Bosnian Journal of Basic Medical Sciences <p>The BJBMS (Bosnian Journal of Basic Medical Sciences) is а premier venue for discoveries in basic and clinical biomedical science. The BJBMS was founded in 1998 and is published by the Association of Basic Medical Sciences, a nonprofit honor organization of physician-scientists.</p> <p>Broad readership and scope. The BJBMS reaches readers across a wide range of medical disciplines and sectors. The journal publishes basic and translational/clinical research submissions and reviews in all biomedical specialties, including Genetics and Molecular biology, Immunology, Microbiology, Pathology, Biochemistry, Pharmacology, Anatomy, Biomaterials, new and emerging research and diagnostic methods, new and emerging medical entities, and others.</p> Association of Basic Medical Sciences of FBIH en-US Bosnian Journal of Basic Medical Sciences 1512-8601 Dose-dependent effects of adalimumab in neonatal rats with hypoxia/reoxygenation-induced intestinal damage <p>Tumor necrosis factor-alpha (TNF-α) has an important role in hypoxia/reoxygenation (H/R)-induced intestinal damage. It was shown that blocking TNF-α with infliximab has beneficial effects on experimental necrotizing enterocolitis and hypoxic intestinal injury. However, there is no data about the effect of adalimumab on H/R-induced intestinal damage. Therefore, we aimed to determine potential dose-dependent benefits of adalimumab in such damage in neonatal rats. Wistar albino rat pups were assigned to one of the four groups: control group, hypoxia group, low-dose adalimumab (5 mg/kg/day) treated group (LDAT), and high-dose adalimumab (50 mg/kg/day) treated group (HDAT). On the fourth day of the experiment, all rats except for the control group were exposed to H/R followed by euthanasia. Malondialdehyde (MDA), myeloperoxidase (MPO), TNF-α, total antioxidant capacity (TAC), and total oxidant capacity (TOC) were measured in intestinal tissue. TAC and TOC values were used to calculate the oxidative stress index (OSI). Histopathological injury scores (HIS) were also evaluated in the tissue samples. MDA levels were significantly lower in the LDAT and HDAT groups (<em>p</em> &lt; 0.001). TNF-α levels were significantly lower in the LDAT group (<em>p</em> &lt; 0.001). OSI was significantly higher in the H/R group than in the control and LDAT groups (<em>p</em> &lt; 0.001). Mean HIS values in the LDAT group were significantly lower than those in the H/R and HDAT groups (<em>p</em> &lt; 0.001). This experimental study showed that low-dose adalimumab appears to have a beneficial effect on intestinal injury induced with H/R in neonatal rats.</p> Halil Kocamaz Özmert MA Özdemir Nilay Şen Türk Yaşar Enli Barbaros Şahin Hacer Ergin Copyright (c) 2020 Halil Kocamaz, Özmert MA Özdemir, Nilay Şen Türk, Yaşar Enli, Barbaros Şahin, Hacer Ergin 2021-02-01 2021-02-01 21 1 33 38 10.17305/bjbms.2020.4823 MicroRNA-126 enhances the biological function of endothelial progenitor cells under oxidative stress via PI3K/Akt/GSK3β and ERK1/2 signaling pathways <p>Endothelial progenitor cell (EPC) transplantation is a safe and effective method to treat acute myocardial infarction (AMI). However, oxidative stress leads to the death of a large number of EPCs in the early stage of transplantation, severely weakening the therapeutic effect. Previous studies demonstrated that microRNAs regulate the biological function of EPCs. The aim of the current study was to investigate the effect of microRNA on the biological function of EPCs under oxidative stress. Quantitative reverse transcription PCR was performed to detect the expression of miR-126, miR-508-5p, miR-150, and miR-16 in EPCs from rats, among which miR-126 showed a relatively higher expression. Treatment with H<sub>2</sub>O<sub>2</sub> decreased miR-126 expression in EPCs in a dose-dependent manner. EPCs were further transfected with miR-126 mimics or inhibitors, followed by H<sub>2</sub>O<sub>2 </sub>treatment. Overexpression of miR-126 enhanced the proliferation, migration, and tube formation of H<sub>2</sub>O<sub>2</sub>-treated EPCs. MiR-126 overexpression also inhibited reactive oxygen species and malondialdehyde levels and enhanced superoxide dismutase levels, as well as increased angiopoietin (Ang)1 expression and decreased Ang2 expression in H<sub>2</sub>O<sub>2</sub>-treated EPCs. Moreover, miR-126 participated in the regulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in EPCs, where both pathways were activated after miR-126 overexpression in H<sub>2</sub>O<sub>2</sub>-treated EPCs. Overall, we showed that miR-126 promoted the biological function of EPCs under H<sub>2</sub>O<sub>2</sub>-induced oxidative stress by activating the PI3K/Akt/GSK3β and ERK1/2 signaling pathway, which may serve as a new therapeutic approach to treat AMI.</p> Qinqin Wu Benling Qi Xiaoyu Duan Xiaoyan Ming Fengqin Yan Yingxia He Xiaofen Bu Shan Sun Hong Zhu Copyright (c) 2020 Qinqin Wu, Benling Qi, Xiaoyu Duan, Xiaoyan Ming, Fengqin Yan, Yingxia He, Xiaofen Bu, Shan Sun, Hong Zhu 2021-02-01 2021-02-01 21 1 71 80 10.17305/bjbms.2019.4493 Association of miRNA-145 with the occurrence and prognosis of hydrosalpinx-induced defective endometrial receptivity <p>MiR-145 is reported to facilitate inflammation and is also associated with unsuccessful embryonic implantation. Whether miR-145 mediates inflammatory response underlying hydrosalpinx-induced defective endometrial receptivity (ER) remains unclear, and this study attempted to clarify this point. Endometrium samples were collected from hydrosalpinx patients (case, n = 243) and patients with tubal patency/obstruction (control, n = 187). The peripheral blood samples of cases and controls were collected to determine the genotypes of miR-145 SNPs. The value of miR-145 expression in the diagnosis and prognostic estimation of hydrosalpinx was assessed using ROC curve and regression analysis, respectively. Lipopolysaccharide (LPS) cell model was established with endometrial cells, and cells were transfected with miR-145 mimic, inhibitor, or negative control. MiR-145 and cytokine levels were quantified by quantitative reverse transcription PCR or western blot. MiR-145 expression was significantly higher in hydrosalpinx compared to control group, and high miR-145 expression was significantly associated with moderate/severe tube lesion, high pulsatility index (&gt;1.06), and high resistance index (&gt;0.61) in hydrosalpinx patients. ROC curve analysis indicated that monitoring miR-145 expression may be useful for the diagnosis of hydrosalpinx (AUC = 0.704). A alleles of rs41291957 (G&gt;A) and rs353292 (G&gt;A) were significantly associated with an increased risk of hydrosalpinx compared to G allele (<em>p </em>&lt; 0.05), yet the mutant allele of rs353291 (A&gt;G) and rs4705343 (T&gt;C) significantly reduced susceptibility to hydrosalpinx compared to the wild type allele. Treatments with miR-145 mimic and LPS in endometrial cells significantly increased the levels of transforming growth factor-β1, tumor necrosis factor -α, interleukin (IL)-6, and IL-8 compared to negative control, while treatment with miR-145 inhibitor decreased the cytokine levels. In conclusion, abnormally expressed miR-145 may be involved in hydrosalpinx-induced ER defects by regulating the inflammatory response.</p> Qingli Wang Haiquan Ai Xia Li Haiqing Tian Bingxue Ning Meng Zhang Xiaolin La Copyright (c) 2020 Qingli Wang, Haiquan Ai, Xia Li, Haiqing Tian, Bingxue Ning, Meng Zhang, Xiaolin La 2021-02-01 2021-02-01 21 1 81 92 10.17305/bjbms.2020.4538 Knockdown of TPT1-AS1 inhibits cell proliferation, cell cycle G1/S transition, and epithelial–mesenchymal transition in gastric cancer <p>Long non-coding RNAs are considered to be critical regulators of tumor progression. Tumor protein translationally controlled 1 antisense RNA 1 (TPT1-AS1) was shown to have an oncogenic role in cervical and ovarian cancer. The clinical significance and biological function of TPT1-AS1 in gastric cancer (GC) are not clear. In this study, we analyzed the expression of TPT1-AS1 in GC tissues and cell lines and performed functional and mechanistic analysis of TPT1-AS1 effects on GC cell proliferation, migration, and invasion. TPT1-AS1 expression was determined in 76 pairs of GC tissues vs. matched adjacent normal tissues and in four GC cell lines (SGC-7901, AGS, BGC-823, and MGC-803) vs. GES-1 cell line by quantitative reverse transcription PCR. SGC-7901 and MGC-803 cells were transfected with small interfering RNA or scrambled negative control, and cell proliferation, colony formation, migration, invasion and cell cycle assays were performed. The expression of proteins involved in cell cycle progression and epithelial–mesenchymal transition was analyzed by Western blot. TPT1-AS1 expression was significantly higher in GC tissues and cell lines compared to controls. The overexpression of TPT1-AS1 was significantly correlated with TNM stage and lymph node metastasis, and it was associated with worse prognosis of GC patients according to the Kaplan–Meier survival analysis and Cox proportional hazard regression analysis. The knockdown of TPT1-AS1 significantly inhibited proliferation, cell cycle G1/S transition, migration, and invasion of SGC-7901 and MGC-803 cells. Moreover, TPT1-AS1 knockdown downregulated the expression of cyclin-dependent kinase (CDK) 4, cyclin D1, and vimentin and upregulated the expression of p21 and E-cadherin. Our findings suggest that TPT1-AS1 may be a promising therapeutic target in GC.</p> Jun Tang Fei Huang Hui Wang Feng Cheng Yaping Pi Juanjuan Zhao Zhihong Li Copyright (c) 2020 Jun Tang, Fei Huang, Hui Wang, Feng Cheng, Yaping Pi, Juanjuan Zhao, Zhihong Li 2021-02-01 2021-02-01 21 1 39 46 10.17305/bjbms.2020.4470 Bioinformatics analysis reveals TSPAN1 as a candidate biomarker of progression and prognosis in pancreatic cancer <p>Pancreatic cancer (PCC) is a common malignant tumor of the digestive system that is resistant to traditional treatments and has an overall 5-year survival rate of &lt;7%. Transcriptomics research provides reliable biomarkers for diagnosis, prognosis, and clinical precision treatment, as well as the identification of molecular targets for the development of drugs to improve patient survival. We sought to identify new biomarkers for PCC by combining transcriptomics and clinical data with current knowledge regarding molecular mechanisms. Consequently, we employed weighted gene co-expression network analysis and differentially expressed gene analysis to evaluate genes co-expressed in tumor versus normal tissues using pancreatic adenocarcinoma data from The Cancer Genome Atlas and dataset GSE16515 from the Gene Expression Omnibus. Twenty-one overlapping genes were identified, with enrichment of key Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways, including epidermal growth factor receptor signaling, cadherin, cell adhesion, ubiquinone, and glycosphingolipid biosynthesis pathways, and retinol metabolism. Protein-protein interaction analysis highlighted 10 hub genes, according to Maximal Clique Centrality. Univariate and multivariate COX analyses indicated that TSPAN1 serves as an independent prognostic factor for PCC patients. Survival analysis distinguished TSPAN1 as an independent prognostic factor among hub genes in PCC. Finally, immunohistochemical staining results suggested that the TSPAN1 protein levels in the Human Protein Atlas were significantly higher in tumor tissue than in normal tissue. Therefore, TSPAN1 may be involved in PCC development and act as a critical biomarker for diagnosing and predicting PCC patient survival.</p> Chenhui Ma ZeLong Cui YiChao Wang Lei Zhang JunYe Wen HuaiBin Guo Na Li WanXing Zhang Copyright (c) 2020 Chenhui Ma, ZeLong Cui, YiChao Wang , Lei Zhang, JunYe Wen , HuaiBin Guo, Na Li, WanXing Zhang 2021-02-01 2021-02-01 21 1 47 60 10.17305/bjbms.2020.5096 Targeting HER2 expression in cancer: New drugs and new indications <p>Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.</p> Semir Vranić Semir Bešlija Zoran Gatalica Copyright (c) 2020 Semir Vranic, Zoran Gatalica 2021-02-01 2021-02-01 21 1 1 4 10.17305/bjbms.2020.4908 Cross-sectional imaging and cytologic investigations in the preoperative diagnosis of parotid gland tumors – An updated literature review <p>An accurate preoperative diagnosis of parotid tumors is essential for the selection and planning of surgical treatment. Various modern cross-sectional imaging and cytologic investigations can support the differential diagnosis of parotid tumors. The aim of this study was to achieve a comprehensive and updated review of modern imaging and cytologic investigations used in parotid tumor diagnosis, based on the latest literature data. This literature review could serve as a guide for clinicians in selecting different types of investigations for the preoperative differential diagnosis of parotid tumors. Magnetic resonance imaging (MRI) with its dynamic and advanced sequences is the first-line imaging investigation used in differentiating parotid tumors. Computed tomography (CT) and positron emission tomography (PET)-CT provide limited indications in differentiating parotid tumors. Fine needle aspiration biopsy and core needle biopsy can contribute with satisfactory results to the cytological diagnosis of parotid tumors. Dynamic MRI with its dynamic contrast-enhanced and diffusion-weighted sequences provides the best accuracy for the preoperative differential diagnosis of parotid tumors. CT allows the best evaluation of bone invasion, being useful when MRI cannot be performed, and PET-CT has value in the follow-up of cancer patients. The dual cytological and imaging approach is the safest method for an accurate differential diagnosis of parotid tumors.</p> Sebastian Stoia Grigore Băciuț Manuela Lenghel Radu Badea Csaba Csutak Georgeta Mihaela Rusu Mihaela Băciuț Tiberiu Tamaș Emil Boțan Gabriel Armencea Simion Bran Cristian Dinu Copyright (c) 2020 Sebastian Stoia, Grigore Băciuț, Manuela Lenghel , Radu Badea , Csaba Csutak , Georgeta Mihaela Rusu , Mihaela Băciuț, Tiberiu Tamaș, Emil Boțan , Gabriel Armencea , Simion Bran , Cristian Dinu 2021-02-01 2021-02-01 21 1 19 32 10.17305/bjbms.2020.5028 The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review <p>Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3β, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.</p> Mislav Glibo Alan Serman Valentina Karin-Kujundzic Ivanka Bekavac Vlatkovic Berivoj Miskovic Semir Vranic Ljiljana Serman Copyright (c) 2020 Mislav Glibo, Alan Serman, Valentina Karin-Kujundzic, Ivanka Bekavac Vlatkovic, Berivoj Miskovic, Semir Vranic, Ljiljana Serman 2021-02-01 2021-02-01 21 1 5 18 10.17305/bjbms.2020.5036 Lessons learned from COVID-19 pandemic in Italy – A commentary <div>Since the COVID-19 outbreak, Italy has been one of the most affected countries in Europe and the second for number of deaths. In this commentary, we discuss some lessons that we learned as health-care providers working in a large public hospital during the pandemic, with a special focus on the importance of infection containment and early diagnosis, the role of swab, serological tests, home isolation and individual protection&nbsp; devices, and the available therapies and management indications to better face a possible new outbreak in the near future. These comments should stimulate a more diffused, efficient, and efficacious management of COVID-19 patients, also reducing the number of admissions to hospital emergency departments and the related spread of the infection.</div> Antonio Minni Massimo Ralli Francesca Candelori Fabrizio Cialente Lucia Ercoli Claudio Parlapiano Antonio Greco Marco de Vincentiis Copyright (c) 2020 Antonio Minni, Massimo Ralli, Francesca Candelori, Fabrizio Cialente, Lucia Ercoli, Claudio Parlapiano, Antonio Greco, Marco de Vincentiis 2021-02-01 2021-02-01 21 1 117 119 10.17305/bjbms.2020.4847 SARS-CoV-2 virus outbreak and the emergency public health measures in Bosnia and Herzegovina: January – July, 2020 <p>Between March 5<sup>th</sup> and July 25<sup>th</sup>, 2020, the total number of SARS-CoV-2 confirmed cases in Bosnia and Herzegovina (BH) was 10,090, corresponding to a cumulative incidence rate of 285.7/100,000 population. Demographic and clinical information on all the cases along with exposure and contact information were collected using a standardized case report form. In suspected SARS-CoV-2 cases, respiratory specimens were collected and tested by real-time reverse-transcriptase polymerase chain reaction assay. The dynamic of the outbreak was summarized using epidemiological curves, instantaneous reproduction number R<sub>t</sub>, and interactive choropleth maps for geographical distribution and spread. The rate of hospitalization was 14.0%(790/5646) in the Federation of Bosnia and Herzegovina (FBH) and 6.2% (267/4299) in the Republic of Srpska (RS). The death rate was 2.2% (122/5646) in FBH and 3.6% in the RS (155/4299). After the authorities lifted mandatory quarantine restrictions, the instantaneous reproduction number increased from 1.13 on May 20<sup>th</sup> to 1.72 on May 31<sup>st</sup>. The outbreak concerns both entities, FBH and RS, and it is more pronounced in those aged 20-44 years. It is important to develop the communication and emergency plan for the SARS-CoV-2 outbreak in BH, including the mechanisms to allow the ongoing notification and updates at the national level.</p> Mirsada Hukic Mirza Ponjavic Emin Tahirovic Almir Karabegovic Elvir Ferhatbegovic Maja Travar Fadila Serdarevic Copyright (c) 2020 Mirsada Hukic, Mirza Ponjavic, Emin Tahirovic, Almir Karabegovic, Elvir Ferhatbegovic, Maja Travar, Fadila Serdarevic 2021-02-01 2021-02-01 21 1 111 116 10.17305/bjbms.2020.5081 Vancomycin-releasing cross-linked collagen sponges as wound dressings <p>The study presents a novel vancomycin-releasing collagen wound dressing derived from <em>Cyprinus carpio </em>collagen type I cross-linked with carbodiimide which retarded the degradation rate and increased the stability of the sponge. Following lyophilization, the dressings were subjected to gamma sterilization. The structure was evaluated via scanning electron microscopy images, micro-computed tomography, and infrared spectrometry. The structural stability and vancomycin release properties were evaluated in phosphate buffered saline. Microbiological testing and a rat model of a wound infected with methicillin-resistant <em>Staphylococcus aureus </em>(MRSA) were then employed to test the efficacy of the treatment of the infected wound. Following an initial mass loss due to the release of vancomycin, the sponges remained stable. After 7 days of exposure in phosphate buffered saline (37°C), 60% of the material remained with a preserved collagen secondary structure together with a high degree of open porosity (over 80%). The analysis of the release of vancomycin revealed homogeneous distribution of the antibiotic both across and between the sponges. The release of vancomycin was retarded as proved by <em>in vitro </em>testing and further confirmed by the animal model from which measurable concentrations were observed in blood samples 24 hours after the subcutaneous implantation of the sponge, which was more than observed following intraperitoneal administration. The sponge was also highly effective in terms of reducing the number of colony-forming units in biopsies extracted from the infected wounds 4 days following the inoculation of the wounds with the MRSA solution. The presented sponges have ideal properties to serve as wound dressing for prevention of surgical site infection or treatment of already infected wounds.</p> Jan Miroslav Hartinger Peter Lukáč Petr Mitáš Mikuláš Mlček Michaela Popková Tomáš Suchý Monika Šupová Jan Závora Václava Adámková Hana Benáková Ondřej Slanař Martin Šíma Martin Bartoš Hynek Chlup Tomáš Grus Copyright (c) 2019 BJBMS 2021-02-01 2021-02-01 21 1 61 70 10.17305/bjbms.2019.4496 Asymptomatic neurotoxicity of amyloid β-peptides (Aβ1-42 and Aβ25-35) on mouse embryonic stem cell-derived neural cells <p>One of the strategies in the establishment of <em>in vitro</em> oxidative stress models for neurodegenerative diseases, such as Alzheimer’s disease (AD), is to induce neurotoxicity by amyloid beta (Aβ) peptides in suitable neural cells. Presently, data on the neurotoxicity of Aβ in neural cells differentiated from stem cells are limited. In this study, we attempted to induce oxidative stress in transgenic 46C mouse embryonic stem cell-derived neurons via treatment with Aβ peptides (Aβ<sub>1-42</sub> and Aβ<sub>25-35</sub>). 46C neural cells were generated by promoting the formation of multicellular aggregates, embryoid bodies in the absence of leukemia inhibitory factor, followed by the addition of all-trans retinoic acid as the neural inducer. Mature neuronal cells were exposed to different concentrations of Aβ<sub>1-42</sub> and Aβ<sub>25-35</sub> for 24 h. Morphological changes, cell viability, and intracellular reactive oxygen species (ROS) production were assessed. We found that 100 µM Aβ<sub>1-42</sub> and 50 µM Aβ<sub>25-35</sub> only promoted 40% and 10%, respectively, of cell injury and death in the 46C-derived neuronal cells. Interestingly, treatment with each of the Aβ peptides resulted in a significant increase of intracellular ROS activity, as compared to untreated neurons. These findings indicate the potential of using neurons derived from stem cells and Aβ peptides in generating oxidative stress for the establishment of an <em>in vitro </em>AD model that could be useful for drug screening and natural product studies.</p> Nur Izzati Mansor Carolindah Makena Ntimi Noraishah Mydin Abdul-Aziz King-Hwa Ling Aishah Adam Rozita Rosli Zurina Hassan Norshariza Nordin Copyright (c) 2020 Nur Izzati Mansor, Carolindah Makena Ntimi, Noraishah Mydin Abdul-Aziz, King-Hwa Ling, Aishah Adam, Rozita Rosli, Zurina Hassan, Norshariza Nordin 2021-02-01 2021-02-01 21 1 98 110 10.17305/bjbms.2020.4639 Rapid, multimodal, critical care knowledge-sharing platform for COVID-19 pandemics <p>In many areas of the world, critical care providers caring for COVID-19 patients lacked specific knowledge and were exposed to the abundance of new and unfiltered information. With support from the World Health Organization, we created a multimodal tele-education intervention to rapidly share critical care knowledge related to COVID-19 targeting providers in a region of Southeastern Europe. We delivered 60-minute weekly interactive tele-education sessions over YouTube<sup>TM</sup> between March 2020 and May 2020, supplemented by a dedicated webpage. The intervention was reinforced using a secure social media platform (Viber<sup>TM</sup>), providing continuous rapid knowledge exchange among faculty and learners. A high level of engagement was observed, with over 2000 clinicians participating and actively interacting over a 6-week period. Surveyed participants were highly satisfied with the intervention. Tele-education interventions using social media platforms are feasible, low-cost, and effective methods to share knowledge during the COVID-19 pandemic.</p> Amra Sakusic Dragana Markotic Yue Dong Emir Festic Vladimir Krajinovic Zoran Todorovic Alan Sustic Natasa Milivojevic Milka Jandric Srdjan Gavrilovic Alexander Niven Pedja Kovacevic Ognjen Gajic Copyright (c) 2020 Amra Sakusic, Dragana Markotic, Yue Dong, Emir Festic, Vladimir Krajinovic, Alan Sustic, Natasa Milivojevic, Milka Jandric, Srdjan Gavrilovic, Alexander Niven, Pedja Kovacevic, Ognjen Gajic 2021-02-01 2021-02-01 21 1 93 97 10.17305/bjbms.2020.4934 Expression of NEDD9 and connexin-43 in neoplastic and stromal cells of gastric adenocarcinoma <p>Gastric cancer is related to high mortality rates and advanced disease stage at the time of diagnosis. Its carcinogenesis is extensively studied and is associated with genetic and epigenetic changes, changed the interaction between tumor and adjacent stromal cells, and changes in the microenvironment molecule status. Neural precursor cell-expressed developmentally down-regulated 9 (NEDD9) affects different signaling proteins and pathways, apoptosis, adhesion, cell migration, and invasiveness. Connexin-43 (Cx43) also assists in intercellular communications and has several channel-independent functions. Aberrant expression of those two gap junction proteins plays an essential role in metastatic processes. Our scope was to detect the expression of Cx43 and NEDD9 in epithelial and stromal gastric cancer compartments and its relation to tumor progression and lymph node metastases. Cancer tissue from 53 cases of node-negative and 55 cases of node-positive primary gastric carcinoma patients was analyzed for Cx43 and NEDD9 expression by immunohistochemical assay, and the results were correlated with the remaining clinical and pathological findings and survival. In our cohort of patients with lymph node metastases, we detected higher expression of epithelial Cx43 in the primary tumor and stromal Cx43 expression correlated with both epithelial NEDD9 (rho = 0.453) and stromal NEDD9 (rho = 0.484). Higher epithelial Cx43 and NEDD9 expression were associated with higher mortality (HR 1.54, 95% CI 1.01-2.37, <em>p</em> = 0.048). Epithelial Cx43 expression, both epithelial and stromal NEDD9 expression, T and N status were all independently associated with shorter survival. In summary, our findings suggest that increased expression of both epithelial and stromal NEDD9 and epithelial Cx43 could potentially be used as prognostic gastric cancer biomarkers.</p> Ivan Lerotić Petra Vuković Davor Hrabar Zvonimir Misir Ivan Kruljac Tajana Pavić Jelena Forgač Petra Ćaćić Monika Ulamec Copyright (c) 2021 Ivan Lerotić, Petra Vuković, Davor Hrabar, Zvonimir Misir, Ivan Kruljac, Tajana Pavić, Jelena Forgač, Petra Čačić, Monika Ulamec 2021-01-11 2021-01-11 21 1 10.17305/bjbms.2020.5379 Development and validation of a SEER-based prognostic nomogram for cervical cancer patients below the age of 45 years <p>This study aimed to establish a nomogram for the prognostic prediction of patients with early-onset cervical cancer (EOCC) in both overall survival (OS) and cancer-specific survival (CSS). The 10,079 patients diagnosed with EOCC between 2004 and 2015 were captured within the Surveillance, Epidemiology, and End Results (SEER) database and further were divided into training and validation sets randomly. The independent prognostic factors were identified in a retrospective study of 7,055 patients training sets randomly. Besides, the prognostic nomogram was developed using R software according to multivariable Cox regression analysis. Furthermore, the model was externally validated using the data of 3,024 patients diagnosed at different times enrolled in the SEER database. In training set, the C-indexes for OS and CSS prediction were 0.831 (95% confidence interval [CI]: 0.815-0.847) and 0.855(95%CI:0.839-0.871). The results of ROC indicated that nomograms possessed better predict performance compared with TNM-stage and SEER-stage. And the areas under the curve (AUC) of the nomogram for OS and CSS prediction in ROC analysis were 0.855(95%CI:0.847-0.864) and 0.782(95%CI:0.760-0.804), respectively. In addition, calibration curves presented perfect agreements between the nomogram-predicted and actual 1-, 3-, and 5-year in the validation cohort, in OS rate and CSS rate. This study established and validated a prognostic nomogram that provided an accurate prediction of 3-, 5-, and 10-year OS and CSS of EOCC patients, which contributed to clinicians to be useful for patients’ counseling and clinical trial designing.</p> Qunlong Liu Wenxia Li Ming Xie Ming Yang Mei Xu Lei Yang Bing Sheng Yanna Peng Li Gao Copyright (c) 2020 Qunlong Liu, Wenxia Li, Ming Xie, Ming Yang, Mei Xu, Lei Yang, Bing Sheng, Yanna Peng, Li Gao 2020-12-31 2020-12-31 21 1 10.17305/bjbms.2020.5271 Machine learning as the new approach in understanding biomarkers of suicidal behavior <p>In psychiatry, compared to other medical fields, the identification of biological markers that would complement current clinical interview, and enable more objective and faster clinical diagnosis, implement accurate monitoring of treatment response and remission, is grave. Current technological development enables analyses of various biological marks in high throughput scale at reasonable costs, and therefore ‘omic’ studies are entering the psychiatry research. However, big data demands a whole new plethora of skills in data processing, before clinically useful information can be extracted. So far the classical approach to data analysis did not really contribute to identification of biomarkers in psychiatry, but the extensive amounts of data might get to a higher level, if artificial intelligence in the shape of machine learning algorithms would be applied. Not many studies on machine learning in psychiatry have been published, but we can already see from that handful of studies that the potential to build a screening portfolio of biomarkers for different psychopathologies, including suicide, exists.</p> Alja Videtič Paska Katarina Kouter Copyright (c) 2020 Alja Videtič Paska, Katarina Kouter 2020-12-31 2020-12-31 21 1 10.17305/bjbms.2020.5146 Significance of chromogranin A and synaptophysin in medullary thyroid carcinoma <p>Medullary thyroid carcinoma (MTC) is a relatively rare thyroid carcinoma of C-cell deviation and produces and secrete calcitonin (CT) and chromogranin A (CgA) into the blood. Thus, both CT and CgA are immunohistochemical and serum markers for MTCs. MTC occurs in both sporadic and inheritable cases and the hallmark of inheritable cases in multiple endocrine neoplasm 2 (NEN2) is MTC. MEN2 cases represent 30% of MTCs through germline RET protooncogene mutation and occur in younger ages involving bilateral thyroid lobes. Sporadic cases are 70% of cases of solitary tumor and occur in older ages. CgA and synaptophysin (SPY) are the two, most widely used and reliable immunohistochemical markers for neuroendocrine tumors including MTCs. This study aimed to detect different immunohistochemical staining patterns for CgA and SPY between non-symptomatic small, microscopic lesions and invading larger aggressive tumors in both MEA2 cases and sporadic cases. There was different CgA and SPY immunostaining in MEA2 cases where small tumors (≤ 0.3 cm) were lesser immunostained for CgA and SPY, despite strong staining for CT, compared to the larger (≥ 0.5cm) tumors, stronger immunostained for CgA. There was also different CgA and SPY immunohistochemical staining in sporadic cases between small lesion (≤ 0.5 cm) and larger tumors (≥ 1.0cm). One small sporadic tumor (0.5 x 0.3 cm) was strongly and weakly, patchy (about 10% of tumor tissue) stained for CgA and SPY, respectively, while larger sporadic tumors were diffusely, stronger stained for CgA and SPY. Therefore, stronger CgA and SPY immunostaining for larger tumors in both MEA2 and sporadic cases may be used as independent aggressive immunohistochemical markers for MTCs.</p> Tatsuo Tomita Copyright (c) 2020 Tatsuo Tomita 2020-12-30 2020-12-30 21 1 10.17305/bjbms.2020.5407 Clinical significance of miR-129-5p in patients with neonatal sepsis and its regulatory role in the LPS-induced inflammatory response <p>Neonatal sepsis (NS) occurs in neonates within 28 days, especially preterm infants. The dysregulation of miRNAs is widely detected in NS. The study investigated the expression changes and clinical significance of miR-129-5p in NS patients and further explored the regulatory role of miR-129-5p in the LPS-induced inflammatory response in monocytes. A total of 75 neonates with NS and 84 neonates without NS were recruited. qRT-PCR was used for the measurement of miR-129-5p expression. The receiver operating characteristic (ROC) curve was constructed for diagnostic value analysis. ELISA was used to detect the concentration of inflammatory cytokines. Monocytes were isolated from the blood of neonates to investigate the role of miR-129-5p in the LPS-induced inflammatory response in vitro. miR-129-5p was low expressed in the serum of NS cases compared with controls. Serum miR-129-5p had a diagnostic value for NS with a sensitivity of 82.7% and specificity of 79.8%. There was close association for serum miR-129-5p with TNF-α (r = -0.652,<em> p</em> &lt; 0.001) and IL-8 (r = -0.700, <em>p</em> &lt; 0.001) levels in NS patients. Overexpression of miR-129-5p reversed the increasing trend of TNF-α and IL-8 induced by LPS, whereas miR-129-5p downregulation aggravated the increase of TNF-α and IL-8 induced by LPS in monocytes. MiR-129-5p was downregulated in the serum of NS patients, and it might be a promising biomarker for disease diagnosis. Overexpression of miR-129-5p alleviated the inflammatory response of NS.</p> Meng Li Xiaoyang Huang Qingcui Zhuo Jinghui Zhang Xiuli Ju Copyright (c) 2020 Meng Li, Xiaoyang Huang, Qingcui Zhuo, Jinghui Zhang, Xiuli Ju 2020-12-29 2020-12-29 21 1 10.17305/bjbms.2020.5184 A novel homozygous exon2 deletion of TRIM32 gene in a Chinese patient with sarcotubular myopathy: A case report and literature review <p>Sarcotubular myopathy (STM) is a rare autosomal recessive myopathy caused by <em>TRIM32</em> gene mutations. It is predominantly characterized by the weakness of the proximal limb and mild to moderate elevation of creatine kinase (CK) levels. In this study, we describe a 50-year-old Chinese man who exhibited a <em>proximal</em>-to-<em>distal</em> weakness in the muscles of the lower limbs and who had difficulty standing up from a squat position. The symptoms gradually became more severe. He denied a history of cognitive or cardiological problems. The patient’s parents and children were healthy. Histopathological examination revealed dystrophic changes and irregular slit-shaped vacuoles containing amorphous materials. Whole-exome sequencing consisting of protein-encoding regions of 19,396 genes was performed, the results of which identified one novel homozygous 2kb deletion chr9.hg19: g.119460021_119461983del (exon2) in the <em>TRIM32 </em>gene. This was confirmed at the homozygous state with quantitative real-time PCR. Here, we present a Chinese case of STM with one novel mutation in <em>TRIM32</em> and provide a brief summary of all known pathogenic mutations in <em>TRIM32</em>.</p> Xiao-Jing Wei Jing Miao Zhi-Xia Kang Yan-Lu Gao Zi-Yi Wang Xue-Fan Yu Copyright (c) 2020 Xiao-Jing Wei, Jing Miao, Zhi-Xia Kang, Yan-Lu Gao, Zi-Yi Wang, Xue-Fan Yu 2020-12-29 2020-12-29 21 1 10.17305/bjbms.2020.5288 Dishevelled family proteins (DVL1-3) expression in intrauterine growth restriction (IUGR) placentas <p>Dishevelled family proteins (DVL1, DVL2, and DVL3) are cytoplasmic proteins that are involved in canonical and non-canonical Wnt signaling pathway during embryonic development. The role of DVL proteins in the placental tissue remains mostly unknown. In the current study, we explored the role of Dishevelled proteins in naturally invasive tissue, trophoblast. Formalin-fixed paraffin-embedded samples of 15 term placentas from physiologic term pregnancies and 15 term placentas from pregnancies complicated with intrauterine growth restrictions (IUGR) were used for the study. Expression levels of mRNA for DVL1, DVL2, and DVL3 in placentas were analyzed by quantitative real-time PCR (qRTPCR). DVL1, DVL2, and DVL3 protein expression were semi-quantitatively analyzed using immunohistochemistry. The expression of DVL2 and DVL3 proteins was significantly higher in trophoblasts in placental villi from IUGR pregnancies compared with the control group of term placentas. In contrast, DVL3 protein expression was significantly higher in endothelial cells in placental villi from IUGR pregnancies compared with normal term placentas. The observed differences at protein levels between normal and IUGR placentas were not confirmed at the mRNA levels of DVL genes. Our data indicate the active involvement of DVL proteins in IUGR-related placentas. No significant changes were observed in DVL mRNA levels between the two groups of placentas. Further studies are required to explore the clinical relevance of these observations.</p> Ida Marija Sola Alan Serman Valentina Karin-Kujundzic Frane Paic Anita Skrtic Paula Slatina Luka Kakarigi Semir Vranic Ljiljana Serman Copyright (c) 2020 Ida Marija Sola, Alan Serman, Valentina Karin-Kujundzic, Frane Paic, Anita Skrtic, Paula Slatina, Luka Kakarigi, Semir Vranic, Ljiljana Serman 2020-12-26 2020-12-26 21 1 10.17305/bjbms.2020.5422