69 results on '"Smolic M"'
Search Results
2. Optimizing the photodynamic therapy treatment approach for recurrent maxilla, sinonasal and anterior skull base malignancies
- Author
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Karakullukçu, M.B., primary, van Doeveren, T.E.M., additional, van Veen, R.L.P., additional, van der Boom, F., additional, Smolic, M., additional, van Mourik, A.M., additional, and Tan, I.B., additional
- Published
- 2017
- Full Text
- View/download PDF
3. OC-0157: Prostate fiducial markers detection with the use of multiparametric-MRI
- Author
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Fernandes, C.D., primary, Dinh, C., additional, Ter Beek, L.C., additional, Steggerda, M., additional, Smolic, M., additional, Van Buuren, L.D., additional, Van Houdt, P.J., additional, and Van der Heide, U.A., additional
- Published
- 2016
- Full Text
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4. Holography out of equilibrium
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Smolic, M., Skenderis, Kostas, Taylor, Marika, and String Theory (ITFA, IoP, FNWI)
- Abstract
Using holography it is possible to write down the dissipative hydrodynamic behaviour of a boundary field theory which describes a non-conformal fluid. It is also possible to write down the evolution equations of the two-point correlators for the various field present within the cornerstone field theory in the AdS/CFT correspondence. Studying out-of-equilibrium phenomena in this way might lead us to discover the process of , among other things, black hole formation/evaporation. Studying black holes had proved a vital ingredient in searching for a unifying theory of quantum mechanics and general relativity.
- Published
- 2013
5. PD-0182: Prediction of needle placement in the first fraction of cervix brachytherapy: pre-MRI plan versus expert opinion
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Smolic, M., primary, Sombroek, C., additional, Bloemers, M., additional, Van Triest, B., additional, and Mans, A., additional
- Published
- 2015
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6. Mn-SOD and Chronic Inflammation of Gastric Mucosa
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Dovhanj, J., primary, Svagelj, D., additional, Smolic, M., additional, Smolic, R., additional, and Maric, I., additional
- Published
- 2010
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7. NADPH and Iron May Have an Important Role in Attenuated Mucosal Defense in Helicobacter pylori Infection?
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Dovhanj, J., primary, Kljaic, K., additional, Smolic, M., additional, and Svagelj, D., additional
- Published
- 2010
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8. New insights into the pathogenesis of bone loss in recurrent calcium stone formers
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Maric, I., Milas-Ahić, J., Smolić, M., Smolić, R., Bilić-Ćurčić, I., Opačak-Bernardi, T., Kizivat, T., Mihaljević, I., Šerić, V., Kuveždić, H., and Tucak, A.
- Published
- 2009
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9. Multi-parametric MRI to guide salvage treatment of recurrent prostate cancer
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Dinis Fernandes, C., Heide, U.A. van der, Smolic, M., Marijnen, C.A.M., Pelger, R.C.M., Haustermans, K., Leeuwen, A.G.J.M. van, and Leiden University
- Subjects
Radiomics ,Radiotherapy ,Machine learning ,Recurrent prostate cancer ,Multi-parametric MRI ,Histopathology - Abstract
Prostate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial treatment. Patients with localised recurrent PCa are candidates for curative (i.e. salvage) treatment. To overcome the toxicity associated with whole-gland approaches, focal salvage treatments target the index lesion while sparing the surrounding tissue. The studies described in this thesis elaborate on the use of quantitative multi-parametric MRI (mp-MRI) for the detection and localisation of locally recurrent PCa after radiotherapy. Pre-treatment radiomic imaging features were found to have potential to improve recurrence-risk prediction models for high-risk PCa patients treated with radiotherapy. In this thesis, the mp-MRI properties of irradiated benign tissue and recurrent tumour were characterised, with access to pathological samples. These findings can be used as a foundation to establish guidelines (which are currently absent) on how to assess and score MRI scans after radiotherapy. Improving radiological knowledge in the recurrent setting can lead to improved staging and result in better patient selection for salvage treatments. Lastly, this thesis provides evidence on how best to define the region to target, leading to a refinement of focal salvage strategies.
- Published
- 2019
10. Individualized 3D-printed applicators for magnetic resonance imaging-guided brachytherapy in nasal vestibule cancer.
- Author
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de Ridder M, Smolic M, Kastelijns M, Kloosterman S, van der Vegt S, Rijken JA, Jürgenliemk-Schulz IM, Dehnad H, Kroon PS, and Moerland MA
- Abstract
Background and Purpose: Brachytherapy is treatment of choice for early stage nasal vestibule cancer. Over the years improvements were achieved by means of image guided target definition, interstitial implant techniques and also individual mold techniques. The aim of this study was to improve the technique of the implant so that the need for interstitial catheters can be limited by making use of patient individualized 3D-printed applicators., Materials and Methods: In 19 patients 3D-printed applicators were used to deliver pulse dose rate (PDR) brachytherapy. All patients underwent computed tomography (CT) and magnetic resonance imaging (MRI). A pre-plan with tumor delineation and manually optimized catheter positions to achieve tumor coverage was made. Based on the pre-plan a 3D-printed applicator was manufactured. Dose was evaluated by several indices: Conformity Index, Healthy Tissues Conformity Index, Dose Homogeneity Index, Dose non-uniformity ratio, Conformal index and high dose (HD) index., Results: A high target coverage was achieved, with a median V100%
CTV of 99.1 % (range, 81.8-100 %) and median CI of 0.99 (range, 0.82-1.00), as well as a median V0.7GyGTV of 100 % (range, 93.0-100 %). The median HD was 0.39 (range, 0.20-0.83). Interstitial catheters were needed in 12 patients. None of the patients developed grade ≥ II toxicity within the median follow up of 18 months., Conclusions: This study shows that using 3D-printed applicators limits the need for interstitial catheters and also limits the high doses in normal tissue., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)- Published
- 2024
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11. Green Tea Polyphenol (-)-Epicatechin Pretreatment Mitigates Hepatic Steatosis in an In Vitro MASLD Model.
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Hefer M, Petrovic A, Roguljic LK, Kolaric TO, Kizivat T, Wu CH, Tabll AA, Smolic R, Vcev A, and Smolic M
- Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is becoming more prominent globally due to an increase in the prevalence of obesity, dyslipidemia, and type 2 diabetes. A great deal of studies have proposed potential treatments for MASLD, with few of them demonstrating promising results. The aim of this study was to investigate the potential effects of (-)-epicatechin (EPI) on the development of MASLD in an in vitro model using the HepG2 cell line by determining the metabolic viability of the cells and the levels of PPARα, PPARγ, and GSH. HepG2 cells were pretreated with 10, 30, 50, and 100 μM EPI for 4 h to assess the potential effects of EPI on lipid metabolism. A MASLD cell culture model was established using HepG2 hepatocytes which were exposed to 1.5 mM oleic acid (OA) for 24 h. Moreover, colorimetric MTS assay was used in order to determine the metabolic viability of the cells, PPARα and PPARγ protein levels were determined using enzyme-linked immunosorbent assay (ELISA), and lipid accumulation was visualized using the Oil Red O Staining method. Also, the levels of intracellular glutathione (GSH) were measured to determine the level of oxidative stress. EPI was shown to increase the metabolic viability of the cells treated with OA. The metabolic viability of HepG2 cells, after 24 h incubation with OA, was significantly decreased, with a metabolic viability of 71%, compared to the cells pretreated with EPI, where the metabolic viability was 74-86% with respect to the concentration of EPI used in the experiment. Furthermore, the levels of PPARα, PPARγ, and GSH exhibited a decrease in response to increasing EPI concentrations. Pretreatment with EPI has demonstrated a great effect on the levels of PPARα, PPARγ, and GSH in vitro. Therefore, considering that EPI mediates lipid metabolism in MASLD, it should be considered a promising hepatoprotective agent in future research.
- Published
- 2024
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12. Monoclonal IgY antibodies: advancements and limitations for immunodiagnosis and immunotherapy applications.
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Tabll AA, Shahein YE, Omran MM, Hussein NA, El-Shershaby A, Petrovic A, Glasnovic M, Smolic R, and Smolic M
- Abstract
Due to their high specificity and scalability, Monoclonal IgY antibodies have emerged as a valuable alternative to traditional polyclonal IgY antibodies. This abstract provides an overview of the production and purification methods of monoclonal IgY antibodies, highlights their advantages over polyclonal IgY antibodies, and discusses their recent applications. Monoclonal recombinant IgY antibodies, in contrast to polyclonal IgY antibodies, offer several benefits. such as derived from a single B-cell clone, monoclonal antibodies exhibit superior specificity, ensuring consistent and reliable results. Furthermore, it explores the suitability of monoclonal IgY antibodies for low- and middle-income countries, considering their cost-effectiveness and accessibility. We also discussed future directions and challenges in using polyclonal IgY and monoclonal IgY antibodies. In conclusion, monoclonal IgY antibodies offer substantial advantages over polyclonal IgY antibodies regarding specificity, scalability, and consistent performance. Their recent applications in diagnostics, therapeutics, and research highlight their versatility., (© The Author(s), 2024.)
- Published
- 2024
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13. MAFLD Pandemic: Updates in Pharmacotherapeutic Approach Development.
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Khaznadar F, Khaznadar O, Petrovic A, Hefer M, Gjoni F, Gjoni S, Steiner J, Smolic M, and Bojanic K
- Abstract
With around one billion of the world's population affected, the era of the metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which to date there are almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it also affects extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn
® ) was approved for metabolic-dysfunction-associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Although the pharmaceutical industry is still lagging behind in developing an approved pharmacologic therapy for MAFLD, research has recently intensified and many molecules which are in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was approved via accelerated procedure for treatment of MAFLD, i.e., of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.- Published
- 2024
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14. Changes in Dickkopf-1, but Not Sclerostin, in Gingival Crevicular Fluid Are Associated with Peroral Statin Treatment in Patients with Periodontitis.
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Duspara K, Sikora R, Petrovic A, Kuna Roguljic L, Matic A, Kralik K, Roguljic H, Kizivat T, Duspara M, Igrec D, Bojanic K, Smolic R, Vcev A, Wyszyńska M, Wu GY, and Smolic M
- Subjects
- Humans, Gingival Crevicular Fluid, Periodontal Pocket therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Periodontitis drug therapy, Bone Resorption
- Abstract
Background and Objectives : Periodontitis is marked by the destruction of alveolar bone. Sclerostin (SOST) and dickkopf-1 (DKK-1) act as inhibitors of the Wingless-type (Wnt) signaling pathway, a key regulator of bone metabolism. Recent studies have suggested that statins play a role in bone resorption and formation by influencing Wnt signaling. The aim of this study was to determine the levels of SOST and DKK-1 in periodontal patients with and without peroral statins treatment in their therapy. Materials and Methods: A total of 79 patients with diagnosed periodontitis were divided into two groups: 39 patients on statin therapy (SP group) and 40 patients without statin therapy as a control group (P group). The periodontal clinical examination probing (pocket) depth (PD) and gingival recession (GR) were measured, and approximal plaque was detected, while vertical and horizontal bone resorption was measured using a panoramic radiograph image. Clinical attachment loss (CAL) values were calculated using PD and GR values. Gingival crevicular fluid (GCF) was collected and used for measuring SOST and DKK-1 levels. A questionnaire was used to assess lifestyle habits and statin intake. Patients' medical records were used to obtain biochemical parameters. Results: There was no significant difference in sclerostin concentration between the SP and P group. DKK-1 values were significantly higher in the SP group compared to the control group ( p = 0.04). Also, PD ( p = 0.001) and GR ( p = 0.03) were significantly higher in the SP group. The level of DKK-1 had a positive relationship with the PD, the greater the PD, the higher the level of DKK-1 (Rho = 0.350), while there was no significant association with other parameters. Conclusions: Peroral statins in periodontal patients are associated with GCF levels of DKK-1 but not with sclerostin levels.
- Published
- 2024
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15. Future Prospects, Approaches, and the Government's Role in the Development of a Hepatitis C Virus Vaccine.
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Tabll AA, Sohrab SS, Ali AA, Petrovic A, Steiner Srdarevic S, Siber S, Glasnovic M, Smolic R, and Smolic M
- Abstract
Developing a safe and effective vaccine against the hepatitis C virus (HCV) remains a top priority for global health. Despite recent advances in antiviral therapies, the high cost and limited accessibility of these treatments impede their widespread application, particularly in resource-limited settings. Therefore, the development of the HCV vaccine remains a necessity. This review article analyzes the current technologies, future prospects, strategies, HCV genomic targets, and the governmental role in HCV vaccine development. We discuss the current epidemiological landscape of HCV infection and the potential of HCV structural and non-structural protein antigens as vaccine targets. In addition, the involvement of government agencies and policymakers in supporting and facilitating the development of HCV vaccines is emphasized. We explore how vaccine development regulatory channels and frameworks affect research goals, funding, and public health policy. The significance of international and public-private partnerships in accelerating the development of an HCV vaccine is examined. Finally, the future directions for developing an HCV vaccine are discussed. In conclusion, the review highlights the urgent need for a preventive vaccine to fight the global HCV disease and the significance of collaborative efforts between scientists, politicians, and public health organizations to reach this important public health goal.
- Published
- 2023
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16. The Role of Occipital Nerve Block for Chronic Migraine Patients: Mechanisms and Management.
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Katalinic D, Aleric I, Smolic M, and Vcev A
- Abstract
Competing Interests: There are no conflicts of interest.
- Published
- 2023
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17. Noninvasive Fibrosis Assessment in Chronic Hepatitis C Infection: An Update.
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Bojanic K, Bogojevic MS, Vukadin S, Sikora R, Ivanac G, Lucic NR, Smolic M, Tabll AA, Wu GY, and Smolic R
- Abstract
Liver biopsy is historically the gold standard for liver fibrosis assessment of chronic hepatitis C patients. However, with the introduction and validation of noninvasive tests (NITs) to evaluate advanced fibrosis, and the direct-acting antiviral agents for treatment of chronic hepatitis C virus (HCV), the role of NITs have become even more complex. There is now need for longitudinal monitoring and elucidation of cutoff values for prediction of liver-related complication after sustained virological response. The aim of this report is to provide a critical overview of the various NITs available for the assessment of liver fibrosis in HCV patients., Competing Interests: GW has been an editor-in-chief of Journal of Clinical and Translational Hepatology since 2013. MS and RS have been editorial board members of Journal of Clinical and Translational Hepatology since 2013. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)
- Published
- 2023
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18. Biomarkers for Assessing Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus on Sodium-Glucose Cotransporter 2 Inhibitor Therapy.
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Khaznadar F, Petrovic A, Khaznadar O, Roguljic H, Bojanic K, Kuna Roguljic L, Siber S, Smolic R, Bilic-Curcic I, Wu GY, and Smolic M
- Abstract
In the current modern era of unhealthy lifestyles, non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and has become a serious global health problem. To date, there is no approved pharmacotherapy for the treatment of NAFLD, and necessary lifestyle changes such as weight loss, diet, and exercise are usually not sufficient to manage this disease. Patients with type 2 diabetes mellitus (T2DM) have a significantly higher risk of developing NAFLD and vice versa. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that have recently been approved for two other indications: chronic kidney disease and heart failure in diabetics and non-diabetics. They are also emerging as promising new agents for NAFLD treatment, as they have shown beneficial effects on hepatic inflammation, steatosis, and fibrosis. Studies in animals have reported favorable effects of SGLT2 inhibitors, and studies in patients also found positive effects on body mass index (BMI), insulin resistance, glucose levels, liver enzymes, apoptosis, and transcription factors. There are some theories regarding how SGLT2 inhibitors affect the liver, but the exact mechanism is not yet fully understood. Therefore, biomarkers to evaluate underlying mechanisms of action of SGLT2 inhibitors on the liver have now been scrutinized to assess their potential as a future in-label therapy for NAFLD. In addition, finding suitable non-invasive biomarkers could be helpful in clinical practice for the early detection of NAFLD in patients. This is crucial for a positive disease outcome. The aim of this review is to provide an overview of the most recent findings on the effects of SGLT2 inhibitors on NAFLD biomarkers and the potential of SGLT2 inhibitors to successfully treat NAFLD.
- Published
- 2023
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19. Biomarkers for Hepatocellular Carcinoma: From Origin to Clinical Diagnosis.
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Omar MA, Omran MM, Farid K, Tabll AA, Shahein YE, Emran TM, Petrovic A, Lucic NR, Smolic R, Kovac T, and Smolic M
- Abstract
The incidence of hepatocellular carcinoma (HCC) and HCC-related deaths has increased over the last few decades. There are several risk factors of HCC such as viral hepatitis (B, C), cirrhosis, tobacco and alcohol use, aflatoxin-contaminated food, pesticides, diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), and metabolic and genetic diseases. Diagnosis of HCC is based on different methods such as imaging ultrasonography (US), multiphasic enhanced computed tomography (CT), magnetic resonance imaging (MRI), and several diagnostic biomarkers. In this review, we examine the epidemiology of HCC worldwide and in Egypt as well as risk factors associated with the development of HCC and, finally, provide the updated diagnostic biomarkers for the diagnosis of HCC, particularly in the early stages of HCC. Several biomarkers are considered to diagnose HCC, including downregulated or upregulated protein markers secreted during HCC development, circulating nucleic acids or cells, metabolites, and the promising, recently identified biomarkers based on quantitative proteomics through the isobaric tags for relative and absolute quantitation (iTRAQ). In addition, a diagnostic model used to improve the sensitivity of combined biomarkers for the diagnosis of early HCC is discussed.
- Published
- 2023
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20. The Role of GLP1-RAs in Direct Modulation of Lipid Metabolism in Hepatic Tissue as Determined Using In Vitro Models of NAFLD.
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Petrovic A, Igrec D, Rozac K, Bojanic K, Kuna L, Kolaric TO, Mihaljevic V, Sikora R, Smolic R, Glasnovic M, Wu GY, and Smolic M
- Abstract
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to improve glucose and lipid homeostasis, promote weight loss, and reduce cardiovascular risk factors. They are a promising therapeutic option for non-alcoholic fatty liver disease (NAFLD), the most common liver disease, associated with T2DM, obesity, and metabolic syndrome. GLP-1RAs have been approved for the treatment of T2DM and obesity, but not for NAFLD. Most recent clinical trials have suggested the importance of early pharmacologic intervention with GLP-1RAs in alleviating and limiting NAFLD, as well as highlighting the relative scarcity of in vitro studies on semaglutide, indicating the need for further research. However, extra-hepatic factors contribute to the GLP-1RA results of in vivo studies. Cell culture models of NAFLD can be helpful in eliminating extrahepatic effects on the alleviation of hepatic steatosis, modulation of lipid metabolism pathways, reduction of inflammation, and prevention of the progression of NAFLD to severe hepatic conditions. In this review article, we discuss the role of GLP-1 and GLP-1RA in the treatment of NAFLD using human hepatocyte models.
- Published
- 2023
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21. Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update.
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Kolaric TO, Kuna L, Covic M, Roguljic H, Matic A, Sikora R, Hefer M, Petrovic A, Mihaljevic V, Smolic R, Bilic-Curcic I, Vcev A, and Smolic M
- Abstract
Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis.
- Published
- 2023
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22. Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?
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Hessien M, Donia T, Tabll AA, Adly E, Abdelhafez TH, Attia A, Alkafaas SS, Kuna L, Glasnovic M, Cosic V, Smolic R, and Smolic M
- Subjects
- Humans, Endocytosis, Antiviral Agents pharmacology, Antiviral Agents metabolism, Cell Membrane metabolism, SARS-CoV-2, COVID-19 metabolism
- Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) canonically utilizes clathrin-mediated endocytosis (CME) and several other endocytic mechanisms to invade airway epithelial cells. Endocytic inhibitors, particularly those targeting CME-related proteins, have been identified as promising antiviral drugs. Currently, these inhibitors are ambiguously classified as chemical, pharmaceutical, or natural inhibitors. However, their varying mechanisms may suggest a more realistic classification system. Herein, we present a new mechanistic-based classification of endocytosis inhibitors, in which they are segregated among four distinct classes including: (i) inhibitors that disrupt endocytosis-related protein-protein interactions, and assembly or dissociation of complexes; (ii) inhibitors of large dynamin GTPase and/or kinase/phosphatase activities associated with endocytosis; (iii) inhibitors that modulate the structure of subcellular components, especially the plasma membrane, and actin; and (iv) inhibitors that cause physiological or metabolic alterations in the endocytosis niche. Excluding antiviral drugs designed to halt SARS-CoV-2 replication, other drugs, either FDA-approved or suggested through basic research, could be systematically assigned to one of these classes. We observed that many anti-SARS-CoV-2 drugs could be included either in class III or IV as they interfere with the structural or physiological integrity of subcellular components, respectively. This perspective may contribute to our understanding of the relative efficacy of endocytosis-related inhibitors and support the optimization of their individual or combined antiviral potential against SARS-CoV-2. However, their selectivity, combined effects, and possible interactions with non-endocytic cellular targets need more clarification.
- Published
- 2023
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23. Management of Glycemia during Acute Aerobic and Resistance Training in Patients with Diabetes Type 1: A Croatian Pilot Study.
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Ivandic M, Cigrovski Berkovic M, Ormanac K, Sabo D, Omanovic Kolaric T, Kuna L, Mihaljevic V, Canecki Varzic S, Smolic M, and Bilic-Curcic I
- Subjects
- Adult, Humans, Middle Aged, Blood Glucose, Pilot Projects, Blood Glucose Self-Monitoring, Hydrocortisone, Prospective Studies, Croatia, Glucose, Hypoglycemic Agents, Lactates, Insulin, Diabetes Mellitus, Type 1 therapy, Diabetes Mellitus, Type 1 complications, Resistance Training, Hypoglycemia prevention & control
- Abstract
(1) Background: The increased risk of developing hypoglycemia and worsening of glycemic stability during exercise is a major cause of concern for patients with type 1 diabetes mellitus (T1DM). (2) Aim: This pilot study aimed to assess glycemic stability and hypoglycemic episodes during and after aerobic versus resistance exercises using a flash glucose monitoring system in patients with T1DM. (3) Participants and Methods: We conducted a randomized crossover prospective study including 14 adult patients with T1DM. Patients were randomized according to the type of exercise (aerobic vs. resistance) with a recovery period of three days between a change of groups. Glucose stability and hypoglycemic episodes were evaluated during and 24 h after the exercise. Growth hormone (GH), cortisol, and lactate levels were determined at rest, 0, 30, and 60 min post-exercise period. (4) Results: The median age of patients was 53 years, with a median HbA1c of 7.1% and a duration of diabetes of 30 years. During both training sessions, there was a drop in glucose levels immediately after the exercise (0'), followed by an increase at 30' and 60', although the difference was not statistically significant. However, glucose levels significantly decreased from 60' to 24 h in the post-exercise period ( p = 0.001) for both types of exercise. Glycemic stability was comparable prior to and after exercise for both training sessions. No differences in the number of hypoglycemic episodes, duration of hypoglycemia, and average glucose level in 24 h post-exercise period were observed between groups. Time to hypoglycemia onset was prolonged after the resistance as opposed to aerobic training (13 vs. 8 h, p = NS). There were no nocturnal hypoglycemic episodes (between 0 and 6 a.m.) after the resistance compared to aerobic exercise (4 vs. 0, p = NS). GH and cortisol responses were similar between the two sessions, while lactate levels were significantly more increased after resistance training. (5) Conclusion: Both exercise regimes induced similar blood glucose responses during and immediately following acute exercise.
- Published
- 2023
- Full Text
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24. MicroRNAs: Small Molecules with Significant Functions, Particularly in the Context of Viral Hepatitis B and C Infection.
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Megahed F, Tabll A, Atta S, Ragheb A, Smolic R, Petrovic A, and Smolic M
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- Humans, Hepatitis B virus genetics, Biomarkers metabolism, MicroRNAs genetics, MicroRNAs therapeutic use, Hepatitis B genetics, Hepatitis B drug therapy, Hepatitis C genetics
- Abstract
A MicroRNA (miRNA) is defined as a small molecule of non-coding RNA (ncRNA). Its molecular size is about 20 nucleotides (nt), and it acts on gene expression's regulation at the post-transcription level through binding to the 3'untranslated regions (UTR), coding sequences, or 5'UTR of the target messenger RNAs (mRNAs), which leads to the suppression or degradation of the mRNA. In recent years, a huge evolution has identified the origin and function of miRNAs, focusing on their important effects in research and clinical applications. For example, microRNAs are key players in HCV infection and have important host cellular factors required for HCV replication and cell growth. Altered expression of miRNAs affects the pathogenicity associated with HCV infection through regulating different signaling pathways that control HCV/immunity interactions, proliferation, and cell death. On the other hand, circulating miRNAs can be used as novel biomarkers and diagnostic tools for HCV pathogenesis and early therapeutic response. Moreover, microRNAs (miRNA) have been involved in hepatitis B virus (HBV) gene expression and advanced antiviral discovery. They regulate HBV/HCV replication and pathogenesis with different pathways involving facilitation, inhibition, activation of the immune system (innate and adaptive), and epigenetic modifications. In this short review, we will discuss how microRNAs can be used as prognostic, diagnostic, and therapeutic tools, especially for chronic hepatitis viruses (HBV and HCV), as well as how they could be used as new biomarkers during infection and advanced treatment.
- Published
- 2023
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25. Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer.
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Peric L, Vukadin S, Petrovic A, Kuna L, Puseljic N, Sikora R, Rozac K, Vcev A, and Smolic M
- Abstract
Although we are lately witnessing major improvements in breast cancer treatment and patient outcomes, there is still a significant proportion of patients not receiving efficient therapy. More precisely, patients with triple-negative breast cancer or any type of metastatic disease. Currently available prognostic and therapeutic biomarkers are not always applicable and oftentimes lack precision. The science of glycans is a relatively new scientific approach to better characterize malignant transformation and tumor progression. In this review, we summarize the most important information about glycosylation characteristics in breast cancer cells and how different glycoproteins and enzymes involved in glycosylation could serve as more precise biomarkers, as well as new therapeutic targets.
- Published
- 2022
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26. Liraglutide Exerts Protective Effects by Downregulation of PPARγ , ACSL1 and SREBP-1c in Huh7 Cell Culture Models of Non-Alcoholic Steatosis and Drug-Induced Steatosis.
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Omanovic Kolaric T, Kizivat T, Mihaljevic V, Zjalic M, Bilic-Curcic I, Kuna L, Smolic R, Vcev A, Wu GY, and Smolic M
- Abstract
(1) Background: With the aging of the population and polypharmacy encountered in the elderly, drug-induced steatosis (DIS) has become frequent cause of non-alcoholic steatosis (NAS). Indeed, NAS and DIS may co-exist, making the ability to distinguish between the entities ever more important. The aim of our study was to study cell culture models of NAS and DIS and determine the effects of liraglutide (LIRA) in those models. (2) Methods: Huh7 cells were treated with oleic acid (OA), or amiodarone (AMD) to establish models of NAS and DIS, respectively. Cells were treated with LIRA and cell viability was assessed by MTT, lipid accumulation by Oil-Red-O staining and triglyceride assay, and intracellular signals involved in hepatosteatosis were quantitated by RT-PCR. (3) Results: After exposure to various OA and AMD concentrations, those that achieved 80% of cells viabilities were used in further experiments to establish NAS and DIS models using 0.5 mM OA and 20 µM AMD, respectively. In both models, LIRA increased cell viability (p < 0.01). Lipid accumulation was increased in both models, with microsteatotic pattern in DIS, and macrosteatotic pattern in NAS which corresponds to greater triglyceride accumulation in latter. LIRA ameliorated these changes (p < 0.001), and downregulated expression of lipogenic ACSL1, PPARγ, and SREBP-1c pathways in the liver (p < 0.01) (4) Conclusions: LIRA ameliorates hepatocyte steatosis in Huh7 cell culture models of NAS and DIS.
- Published
- 2022
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27. Anabolic androgenic steroid-induced liver injury: An update.
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Petrovic A, Vukadin S, Sikora R, Bojanic K, Smolic R, Plavec D, Wu GY, and Smolic M
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- Androgens adverse effects, Humans, Testosterone, Testosterone Congeners adverse effects, Anabolic Agents adverse effects, Chemical and Drug Induced Liver Injury, Chronic
- Abstract
Anabolic androgenic steroids (AASs) are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects. These properties make them therapeutically beneficial in medical conditions such as hypogonadism. However, they are commonly bought illegally and misused for their anabolic, skeletal muscle building, and performance-enhancing effects. Supraphysiologic and long-term use of AASs affects all organs, leading to cardiovascular, neurological, endocrine, gastrointestinal, renal, and hematologic disorders. Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse. Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis, peliosis hepatis, and hepatic benign and malignant tumors. It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors, upregulation of bile acid synthesis, and induction of hepatocyte hyperplasia. Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS. However, some long-term consequences are irreversible. AAS-induced liver injury should be taken in consideration in patients with liver disorders, especially with the increasing unintentional ingestion of supplements containing AAS. In this paper, we review the most current knowledge about AAS-associated adverse effects on the liver, and their clinical presentations, prevalence, and pathophysiological mechanisms., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)
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- 2022
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28. Serotonin Receptor Agonists in the Treatment of Migraine: A Meta-Analysis Considering Possible Connection with Paresthesia.
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Katalinic D, Vcev A, Smolic M, and Aleric I
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- 2022
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29. Pretreatment of Garlic Oil Extracts Hampers Epithelial Damage in Cell Culture Model of Peptic Ulcer Disease.
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Kuna L, Zjalic M, Kizivat T, Roguljic H, Nincevic V, Omanovic Kolaric T, Wu CH, Vcev A, Smolic M, and Smolic R
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- Cell Culture Techniques, Humans, Plant Extracts pharmacology, Plant Extracts therapeutic use, Sulfides, Allyl Compounds, Peptic Ulcer drug therapy
- Abstract
Background and Objectives: Peptic ulcer disease is a chronic disease affecting up to 10% of the world's population. Proton pump inhibitors, such as lansoprazole are the gold standard in the treatment of ulcer disease. However, various studies have shown the effectiveness of garlic oil extracts in the treatment of ulcer disease. A cellular model can be established in the human gastric cell line by sodium taurocholate. The aim of this study was to explore the effects of garlic oil extracts pretreatment and LPZ addition in the cell culture model of peptic ulcer disease by examining oxidative stress and F-actin distribution. Materials and Methods: Evaluation was performed by determination of glutathione and prostaglandin E2 concentrations by ELISA; human gastric cell line proliferation by cell counting; expression of ATP-binding cassette, sub-family G, member 2; nuclear factor kappa B subunit 2 by RT PCR; and F-actin cytoskeleton visualization by semi-quantification of Rhodamine Phalloidin stain. Results: Our results showed significant reduction of cell damage after sodium taurocholate incubation when the gastric cells were pretreated with lansoprazole ( p < 0.001) and increasing concentrations of garlic oil extracts ( p < 0.001). Pretreatment with lansoprazole and different concentrations of garlic oil extracts increased prostaglandin E2 and glutathione concentrations in the cell culture model of peptic ulcer disease ( p < 0.001). Positive correlation of nuclear factor kappa B subunit 2 ( p < 0.01) with lansoprazole and garlic oil extracts pretreatment was seen, while ATP-binding cassette, sub-family G, member 2 expression was not changed. Treatment with sodium taurocholate as oxidative stress on F actin structure was less pronounced, although the highest concentration of garlic oil extracts led to a statistically significant increase of total amount of F-actin ( p < 0.001). Conclusions: Hence, pretreatment with garlic oil extracts had gastroprotective effect in the cell model of peptic ulcer disease. However, further experiments are needed to fully elucidate the mechanism of this protective role.
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- 2022
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30. Mini-review: The market growth of diagnostic and therapeutic monoclonal antibodies - SARS CoV-2 as an example.
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El Abd Y, Tabll A, Smolic R, and Smolic M
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- Animals, Antibodies, Viral therapeutic use, Epitopes, Humans, Hybridomas, Mice, SARS-CoV-2, Antibodies, Monoclonal, COVID-19
- Abstract
Background: The emergence of novel viruses poses severe challenges to global public health highlighting the crucial necessity for new antivirals., Main Body: Monoclonal antibodies (mAbs) are immunoglobulins that bind to a single epitope. Mouse mAbs are generated by classic hybridoma technology and are mainly used for immunodiagnostics. For immunotherapy, it is critical to use monoclonal antibodies in their human form to minimize adverse reactions. They have been successfully used to treat numerous illnesses, accordingly, an increasing number of mAbs, with high potency against emerging viruses is the target of every biopharmaceutical company. The diagnostic and therapeutic mAbs market grows rapidly into a multi-billion-dollar business. Biopharmaceuticals are innovative resolutions which revolutionized the treatment of significant chronic diseases and malignancies. Currently, a variety of therapeutic options that include antiviral medications, monoclonal antibodies, and immunomodulatory agents are available for the management of COVID-19., Short Conclusion: The invasion of mAbs in new medical sectors will increase the market magnitude as it is expected to generate revenue of about 300 billion $ by 2025. In the current mini-review, the applications of monoclonal antibodies in immune-diagnosis and immunotherapy will be demonstrated, particularly for COVID-19 infection and will focus mainly on monoclonal antibodies in the market.
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- 2022
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31. Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update.
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Duspara K, Bojanic K, Pejic JI, Kuna L, Kolaric TO, Nincevic V, Smolic R, Vcev A, Glasnovic M, Curcic IB, and Smolic M
- Abstract
Liver fibrosis is a life-threatening disease, with challenging morbidity and mortality for healthcare systems worldwide. It imparts an enormous economic burden to societies, making continuous research and informational updates about its pathogenesis and treatment crucial. This review's focus is on the current knowledge about the Wnt signaling pathway, serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells (HSCs). Two types of Wnt pathways are distinguished, namely the ß-catenin-dependent canonical and non-canonical Ca
2+ or planar cell polarity (PCP)-dependent pathway. The dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver injuries. Activation of the ß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix (ECM), leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes, lacking the original function of healthy hepatocytes. Therefore, liver function is reduced due to the severely advanced disease. Selective inhibition of ß-catenin inhibits inflammatory processes (since chemokines and pro-inflammatory cytokines are produced during Wnt activation), reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis, thereby reducing the progression of liver fibrosis in vivo . While the canonical Wnt pathway is usually inactive in a physiologically healthy liver, it shows activity during cell regeneration or renewal and in certain pathophysiological conditions, such as liver diseases and cancer. Targeted blocking of some of the basic components of the Wnt pathway is a therapeutic approach. These include the frizzled transmembrane receptor (Fz) receptors using the secreted frizzled-related protein family (sFRP), Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1 (DKK1) or niclosamide, glycogen kinase-3 beta (GSK-3β) using SB-216763, cyclic-AMP response element-binding protein (CBP) using PRI-724 and ICG-001, the lymphoid enhancer binding factor (LEF)/T cell-specific transcription factor (TCF) system as well as Wnt inhibitory factor 1 (WIF1) and miR-17-5p using pinostilbene hydrate (PSH). Significant progress has been made in inhibiting Wnt and thus stopping the progression of liver fibrosis by diminishing key components for its action. Comprehending the role of the Wnt signaling pathway in liver fibrosis may lead to discovery of novel targets in liver fibrosis therapeutic strategies' development., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)- Published
- 2021
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32. Drug-induced Fatty Liver Disease: Pathogenesis and Treatment.
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Kolaric TO, Nincevic V, Kuna L, Duspara K, Bojanic K, Vukadin S, Raguz-Lucic N, Wu GY, and Smolic M
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Metabolic dysfunction-associated fatty liver disease (commonly known as MAFLD) impacts global health in epidemic proportions, and the resulting morbidity, mortality and economic burden is enormous. While much attention has been given to metabolic syndrome and obesity as offending factors, a growing incidence of polypharmacy, especially in the elderly, has greatly increased the risk of drug-induced liver injury (DILI) in general, and drug-induced fatty liver disease (DIFLD) in particular. This review focuses on the contribution of DIFLD to DILI in terms of epidemiology, pathophysiology, the most common drugs associated with DIFLD, and treatment strategies., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)
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- 2021
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33. Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update.
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Vukadin S, Khaznadar F, Kizivat T, Vcev A, and Smolic M
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Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma and ensured significant improvement in overall survival versus chemotherapy. ICI or targeted therapy are now the first line treatment in advanced melanoma, depending on the tumor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational status. While these new approaches have changed the outcomes for many patients, a significant proportion of them still experience lack of response, known as primary resistance. Mechanisms of primary drug resistance are not fully elucidated. However, many alterations have been found in ICI-resistant melanomas and possibly contribute to that outcome. Furthermore, some tumors which initially responded to ICI treatment ultimately developed mechanisms of acquired resistance and subsequent tumor progression. In this review, we give an overview of tumor primary and acquired resistance mechanisms to ICI and discuss future perspectives with regards to new molecular targets and combinatorial therapies.
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- 2021
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34. Effect of COVID-19 on management of type 1 diabetes: Pushing the boundaries of telemedical healthcare.
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Bilic Curcic I, Cigrovski Berkovic M, Kizivat T, Canecki Varzic S, Smolic R, and Smolic M
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The new coronavirus disease 2019 (COVID-19) pandemic posed a great burden on health care systems worldwide and is an enormous and real obstacle in providing needed health care to patients with chronic diseases such as diabetes. Parallel to COVID-19, there have been great advances in technology used for management of type 1 diabetes, primarily insulin pumps, sensors, integrated and closed loop systems, ambulatory glucose profile software, and smart phone apps providing necessary essentials for telemedicine implementation right at the beginning of the COVID-19 pandemic. The results of these remote interventions are reassuring in terms of glycemic management and hemoglobin A1c reductions. However, data on long-term outcomes and cost reductions are missing as well as proper technical infrastructure and government health policy support., Competing Interests: Conflict-of-interest statement: There is no conflict of interest associated with the senior author or other coauthors., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)
- Published
- 2021
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35. Impact of DAA Treatment on Cardiovascular Disease Risk in Chronic HCV Infection: An Update.
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Roguljic H, Nincevic V, Bojanic K, Kuna L, Smolic R, Vcev A, Primorac D, Vceva A, Wu GY, and Smolic M
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Hepatitis C virus (HCV) infection is a systemic disease associated with multiple significant extrahepatic manifestations. Emerging studies indicate association between the HCV infection and a higher incidence of major adverse cardiovascular events such as: coronary artery disease, heart failure, stroke and peripheral artery disease, when compared to general population. Atherosclerosis is a common pathophysiologic mechanism of cardiovascular disease (CVD) development which is the leading cause of mortality in the Western world. Proposed mechanisms of HCV-induced atherosclerosis includes systemic inflammation due to the chronic infection with increased levels of pro-atherogenic cytokines and chemokines. Furthermore, it has been demonstrated that HCV exists and replicates within atheroschlerotic plaques, supporting the theory of direct pro-atherogenic effect of the virus. Direct acting antiviral agents (DAAs) represent a safe and highly effective treatment of HCV infection. Beside the improvement in liver-related outcomes, DAAs exhibit a beneficial effect on extra-hepatic manifestations of chronic HCV infection. Recently, it has been shown that patients with chronic HCV infection treated with DAA-based therapeutic regimes had a 43% reduction of CVD events incidence risk. Moreover, eradication of HCV with DAAs results in a significant positive effect on risk factors for cardiovascular disease, despite a general worsening of the lipid profile. This positive effects is mainly due to an improvement of endothelial function and glucose metabolism. Although DAA treatment is associated with a beneficial impact on cardiovascular events, further studies are needed to fully elucidate the mechanisms responsible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Roguljic, Nincevic, Bojanic, Kuna, Smolic, Vcev, Primorac, Vceva, Wu and Smolic.)
- Published
- 2021
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36. An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents.
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Rupcic Rubin V, Bojanic K, Smolic M, Rubin J, Tabll A, and Smolic R
- Abstract
Liver fibrosis represents a response to chronic liver injury. Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases, both with increasing incidence. Therefore, there is a great impetus for development of agents targeting these conditions. Accumulating data on possible treatment options for liver fibrosis are emerging in the literature. However, despite extensive research and much effort in the field, approved agents for liver fibrosis are still lacking. In this critical review, we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials, with an emphasis on efficacy and safety of these agents., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)
- Published
- 2021
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37. The accuracy of breast cancer risk self-assessment does not correlate with knowledge about breast cancer and knowledge and attitudes towards primary chemoprevention.
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Bojanic K, Vukadin S, Grgic K, Malenica L, Sarcevic F, Smolic R, Kralik K, Včev A, Wu GY, and Smolic M
- Abstract
The increase of breast cancer (BC) incidence has drawn attention to BC risk as means of reducing mortality and morbidity of the disease. The aim of this study was to determine the accuracy of BC risk perception, evaluate factors that affect risk perception and assess the correlation between BC risk perception and attitudes towards BC chemoprevention. A cross-sectional study included total of 258 women with average and high-risk for BC according to the Breast Cancer Risk Assessment Tool (BCRAT). All data were collected by face-to-face interview by three trained 6th year medical school students using a 54-item questionnaire. Each participant's actual BC risk was compared to a perceived risk and the accuracy of the BC risk self-assessment was determined. 72% of high-risk women underestimated their BC risk (p < 0.001). One third of subjects with a family history of BC have also underestimated their own risk (p = 0.002). Women who responded to screening mammography were more informed about BC risk factors (p = 0.001). General knowledge about BC chemoprevention was surprisingly low, regardless of the accuracy of BC risk self-assessment. High-risk women appear to be unrealistically optimistic, since there was a significant difference between the accuracy of self-perceived risk and the objective BC risk., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)
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- 2020
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38. Hypothyroidism and Nonalcoholic Fatty Liver Disease: Pathophysiological Associations and Therapeutic Implications.
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Kizivat T, Maric I, Mudri D, Curcic IB, Primorac D, and Smolic M
- Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complex clinical entity which can be secondary to many other diseases including hypothyroidism, characterized by lowering of thyroid hormones and increased thyroid stimulating hormone (TSH). A lot of emerging data published recently advocates the hypothesis that hypothyroid induced NAFLD could be a separate clinical entity, even suggesting possible treatment options for NAFLD involving substitution therapy for hypothyroidism along with lifestyle modifications. In addition, a whole new field of research is focused on thyromimetics in NAFLD/NASH treatment, currently in phase 3 clinical trials. In this critical review we summarized epidemiological and pathophysiological evidence linking these two clinical entities and described specific treatment options with the accent on promising new agents in NAFLD treatment, specifically thyroid hormone receptor (THR) agonist and its metabolites., Competing Interests: The authors have no conflict of interests related to this publication., (© 2020 Authors.)
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- 2020
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39. Impact of Breast Density Awareness on Knowledge about Breast Cancer Risk Factors and the Self-Perceived Risk of Breast Cancer.
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Bojanic K, Vukadin S, Sarcevic F, Malenica L, Grgic K, Smolic R, Kralik K, Bilic Curcic I, Ivanac G, Wu GY, and Smolic M
- Abstract
Breast density (BD) reduces sensitivity of mammography, and is a strong risk factor for breast cancer (BC). Data about women's awareness and knowledge of BD are limited. Our aim is to examine whether the BD information disclosure and BD awareness among women without BC are related to their knowledge about BC risk factors. We examined self-reported BC risk perception and its association to BD awareness and level of health literacy. A cross-sectional, single site study included 263 Croatian women without BC who had mammographic examination. Data were collected by interviews using questionnaires and a validated survey. Of the total, 77.1% had never heard of BD, and 22.9% were aware of their BD. Most participants who knew their BD (88.2%, p < 0.001) had higher levels of education. Majority of subjects (66.8%) had non-dense breasts and 33.2% had dense breasts. Subjects aware of their BD knew that post-menopausal hormone replacement therapy ( p = 0.04) and higher BD ( p = 0.03) are BC risk factors. They could more easily access information about health promotion ( p = 0.03). High-BD informed women assessed their lifetime BC risk as significantly higher than all others ( p = 0.03). Comprehension of BD awareness and knowledge is crucial for reinforcement of educational strategies and development of amendatory BC screening decisions.
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- 2020
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40. Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals.
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Kishta S, Tabll A, Omanovic Kolaric T, Smolic R, and Smolic M
- Abstract
Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has been a lot of controversy surrounding the recurrence of hepatocellular carcinoma (HCC) after DAA treatment of hepatic cells infected with chronic HCV. One of the main risk factors that leads to de novo HCC is the chronicity of HCV in hepatic cells. There are many studies regarding the progression of HCV-infected hepatic cells to HCC. However, there is a lack of research on the different molecular mechanisms that lead to the progression of chronic HCV infection to HCC, as well as on the effect of HCV on the alteration of DNA ploidy, which eventually leads to a recurrence of HCC after DAA treatment. In this review article, we will address some risk factors that could lead to the development/recurrence of HCC after treatment of HCV with DAA therapy, such as the role of liver cirrhosis, the alteration of DNA ploidy, the reactivation of hepatitis B virus (HBV), the role of cytokines and the alteration of the immune system, concomitant non- alcoholic fatty liver disease (NAFLD), obesity, alcohol consumption and also occult HCV infection/co-infection. Clinicians should be cautious considering that full eradication of hepatocarcinogenesis cannot be successfully accomplished by anti-HCV treatment alone.
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- 2020
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41. Exploring Association of Breast Pain, Pregnancy, and Body Mass Index with Breast Tissue Elasticity in Healthy Women: Glandular and Fat Differences.
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Dzoic Dominkovic M, Ivanac G, Bojanic K, Kralik K, Smolic M, Divjak E, Smolic R, and Brkljacic B
- Abstract
Breast sonoelastography is a relatively novel ultrasound (US) method that enables estimation of tissue stiffness to estimate the elasticity of normal breast tissue and seek to correlate it with well-known breast cancer risk factors. Two hundred women of different age were included in the study and completed a questionnaire about personal, familiar, and reproductive history. Glandular and fatty tissue elasticity in all breast quadrants was measured by shear wave elastography (SWE). Mean elastographic values of breast tissue were calculated and compared to personal history risk factors. Elasticity of normal glandular tissue (66.4 kilopascals (kPa)) was higher than fatty tissue (26.1 kPa) in all breast quadrants and in both breasts. Lower outer quadrant (LOQ) had the lowest elasticity values of both parenchyma and fat. Higher elasticity values of breast tissue were confirmed in the left breast than in the right breast. Glandular and fat tissue elasticity negatively correlated with body mass index (BMI). Women with mastodynia had higher glandular elastographic values compared to subjects without breast pain. Nuliparity was also associated with higher elasticity of glandular breast tissue. The results of this study are promising and could, over time, contribute to a better understanding of glandular breast tissue elasticity as a potential risk factor for breast cancer.
- Published
- 2020
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42. Representation of CYP3A4, CYP3A5 and UGT1A4 Polymorphisms within Croatian Breast Cancer Patients' Population.
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Bojanic K, Kuna L, Bilic Curcic I, Wagner J, Smolic R, Kralik K, Kizivat T, Ivanac G, Vcev A, Wu GY, and Smolic M
- Subjects
- Aged, Alleles, Anastrozole therapeutic use, Breast Neoplasms drug therapy, Croatia, Female, Genetics, Population, Genotype, Homozygote, Humans, Linkage Disequilibrium, Middle Aged, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Cytochrome P-450 CYP3A genetics, Glucuronosyltransferase genetics
- Abstract
Single nucleotide polymorphism (SNP) in genes encoding drug-metabolizing enzymes (DME) could have a critical role in individual responses to anastrozole. Frequency of CYP3A4*1B, CYP3A5*3 and UGT1A4*2 SNPs in 126 Croatian breast cancer (BC) patients and possible association with anastrozole-induced undesirable side effects were analyzed. Eighty-two postmenopausal patients with estrogen receptor (ER)-positive BC treated with anastrozole and 44 postmenopausal ER-positive BC patients before hormonal adjuvant therapy were included in the study. Genomic DNA was genotyped by TaqMan Real-Time PCR. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The homozygotes for the variant G allele of CYP3A5*3 were predominant (88%), and the homozygotes for the reference A allele were not detected. While homozygotes for the variant G allele of CYP3A4*1B were not detected, predominantly wild type homozygotes for A allele (94%) were present. CYP3A4*1B and CYP3A5*3 SNPs were in 84.3% linkage disequilibrium (D' = 0.843) and 95.1% (D' = 0.951) in group treated with anastrozole and w/o treatment, respectively. Homozygotes for the A allele of UGT1A4*2 were not detected in our study groups. Although the variant CYP3A5*3 allele, which might result in poor metabolizer phenotype and more pronounced side effects, was predominant, significant association with BMD changes induced by anastrozole were not confirmed., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
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43. CXCL9 chemokine level is associated with spontaneous clearance and sustained virological response in Egyptian Chronic Hepatitis C patients receiving direct acting antivirals.
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Tabll AA, Afifi MS, El-Etrawy AS, El-Kousy SM, Smolic M, and El Abd YS
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- Adult, Egypt, Female, Hepatitis C Antibodies metabolism, Hepatitis C, Chronic virology, Humans, Male, Middle Aged, RNA, Viral drug effects, Viral Load drug effects, Young Adult, Antiviral Agents therapeutic use, Chemokine CXCL9 metabolism, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic metabolism
- Abstract
Background: Chronic Hepatitis C virus (HCV) infection is associated with progressive liver inflammation which in turn leads to cirrhosis and finally causes hepatocellular carcinoma (HCC). By different escape mechanisms, the virus succeeds to evade the innate and acquired immune responses to establish chronic infection., Aim: This study aimed to evaluate the level of chemokine CXCL9 and its correlation with some biochemical parameters in different subjects of HCV patients., Materials and Methods: A total of 83 persons participated in this study including healthy subjects without both HCV antibodies and HCV RNA (22.9%), HCV treated responders accomplished SVR post treatment, with HCV antibodies and absence of HCV RNA (24.1%), spontaneous or natural clearance patients, with positive HCV antibodies and negative HCV RNA without treatment (26.5%) and chronic HCV-patients, with both positive HCV antibodies and HCV RNA with no treatment (26.5%). HCV RNA was quantitated by real time PCR and serum CXCL9 level was measured by ELISA commercial kit pre-coated with human MIG/CXCL9 antibody. Assessment of biochemical and hematological parameters was carried out., Results: Data showed that, the level of CXCL9 was significantly increased in chronic individuals (627.1 pg/ml) (P< 0.001) than spontaneous clearance (107.76 pg/ml) and responder subjects (117.28 pg/ml) (P⩽ 0.05). No correlation has been found between CXCL9 level and viral load. Furthermore, CXCL9 levels correlated variably with some biochemical and hematological parameters according to each subject., Conclusion: Serum Chemokine CXCL9 level is associated with spontaneous clearance of HCV and response to HCV treatment, which may be identified as a predictive marker among HCV patients.
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- 2020
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44. Obesity Paradox in Chronic Liver Diseases: Product of Bias or a Real Thing?
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Curcic IB, Berkovic MC, Kuna L, Roguljic H, Smolic R, Varzic SC, Jukic LV, and Smolic M
- Abstract
In recent years, evidence supporting the theory of obesity paradox has increased, showing that obese/overweight people with prevalent chronic diseases experience lower mortality compared with patients of normal weight. So far, evidence is most comprehensive in cardiovascular and chronic renal diseases; however, published studies are prone to many biases, enabling us to reach a definite conclusion. Available data in chronic liver disease is scarce and ambiguous. Obesity is traditionally associated with nonalcoholic fatty liver disease and steatosis in viral hepatitis and as such one would not expect the obesity paradox to be a real possibility in liver disease. Yet, there seem to be new data indicating the opposite - the obesity paradox exists in severe and end-stage liver cirrhosis, which could be attributed to a better lean mass in patients with higher body mass index, meaning that sarcopenia, as one of the most important prognostic factors of survival, is less likely to be present. Nonetheless, the problem of various methodological problems addressing the association between body weight and mortality, which is present both in liver disease and other chronic diseases, are preventing us from attaining an unanimous conclusion. Still, we should be aware that the obesity paradox might be true, especially in severe and end-stage illness. This suggests focusing our efforts toward preserving or building up fat-free mass and decreasing inflammatory activity responsible for catabolism and sarcopenia, and implying that the underlaying cause should be treated., Competing Interests: The authors have no conflict of interests related to this publication., (© 2019 Authors.)
- Published
- 2019
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45. Multiparametric MRI Tumor Probability Model for the Detection of Locally Recurrent Prostate Cancer After Radiation Therapy: Pathologic Validation and Comparison With Manual Tumor Delineations.
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Dinis Fernandes C, Simões R, Ghobadi G, Heijmink SWTPJ, Schoots IG, de Jong J, Walraven I, van der Poel HG, van Houdt PJ, Smolic M, Pos FJ, and van der Heide UA
- Subjects
- Area Under Curve, Cohort Studies, Humans, Logistic Models, Male, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local surgery, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Radiotherapy Planning, Computer-Assisted, Retrospective Studies, Salvage Therapy, Sensitivity and Specificity, Tumor Burden, Models, Statistical, Multiparametric Magnetic Resonance Imaging, Neoplasm Recurrence, Local diagnostic imaging, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms radiotherapy
- Abstract
Purpose: Focal salvage treatments of recurrent prostate cancer (PCa) after radiation therapy require accurate delineation of the target volume. Magnetic resonance imaging (MRI) is used for this purpose; however, radiation therapy-induced changes complicate image interpretation, and guidelines are lacking on the assessment and delineation of recurrent PCa. A tumor probability (TP) model was trained and independently tested using multiparametric magnetic resonance imaging (mp-MRI) of patients with radio-recurrent PCa. The resulting probability maps were used to derive target regions for radiation therapy treatment planning., Methods and Materials: Two cohorts of patients with radio-recurrent PCa were used in this study. All patients underwent mp-MRI (T2 weighted, diffusion-weighted imaging, and dynamic contrast enhanced). A logistic regression model was trained using imaging features from 21 patients with biopsy-proven recurrence who qualified for salvage treatment. The test cohort consisted of 17 patients treated with salvage prostatectomy. The model was tested against histopathology-derived tumor delineations. The voxel-wise TP maps were clustered using k-means to generate a gross tumor volume (GTV) contour for voxel-level comparisons with manual tumor delineations performed by 2 radiologists and with histopathology-validated contours. Later, k-means was used with 3 clusters to define a clinical target volume (CTV), high-risk CTV, and GTV, with increasing tumor risk., Results: In the test cohort, the model obtained a median (range) area under the curve of 0.77 (0.41-0.99) for the whole prostate. The GTV delineation resulted in a median sensitivity of 0.31 (0-0.87) and specificity of 0.97 (0.84-1.0) with no significant differences between model and manual delineations. The 3-level clustering GTV and high-risk CTV delineations had median sensitivities of 0.17 (0-0.59) and 0.49 (0-0.97) and specificities of 0.98 (0.84-1.00) and 0.94 (0.84-0.99), respectively., Conclusions: The TP model had a good performance in predicting voxel-wise presence of recurrent tumor. Model-derived tumor risk levels achieved sensitivity and specificity similar to manual delineations in localizing recurrent tumor. Voxel-wise TP derived from mp-MRI can in this way be incorporated for target definition in focal salvage of radio-recurrent PCa., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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46. Quantitative 3-T multi-parametric MRI and step-section pathology of recurrent prostate cancer patients after radiation therapy.
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Dinis Fernandes C, Ghobadi G, van der Poel HG, de Jong J, Heijmink SWTPJ, Schoots I, Walraven I, van Houdt PJ, Smolic M, Pos FJ, and van der Heide UA
- Subjects
- Aged, Histological Techniques, Humans, Magnetic Resonance Imaging methods, Male, Margins of Excision, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local radiotherapy, Neoplasm Recurrence, Local surgery, Prostatectomy methods, Prostatic Neoplasms radiotherapy, Retrospective Studies, Salvage Therapy methods, Seminal Vesicles pathology, Tumor Burden, Neoplasm Recurrence, Local pathology, Prostatic Neoplasms pathology
- Abstract
Objectives: Diagnosis of radio-recurrent prostate cancer using multi-parametric MRI (mp-MRI) can be challenging due to the presence of radiation effects. We aim to characterize imaging of prostate tissue after radiation therapy (RT), using histopathology as ground truth, and to investigate the visibility of tumor lesions on mp-MRI., Methods: Tumor delineated histopathology slides from salvage radical prostatectomy patients, primarily treated with RT, were registered to MRI. Median T2-weighted, ADC, K
trans , and kep values in tumor and other regions were calculated. Two radiologists independently performed mp-MRI-based tumor delineations which were compared with the true pathological extent. General linear mixed-effect modeling was used to establish the contribution of each imaging modality and combinations thereof in distinguishing tumor and benign voxels., Results: Nineteen of the 21 included patients had tumor in the available histopathology slides. Recurrence was predominantly multifocal with large tumor foci seen after external beam radiotherapy, whereas these were small and sparse after low-dose-rate brachytherapy. MRI-based delineations missed small foci and slightly underestimated tumor extent. The combination of T2-weighted, ADC, Ktrans , and kep had the best performance in distinguishing tumor and benign voxels., Conclusions: Using high-resolution histopathology delineations, the real tumor extent and size were found to be underestimated on MRI. mp-MRI obtained the best performance in identifying tumor voxels. Appropriate margins around the visible tumor-suspected region should be included when designing focal salvage strategies. Recurrent tumor delineation guidelines are warranted., Key Points: • Compared to the use of individual sequences, multi-parametric MRI obtained the best performance in distinguishing recurrent tumor from benign voxels. • Delineations based on mp-MRI miss smaller foci and slightly underestimate tumor volume of local recurrent prostate cancer. • Focal salvage strategies should include appropriate margins around the visible tumor.- Published
- 2019
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47. Quantitative 3T multiparametric MRI of benign and malignant prostatic tissue in patients with and without local recurrent prostate cancer after external-beam radiation therapy.
- Author
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Dinis Fernandes C, van Houdt PJ, Heijmink SWTPJ, Walraven I, Keesman R, Smolic M, Ghobadi G, van der Poel HG, Schoots IG, Pos FJ, and van der Heide UA
- Subjects
- Biopsy, Case-Control Studies, Hormones therapeutic use, Humans, Male, Neoplasm Metastasis, Neoplasm Recurrence, Local, Probability, Prospective Studies, Prostate radiation effects, Salvage Therapy, Multiparametric Magnetic Resonance Imaging, Prostate diagnostic imaging, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms radiotherapy
- Abstract
Background: Post-radiotherapy locally recurrent prostate cancer (PCa) patients are candidates for focal salvage treatment. Multiparametric MRI (mp-MRI) is attractive for tumor localization. However, radiotherapy-induced tissue changes complicate image interpretation. To develop focal salvage strategies, accurate tumor localization and distinction from benign tissue is necessary., Purpose: To quantitatively characterize radio-recurrent tumor and benign radiation-induced changes using mp-MRI, and investigate which sequences optimize the distinction between tumor and benign surroundings., Study Type: Prospective case-control., Subjects: Thirty-three patients with biochemical failure after external-beam radiotherapy (cases), 35 patients without post-radiotherapy recurrent disease (controls), and 13 patients with primary PCa (untreated)., Field Strength/sequences: 3T; quantitative mp-MRI: T
2 -mapping, ADC, and Ktrans and kep maps., Assessment: Quantitative image-analysis of prostatic regions, within and between cases, controls, and untreated patients., Statistical Tests: Within-groups: nonparametric Friedman analysis of variance with post-hoc Wilcoxon signed-rank tests; between-groups: Mann-Whitney tests. All with Bonferroni corrections. Generalized linear mixed modeling to ascertain the contribution of each map and location to tumor likelihood., Results: Benign imaging values were comparable between cases and controls (P = 0.15 for ADC in the central gland up to 0.91 for kep in the peripheral zone), both with similarly high peri-urethral Ktrans and kep values (min-1 ) (median [range]: Ktrans = 0.22 [0.14-0.43] and 0.22 [0.14-0.36], P = 0.60, kep = 0.43 [0.24-0.57] and 0.48 [0.32-0.67], P = 0.05). After radiotherapy, benign central gland values were significantly decreased for all maps (P ≤ 0.001) as well as T2 , Ktrans , and kep of benign peripheral zone (all with P ≤ 0.002). All imaging maps distinguished recurrent tumor from benign peripheral zone, but only ADC, Ktrans , and kep were able to distinguish it from benign central gland. Recurrent tumor and peri-urethral Ktrans values were not significantly different (P = 0.81), but kep values were (P < 0.001). Combining all quantitative maps and voxel location resulted in an optimal distinction between tumor and benign voxels., Data Conclusion: Mp-MRI can distinguish recurrent tumor from benign tissue., Level of Evidence: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:269-278., (© 2018 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)- Published
- 2019
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48. HCV Extrahepatic Manifestations.
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Kuna L, Jakab J, Smolic R, Wu GY, and Smolic M
- Abstract
Hepatitis C virus (HCV) has been shown to affect many tissues other than liver. However, of the many extrahepatic manifestations (EMs) that have been associated with HCV, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes and neurological disorders, only a few have been shown to be directly related to HCV infection of extrahepatic tissues. HCV-triggered immune-mediated mechanisms account for most of the EMs. It is estimated that up to 74% of patients with chronic hepatitis C can develop at least one EM. All HCV patients with EMs should be considered for antiviral therapy, although not all will resolve with sustained virological response., Competing Interests: The authors have no conflict of interests related to this publication.
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- 2019
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49. Prediction of optimal needle configuration in the first fraction of cervix brachytherapy.
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Smolic M, Sombroek C, Bloemers MCWM, van Triest B, Nowee ME, and Mans A
- Abstract
Background and Purpose: Applying needles in the first brachytherapy (BT) fraction for patients with locally advanced cervical cancer allows for more dose conformality and OAR sparing, but is more challenging than in subsequent fractions, as pre-implant imaging with applicator in situ is lacking. We investigate whether a needle simulation, a fixed needle configuration or a multidisciplinary discussion-based configuration can predict more accurately which applicator needle positions are best suited for use in the first BT fraction., Materials and Methods: For 20 patients we retrospectively determined the "reference" needle configuration (RC) for the first BT fraction using magnetic resonance imaging (MRI) scans with applicator in situ . We simulated a pre-MRI needle configuration (PC) using the MRI made in the fourth week of external beam radiotherapy (EBRT) without applicator in situ . We generated a fixed needle configuration (FC) from the most common RC needles. Using Dice's similarity coefficient (DSC) we compared each of these needle configurations, including the clinically applied "multidisciplinary consensus" needle configuration (MC), with RC. We considered two scenarios: allowing up to ten needles (scenario 1), and limiting the needle number (scenario 2). The analysis was repeated omitting two mid-ventral needles previously determined as non-essential to treatment planning., Results: For both scenarios, the median DSC for PC and FC was higher than for MC (scenario1:DSC
PC = 0,78; DSCFC = 0,75; DSCMC = 0,57; scenario 2:DSCPC = 0,74; DSCFC = 0,73; DSCMC = 0,59), while omitting mid-ventral needles resulted in no statistically significant differences in DSC., Conclusions: The PC or FC method are at least as accurate as the MC, with the FC preferred for efficiency., (© 2019 The Authors.)- Published
- 2019
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50. Peptic Ulcer Disease: A Brief Review of Conventional Therapy and Herbal Treatment Options.
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Kuna L, Jakab J, Smolic R, Raguz-Lucic N, Vcev A, and Smolic M
- Abstract
Peptic ulcer is a chronic disease affecting up to 10% of the world's population. The formation of peptic ulcers depends on the presence of gastric juice pH and the decrease in mucosal defenses. Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) infection are the two major factors disrupting the mucosal resistance to injury. Conventional treatments of peptic ulcers, such as proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists, have demonstrated adverse effects, relapses, and various drug interactions. On the other hand, medicinal plants and their chemical compounds are useful in the prevention and treatment of numerous diseases. Hence, this review presents common medicinal plants that may be used for the treatment or prevention of peptic ulcers.
- Published
- 2019
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