "de novo," and "acquired," in all possible combinations. 53 articles including a total of 58 patients harboring allegedly acquired AVMs were identified by researching the literature. Of these, 32 were male (55.17%), and 25 were female (43.10%). Mean age at de novo AVM diagnosis was 27.833 years (standard deviation (SD) of 21.215 years and a 95% confidence interval (CI) of 22.3 to 33.3). Most de novo AVMs were managed via microsurgical resection (20 out of 58, 34.48%), followed by radiosurgery and conservative treatment for 11 patients (18.97%) each, endovascular embolization combined with resection for five patients (8.62%), and embolization alone for three (5.17%), the remaining eight cases (13.79%) having an unspecified therapy. Increasing evidence suggests that some of the AVMs discovered develop some time after birth. We are still a long way from finally elucidating their true nature, though there is reason to believe that they can also appear after birth. Thus, we reason that the de novo AVMs are the result of a 'second hit' of a variable type, such as a previous intracranial hemorrhage or vascular pathology. The congenital or acquired characteristic of AVMs may have a tremendous impact on prognosis, risk of hemorrhage, and short and long-term management.
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http://dx.doi.org/10.3390/medicina57030201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996785PMC
February 2021

Ovarian endometriosis, a precursor of ovarian cancer: Histological aspects, gene expression and microRNA alterations (Review).

Exp Ther Med 2021 Mar 22;21(3):243. Epub 2021 Jan 22.

Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 40015 Cluj-Napoca, Romania.

Ovarian endometriosis is a frequent chronic gynecological disease with an uncertain evolution regarding its progression or association with ovarian malignant lesions. The present review summarized the histological aspects, gene expression and microRNA (miRNA/miR) alterations associated with ovarian endometriosis and cancer and their possible interaction. The endometriosis-ovarian cancer interaction has been proposed by certain researchers as a single entity. Histological results indicated that endometriosis has been in different circumstances coexisting with ovarian cancer, with reference to endometrioid and clear cell carcinoma. Endometriosis with moderate and severe atypia can influence cell proliferation and architecture, resulting in a possible malignant transformation. Gene expression analysis indicated that the pathologies of both endometriosis and ovarian cancer are characterized by genetic instability from a molecular point of view, as several important genetic mutations, including ARID1A, PI3KCA, PTEN, BRCA1, BRCA2, TP53 and KRAS genes, were identified. miRNA alterations have been implicated in the regulation of gene expression. Common dysregulated miRNAs, such as miR-331, miR-335, miR-891, miR-548, miR-124, miR-148, miR-215, miR-192, miR-337, miR-153, miR-155, miR-144, miR-221 and miR-3688 were extensively investigated in understanding endometriosis and ovarian cancer evolution. From a combined viewpoint including histological aspects, gene expression and miRNA alterations, it is reasonable to speculate that endometriosis is associated with ovarian cancer. Ovarian endometriosis lesions may present a risk for ovarian malignant lesions, which supports a model of endometriosis as a malignant precursor. However, the endometriosis-ovarian cancer association is not widely accepted in the literature and additional studies are required to validate this association.
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http://dx.doi.org/10.3892/etm.2021.9674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851621PMC
March 2021

circFOXO3: Going around the mechanistic networks in cancer by interfering with miRNAs regulatory networks.

Biochim Biophys Acta Mol Basis Dis 2021 May 26;1867(5):166045. Epub 2021 Jan 26.

Research Center for Functional Genomics Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; Department of Functional Genomics and Experimental Pathology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania. Electronic address:

Circular RNAs (circRNA) have gained recent interest due to their functional versatility due to their interactions with other RNA species and proteins, all of which underline complex regulatory networks involved in pathogenic mechanisms. As a result, recent insights in circRNA biology are investigating their biomarker and therapeutic potential. One such circRNA is CircFOXO3, which consists of the circularized second exon of the FOXO3 mRNA, a member of the forkhead box transcription factor family involved in the regulation of developmental programs. Recent research focused on the role of circFOXO3 in the context of cancer has highlighted several implications in key tumorigenesis mechanisms, thus consolidating its relevance among other identified circRNAs. In this paper, we will focus on the currently identified case-specific implications of circFOXO3 in cancer, with a focus on the circFOXO3-miRNA-mRNA regulatory networks, its interactions with different proteins, and their cumulated biological effects upon tumor development. Therefore, we aim to provide an integrated perspective of the mechanistic implications of circFOXO3 in different cancers while also highlighting its biomarker or therapeutic potential based on the current evidence.
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http://dx.doi.org/10.1016/j.bbadis.2020.166045DOI Listing
May 2021

Angiogenesis in Regenerative Dentistry: Are We Far Enough for Therapy?

Int J Mol Sci 2021 Jan 19;22(2). Epub 2021 Jan 19.

Department of Preventive Dentistry, Iuliu Hatieganu University of Medicine and Pharmacy, Avram Iancu 31, 400083 Cluj-Napoca, Romania.

Angiogenesis is a broad spread term of high interest in regenerative medicine and tissue engineering including the dental field. In the last two decades, researchers worldwide struggled to find the best ways to accelerate healing, stimulate soft, and hard tissue remodeling. Stem cells, growth factors, pathways, signals, receptors, genetics are just a few words that describe this area in medicine. Dental implants, bone and soft tissue regeneration using autologous grafts, or xenografts, allografts, their integration and acceptance rely on their material properties. However, the host response, through its vascularization, plays a significant role. The present paper aims to analyze and organize the latest information about the available dental stem cells, the types of growth factors with pro-angiogenic effect and the possible therapeutic effect of enhanced angiogenesis in regenerative dentistry.
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http://dx.doi.org/10.3390/ijms22020929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832295PMC
January 2021

Field Cancerization in NSCLC: A New Perspective on MicroRNAs in Macrophage Polarization.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, The "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.

Lung cancer is currently the first cause of cancer-related death. The major lung cancer subtype is non-small cell lung cancers (NSCLC), which accounts for approximatively 85% of cases. The major carcinogenic associated with lung cancer is tobacco smoke, which produces long-lasting and progressive damage to the respiratory tract. The progressive and diffuse alterations that occur in the respiratory tract of patients with cancer and premalignant lesions have been described as field cancerization. At the level of tumor cells, adjacent tumor microenvironment (TME) and cancerized field are taking place dynamic interactions through direct cell-to-cell communication or through extracellular vesicles. These molecular messages exchanged between tumor and nontumor cells are represented by proteins, noncoding RNAs (ncRNAs) and microRNAs (miRNAs). In this paper, we analyze the miRNA roles in the macrophage polarization at the level of TME and cancerized field in NSCLC. Identifying molecular players that can influence the phenotypic states at the level of malignant cells, tumor microenvironment and cancerized field can provide us new insights into tumor regulatory mechanisms that can be further modulated to restore the immunogenic capacity of the TME. This approach could revert alterations in the cancerized field and could enhance currently available therapy approaches.
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http://dx.doi.org/10.3390/ijms22020746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828565PMC
January 2021

Zeaxanthin-Rich Extract from Superfood Selectively Modulates the Cellular Adhesion and MAPK Signaling in Melanoma versus Normal Skin Cells In Vitro.

Molecules 2021 Jan 11;26(2). Epub 2021 Jan 11.

Department of Otolaryngology, University of Medicine and Pharmacy "Iuliu Hatieganu", RO-400372 Cluj-Napoca, Romania.

The concern for implementing bioactive nutraceuticals in antioxidant-related therapies is of great importance for skin homeostasis in benign or malignant diseases. In order to elucidate some novel insights of (Goji berry) activity on skin cells, the present study focused on its active compound zeaxanthin. By targeting the stemness markers CD44 and CD105, with deep implications in skin oxidative stress mechanisms, we revealed, for the first time, selectivity in zeaxanthin activity. When applied in vitro on BJ human fibroblast cell line versus the A375 malignant melanoma cells, despite the moderate cytotoxicity, the zeaxanthin-rich extracts and were able to downregulate significantly the CD44 and CD105 membrane expression and extracellular secretion in A375, and to upregulate them in BJ cells. At mechanistic level, the present study is the first to demonstrate that the zeaxanthin-rich Goji extracts are able to influence selectively the mitogen-activated protein kinases (MAPK): ERK, JNK and p38 in normal BJ versus tumor-derived A375 skin cells. These results point out towards the applications of zeaxanthin from as a cytoprotective agent in normal skin and raises questions about its use as an antitumor prodrug alone or in combination with standard therapy.
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http://dx.doi.org/10.3390/molecules26020333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827977PMC
January 2021

Multiple potential targets of opioids in the treatment of acute respiratory distress syndrome from COVID-19.

J Cell Mol Med 2021 01 19;25(1):591-595. Epub 2020 Nov 19.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, The "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

COVID-19 can present with a variety of clinical features, ranging from asymptomatic or mild respiratory symptoms to fulminant acute respiratory distress syndrome (ARDS) depending on the host's immune responses and the extent of the associated pathologies. This implies that several measures need to be taken to limit severely impairing symptoms caused by viral-induced pathology in vital organs. Opioids are most exploited for their analgesic effects but their usage in the palliation of dyspnoea, immunomodulation and lysosomotropism may represent potential usages of opioids in COVID-19. Here, we describe the mechanisms involved in each of these potential usages, highlighting the benefits of using opioids in the treatment of ARDS from SARS-CoV-2 infection.
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http://dx.doi.org/10.1111/jcmm.15927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753383PMC
January 2021

Cannabidiol and Vitamin D3 Impact on Osteogenic Differentiation of Human Dental Mesenchymal Stem Cells.

Medicina (Kaunas) 2020 Nov 12;56(11). Epub 2020 Nov 12.

Department of Oral Rehabilitation, University of Medicine and Pharmacy "Iuliu Hatieganu", Victor Babes street, No. 15, 400012 Cluj-Napoca, Romania.

The aim of the present study was to establish a new differentiation protocol using cannabidiol (CBD) and vitamin D3 (Vit. D3) for a better and faster osteogenic differentiation of dental tissue derived mesenchymal stem cells (MSCs). MSCs were harvested from dental follicle (DFSCs), dental pulp (DPSCs), and apical papilla (APSCs) of an impacted third molar of a 17-year old patient. The stem cells were isolated and characterized using flow cytometry; reverse transcription polymerase chain reaction (RT-PCR); and osteogenic, chondrogenic, and adipogenic differentiation. The effects of CBD and Vit. D3 on osteogenic differentiation of dental-derived stem cell were evaluated in terms of viability/metabolic activity by alamar test, expression of collagen1A, osteopontin (OP), osteocalcin (OC), and osteonectin genes and by quantification of calcium deposits by alizarin red assay. Stem cell characterization revealed more typical stemness characteristics for DFSCs and DPSCs and atypical morphology and markers expression for APSCs, a phenotype that was confirmed by differences in multipotential ability. The RT-PCR quantification of bone matrix proteins expression revealed a different behavior for each cell type, APSCs having the best response for CBD. DPSCs showed the best osteogenic potential when treated with Vit. D3. Cultivation of DFSC in standard stem cell conditions induced the highest expression of osteogenic genes, suggesting the spontaneous differentiation capacity of these cells. Regarding mineralization, alizarin red assay indicated that DFSCs and APSCs were the most responsive to low doses of CBD and Vit. D3. DPSCs had the lowest mineralization levels, with a slightly better response to Vit. D3. This study provides evidence that DFSCs, DPSCs, and APSCs respond differently to osteoinduction stimuli and that CBD and Vit. D3 can enhance osteogenic differentiation of these types of cells under certain conditions and doses.
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http://dx.doi.org/10.3390/medicina56110607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697067PMC
November 2020

Cardiomyopathies and Arrhythmias Induced by Cancer Therapies.

Biomedicines 2020 Nov 12;8(11). Epub 2020 Nov 12.

Department of Chemotherapy, Ion Chiricuta Clinical Cancer Center, 400139 Cluj Napoca, Romania.

Cardiology and oncology are two fields dedicated to the study of various types of oncological and cardiac diseases, but when they collide, a new specialty is born, i.e., cardio-oncology. Continuous research on cancer therapy has brought into the clinic novel therapeutics that have significantly improved patient survival. However, these therapies have also been associated with adverse effects that can impede the proper management of oncological patients through the necessity of drug discontinuation due to life-threatening or long-term morbidity risks. Cardiovascular toxicity from oncological therapies is the main issue that needs to be solved. Proper knowledge, interpretation, and management of new drugs are key elements for developing the best therapeutic strategies for oncological patients. Upon continuous investigations, the profile of cardiotoxicity events has been enlarged with the inclusion of myocarditis upon administration of immune checkpoint inhibitors and cardiac dysfunction in the context of cytokine release syndrome with chimeric antigen receptor T cell therapy. Affinity enhanced and chimeric antigen receptor T cells have both been associated with hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Therefore, the cardiologist must adhere to the progressing field of cancer therapy and become familiar with the adverse effects of novel drugs, and not only the ones of standard care, such as anthracycline, trastuzumab, and radiation therapy. The present review provides essential information summarized from the latest studies from cardiology, oncology, and hematology to bring together the three specialties and offers proper management options for oncological patients.
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http://dx.doi.org/10.3390/biomedicines8110496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696637PMC
November 2020

The Clinical Utility of miR-21 and let-7 in Non-small Cell Lung Cancer (NSCLC). A Systematic Review and Meta-Analysis.

Front Oncol 2020 19;10:516850. Epub 2020 Oct 19.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania.

Non-small cell lung cancer (NSCLC) remains a problem worldwide due to its rapid progression and low rate of response to treatment. The heterogeneity of these tumors observed in histopathology exam but also in the mutational status and gene expression pattern makes this malignancy difficult to treat in clinic. The present study investigated the effect of miR-21 and let-7 family members as prognostic biomarkers in NSCLC patients based on the results published in different studies regarding this subject until March 2019. The analysis revealed that these two transcripts are steady biomarkers for prediction of patient outcome or survival. Upregulated expression of miR-21 is associated with poor outcome of patients with NSCLC [HR = 1.87, 95% CI = (1.41, 2.47), < 0.001]. The analysis regarding let-7 family, specifically let-7a/b/e/f, revealed that downregulated expression of these transcripts predicts poor outcome for NSCLC patients [HR = 2.61, 95% CI = (1.58, 4.30), < 0.001]. Besides, the reliability of these microRNAs is reflected in the fact that their prognostic significance is constant given the different sample types (tissue, FFPE tissue, serum, serum/plasma or exosomes) used in the selected studies.
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http://dx.doi.org/10.3389/fonc.2020.516850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604406PMC
October 2020

New insights in gene expression alteration as effect of doxorubicin drug resistance in triple negative breast cancer cells.

J Exp Clin Cancer Res 2020 Nov 13;39(1):241. Epub 2020 Nov 13.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Background: Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and an unfavorable prognosis rate. Due to the lack of surface receptors, TNBC must be intensely investigated in order to establish a suitable treatment for patients with this pathology. Chemoresistance is an important reason for therapeutic failure in TNBC.

Method: The aim of this study was to investigate the effect of doxorubicin in TNBC cell lines and to highlight cellular and molecular alterations after a long exposure to doxorubicin.

Results: The results revealed that doxorubicin significantly increased the half maximal inhibitory concentration (IC) values at P12 and P24 compared to parenteral cells P0. Modifications in gene expression were investigated through microarray technique, and for detection of mutational pattern was used Next Generation Sequencing (NGS). 196 upregulated and 115 downregulated genes were observed as effect of multiple dose exposure, and 15 overexpressed genes were found to be involved in drug resistance. Also, the presence of some additional mutations in both cell lines was observed.

Conclusion: The outcomes of this research may provide novel biomarkers for drug resistance in TNBC. Also, this activity can highlight the potential mechanisms associated with drug resistance, as well as the potential therapies to counteract these mechanisms.
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http://dx.doi.org/10.1186/s13046-020-01736-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664031PMC
November 2020

COVID-19 and antimalarials. Have we been doing it wrong all along?

Eur J Pharmacol 2021 Jan 31;891:173694. Epub 2020 Oct 31.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, The "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; The Functional Genomics Department - The Oncology Institute "Prof. Dr. Ion Chiricuta", Cluj-Napoca, Romania.

In the context of the current SARS-CoV-2 pandemic, associations of drugs which interfere with specific steps of the viral infectious cycle are currently being exploited as therapeutic strategies since a specific treatment by vaccination is still unavailable. A widespread association of repurposed agents is the combination of the antimalarial drug Hydroxychloroquine and the macrolide antibiotic Azithromycin in the setting of clinical trials. But a closer analysis of their mechanism of action suggests that their concomitant administration may be impractical, and this is supported by experimental data with other agents of the same classes. However a sequential administration of the lysosomotropic antimalarial with the addition of the macrolide proton pump inhibitor after the first has reached a certain threshold could better exploit their antiviral potential.
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http://dx.doi.org/10.1016/j.ejphar.2020.173694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604012PMC
January 2021

Beyond Conventional: The New Horizon of Anti-Angiogenic microRNAs in Non-Small Cell Lung Cancer Therapy.

Int J Mol Sci 2020 Oct 27;21(21). Epub 2020 Oct 27.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.

GLOBOCAN 2018 identified lung cancer as the leading oncological pathology in terms of incidence and mortality rates. Angiogenesis is a key adaptive mechanism of numerous malignancies that promotes metastatic spread in view of the dependency of cancer cells on nutrients and oxygen, favoring invasion. Limitation of the angiogenic process could significantly hamper the disease advancement through starvation of the primary tumor and impairment of metastatic spread. This review explores the basic molecular mechanisms of non-small cell lung cancer (NSCLC) angiogenesis, and discusses the influences of the key proangiogenic factors-the vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (FGF2), several matrix metalloproteinases (MMPs-MMP-2, MMP-7, MMP-9) and hypoxia-and the therapeutic implications of microRNAs (miRNAs, miRs) throughout the entire process, while also providing critical reviews of a number of microRNAs, with a focus on miR-126, miR-182, miR-155, miR-21 and let-7b. Finally, current conventional NSCLC anti-angiogenics-bevacizumab, ramucirumab and nintedanib-are briefly summarized through the lens of evidence-based medicine.
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http://dx.doi.org/10.3390/ijms21218002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663714PMC
October 2020

Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic.

Cancers (Basel) 2020 Oct 20;12(10). Epub 2020 Oct 20.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.

Breast cancer is one of the most common oncological diseases in women, as its incidence is rapidly growing, rendering it unpredictable and causing more harm than ever before on an annual basis. Alterations of coding and noncoding genes are related to tumorigenesis and breast cancer progression. In this study, several key genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) features were identified. EMT and CSCs are two key mechanisms responsible for self-renewal, differentiation, and self-protection, thus contributing to drug resistance. Therefore, understanding of the relationship between these processes may identify a therapeutic vulnerability that can be further exploited in clinical practice, and evaluate its correlation with overall survival rate. To determine expression levels of altered coding and noncoding genes, The Cancer Omics Atlas (TCOA) are used, and these data are overlapped with a list of CSCs and EMT-specific genes downloaded from NCBI. As a result, it is observed that CSCs are reciprocally related to EMT, thus identifying common signatures that allow for predicting the overall survival for breast cancer genes (BRCA). In fact, common CSCs and EMT signatures, represented by ALDH1A1, SFRP1, miR-139, miR-21, and miR-200c, are deemed useful as prognostic biomarkers for BRCA. Therefore, by mapping changes in gene expression across CSCs and EMT, suggesting a cross-talk between these two processes, we have been able to identify either the most common or specific genes or miRNA markers associated with overall survival rate. Thus, a better understanding of these mechanisms will lead to more effective treatment options.
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http://dx.doi.org/10.3390/cancers12103053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589570PMC
October 2020

Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer.

Int J Mol Sci 2020 Oct 17;21(20). Epub 2020 Oct 17.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania.

Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials.
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http://dx.doi.org/10.3390/ijms21207688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589964PMC
October 2020

Ruptured pontine cavernomas in infants: a report of two cases.

Childs Nerv Syst 2021 Mar 18;37(3):1009-1015. Epub 2020 Oct 18.

The Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Background: Cavernous malformations (CMs) are either congenital or acquired vascular lesions comprised of sinusoid spaces filled with either blood or its breakdown products. They possess a relatively reduced risk of hemorrhage, yet placement within the posterior fossa and especially the brainstem heightens their likelihood to rupture, making them a likely cause of permanent and debilitating neurological deficit, as well as a veritable surgical challenge. Although the incidence of rupture varies with age among reported case series, it is undoubtable that the severity of this occurrence is the highest while the brain is as its most vulnerable period, i.e. during infancy.

Case Presentations: We present two patients, both female, 6.5- and 5-months-old respectively, who presented with brainstem hemorrhage from CM. They suffered from a sudden onset of hemiparesis and were subjected to surgical removal of their lesions and resulting hematomas. Both patients were discharged in a favorable neurological status and are currently alive and in good health.

Conclusion: Microsurgical treatment of brainstem CMs in infants is not only possible with minimal deficit, but also advisable if the lesions are symptomatic. Nevertheless, this requires substantial patience and experience to prevent significant loss of blood and injury to the structures of the posterior fossa. We argue that the safest method to prevent further damage from brainstem CM rebleed is to remove these lesions shortly after the initial hemorrhage.
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http://dx.doi.org/10.1007/s00381-020-04898-8DOI Listing
March 2021

PSA Based Biomarkers, Imagistic Techniques and Combined Tests for a Better Diagnostic of Localized Prostate Cancer.

Diagnostics (Basel) 2020 Oct 10;10(10). Epub 2020 Oct 10.

Department of Urology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.

Prostate cancer represents the most encountered urinary malignancy in males over 50 years old, and the second most diagnosed after lung cancer globally. Digital rectal examination and prostatic specific antigen were the long-time standard tools for diagnosis but with a significant risk of overdiagnosis and overtreatment. Magnetic resonance imaging recently entered the diagnosis process, but to this date, there is no specific biomarker that accurately indicates whether to proceed with the prostate biopsy. Research in this area has gone towards this direction, and recently, serum, urine, imagistic, tissue biomarkers, and Risk Calculators promise to help better diagnose and stratify prostate cancer. In order to eliminate the comorbidities that appear along with the diagnosis and treatment of this disease, there is a constant need to implement new diagnostic strategies. Important uro-oncology associations recommend the use of novel biomarkers in the grey area of prostate cancer, to better distinguish the next step in the diagnostic process. Although it is not that simple, they should be integrated according to the clinical policies, and it should be considered that statistical significance does not always equal clinical significance. In this review, we analyzed the contribution of prostate-specific antigen (PSA)-based biomarkers (PHI, PHID, 4Kscore, STHLM3), imagistic techniques (mp-MRI and mp-US), and combined tests in the early diagnosis process of localized prostate cancer.
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http://dx.doi.org/10.3390/diagnostics10100806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601671PMC
October 2020

Identification of Core Genes Involved in the Progression of Cervical Cancer Using an Integrative mRNA Analysis.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.

In spite of being a preventable disease, cervical cancer (CC) remains at high incidence, and it has a significant mortality rate. Although hijacking of the host cellular pathway is fundamental for developing a better understanding of the human papillomavirus (HPV) pathogenesis, a major obstacle is identifying the central molecular targets involved in HPV-driven CC. The aim of this study is to investigate transcriptomic patterns of HPV-infected and normal tissues to identify novel prognostic markers. Analyses of functional enrichment and interaction networks reveal that altered genes are mainly involved in cell cycle, DNA damage, and regulated cell-to-cell signaling. Analysis of The Cancer Genome Atlas (TCGA) data has suggested that patients with unfavorable prognostics are more likely to have DNA repair defects attributed, in most cases, to the presence of HPV. However, further studies are needed to fully unravel the molecular mechanisms of such genes involved in CC.
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http://dx.doi.org/10.3390/ijms21197323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583959PMC
October 2020

Glucose-6-phosphate dehydrogenase deficiency and SARS-CoV-2 mortality: Is there a link and what should we do?

Clin Biochem 2020 Dec 17;86:31-33. Epub 2020 Sep 17.

Division of Translational Medicine, Baqiyatallah Hospital, Baqiyatallah University of Medical Sciences, Tehran, Iran; Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.clinbiochem.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497541PMC
December 2020

Circulating microRNA-194 and microRNA-1228 Could Predict Colon Cancer Proliferation via Phospho S6 Modulation.

J Gastrointestin Liver Dis 2020 Sep 9;29(3):361-367. Epub 2020 Sep 9.

Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca; 5 th Surgical Department, Municipal Hospital, Cluj- Napoca, Romania.

Background And Aims: Although colon cancer has a decreasing incidence trend in Europe, because of its still high frequency and not fully understood pathogenesis, this malignancy still remains a subject of intense research. The aim of this study was to investigate the role of microRNA-194 and microRNA-1228 in colon cancer proliferation.

Methods: RNA was extracted from patients with colon cancer with or without advanced disease and microRNA expression levels were determined through qRT-PCR. Assays were performed on HCT116 cell line and included qRT-PCR, western blotting and cell counting.

Results: We observed that both microRNAs 194 and 1228 were altered in patients with colon cancer compared with healthy individuals. We observed a lower expression of both microRNA-194 and microRNA-1228 in patients with advanced colon cancer. To validate their pathogenetic role we performed viability and invasion assays on HCT116 cell line transfected with mimics or inhibitors of the mentioned microRNAs, with observable changes in viability and invasion. Furthermore, to determine the altered signaling induced by these microRNAs, we performed western blotting for phospho S6 on HCT116 cells transfected with mimic and inhibitor of the above-mentioned microRNAs with observable differences.

Conclusion: In the current study we have shown that both microRNA-194 and microRNA-1228 alteration was correlated with the presence of advanced colon cancer, a fact that was further validated in vitro through an invasion assay. Moreover, we have also shown that their effect might be mediated through phospho S6 expression.
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http://dx.doi.org/10.15403/jgld-2558DOI Listing
September 2020