BJBMS <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 BJBMS 1512-8601 <p>© Association of Basic Medical Sciences of FBIH.</p> MALAT1 inhibits the Wnt/β-catenin signaling pathway in colon cancer cells and affects cell proliferation and apoptosis <p>Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long noncoding RNA, which has been related to various pathological processes, including cancer. The role and mechanism of MALAT1 in colon cancer are not clear. We investigated MALAT1 expression in colon cancer tissues, the effect of MALAT1 on proliferation and apoptosis of SW480 cells, and the signaling pathway involved in the MALAT1 effects. MALAT1 expression was determined in 60 colon cancer and para-carcinoma tissues using reverse transcription polymerase chain reaction (RT-PCR). Knockdown of MALAT1 in SW480 cells was induced by small interfering RNA (siRNA), and the cells were divided into three groups: untreated control, nonsense siRNA-treated control, and MALAT1 siRNA-treated group. SW480 cell apoptosis was assessed using TUNEL assay and flow cytometry. Apoptosis-related and Wnt/β-catenin signaling pathway-related proteins were detected by Western blotting in SW480 cells. SW480 cell proliferation was assessed by CCK-8 assay. MALAT1 expression was significantly higher in colon cancer vs. para-carcinoma tissues. Knockdown of MALAT1 by siRNA increased the number of apoptotic cells and the apoptosis rate at 24 h post-transfection in SW480 cells. Bcl2 associated X protein (Bax) expression was increased, B-cell lymphoma 2 (Bcl-2) expression was decreased, and the ratio of cleaved caspase-3 to truncated caspase-3 was increased in MALAT1 siRNA-transfected SW480 cells. MALAT1 knockdown decreased the proliferation of SW480 cells at 24 h, 48 h, and 72 h post-transfection. Wnt and β-catenin expression was inhibited in MALAT1 siRNA-transfected SW480 cells. Inhibition of MALAT1 expression in colon cancer may promote apoptosis and hinder cell proliferation by suppressing the activation of Wnt/β-catenin signaling pathway.</p> Junjun Zhang Qian Li Bing Xue Rui He Copyright (c) 2019 AMBSFBIH 2019-11-15 2019-11-15 19 4 10.17305/bjbms.2019.4408 Inhibition of miR-9 decreases osteosarcoma cell proliferation <p>Osteosarcoma (OS) is the most common primary bone tumor that affects adolescents and young adults. Disruption of microRNA (miRNA) regulation is well established in the pathophysiology of different cancers, including OS. Increased expression of miR-9 in OS positively correlates with the tumor size, clinical stage, and distant metastasis. In the present study, we used two different OS cell lines, MG-63 and Saos-2, as <em>in vitro</em> models. Small interfering RNA against miR-9 and miR-9 mimics were used to study the function of miR-9 in these two cell lines. We determined the effect of miR-9 inhibition on cell proliferation, cell cycle, apoptosis, and the protein expression of different genes. Our results demonstrated that miR-9 knockdown in the human OS cell lines inhibits their metastatic potential, as determined by decreased cell proliferation and cell cycle arrest, decreased invasion, and increased apoptosis. The western blot analysis showed that cadherin-1 (CDH1), matrix metalloproteinase 13 (MMP-13), forkhead box O3 (FOXO3a), Bcl-2-like protein 11 (BCL2L11), and β-catenin (CTNNB1) are involved in miR-9 signaling. Moreover, miR-9 mimics rescued the effects caused by the inhibition of miR-9 in the OS cell lines. Our findings suggest that miR-9 is important for mediating OS cell migration, invasion, metastasis, and apoptosis. Inhibition of miR-9 could be further explored as a therapeutic target to treat OS.</p> Wu Gang Wei Tanjun Huang Yong Qin Jiajun Zhang Yi Hu Hao Copyright (c) 2019 ABMSFBIH 2019-11-14 2019-11-14 19 4 10.17305/bjbms.2019.4434 Prognostic role of NLR, PLR, and LMR in patients with pulmonary embolism <p>Pulmonary embolism (PE) is associated with significant morbidity and mortality. New biological markers are being investigated for estimating the prognosis of PE patients. Since PE is closely associated with inflammatory status, the neutrophil-lymphocyte (NLR), platelet-lymphocyte (PLR), and lymphocyte-monocyte (LMR) ratios were suggested to be useful in predicting patient outcomes. This study aimed to evaluate the prognostic role of NLR, PLR, and LMR in PE. A total of 103 PE cases from a cardiology department were included in the study. Control group consisted of 102 patients selected from outpatient clinics other than cardiology, cardiovascular surgery, and chest diseases. We retrospectively evaluated demographic and clinical characteristics, treatments, laboratory and imaging findings, and outcomes of patients. The median follow-up of PE patients was 39 months, and the 5-year overall survival probability was 73.8%. Out of 103 patients, 20 were classified as high risk PE cases (19.4%). Thrombolytic treatment was administered to 23 patients (22.3%). Systolic pulmonary arterial pressure was measured during one year, showing a significant decrease from 51.7 ± 15.7 mmHg at admission to 26.6 ± 4.0 mmHg at first year assessment. Age (OR: 1.06, <em>p</em> &lt; 0.001) and NLR (OR: 1.52, <em>p</em> &lt; 0.0019) were significantly associated with the disease status. The independent prognostic factors in moderate-low and low risk PE groups were NLR (HR: 1.17, <em>p</em> = 0.033) and LMR (HR: 1.58, <em>p</em> = 0.046). In moderate-high and high risk PE patients, the independent prognostic factors were age (HR: 1.07, <em>p</em> = 0.014) and PLR (HR: 1.01, <em>p</em> = 0.046). NLR, PLR, and LMR were associated with the prognosis of PE patients. The clinical severity of PE should be considered when utilizing these markers to assess patient outcomes.</p> Nuri Köse Tarık Yıldırım Fatih Akın Seda Elçim Yıldırım İbrahim Altun Copyright (c) 2019 ABMSFBIH 2019-11-13 2019-11-13 19 4 10.17305/bjbms.2019.4445 p16/Ki-67 dual staining has a better accuracy than human papillomavirus (HPV) testing in women with abnormal cytology under 30 years old <p>Due to a high rate of transient human papillomavirus (HPV) infection, HPV genotyping has a low specificity for high-grade cervical lesions, especially in young women. p16/Ki-67 dual immunocytochemical staining can also be used for the detection of oncogenic changes in cervical cells. Our aim was to compare the performance of p16/Ki-67 dual staining and HPV genotyping in the detection of high-grade cervical lesions in patients with atypical squamous cells of undetermined significance (ASCUS)/low-grade squamous intraepithelial lesion (LSIL) on Pap smear. We retrospectively analyzed 310 patients with ASCUS/LSIL on Pap smear, who underwent colposcopy. Among these, 161 patients with suspected lesions detected by colposcopy were referred for biopsy. HPV genotyping by LINEAR ARRAY HPV Genotyping Test (CE-IVD) and p16/Ki-67 dual staining by CINtec PLUS Cytology kit was performed prior to cervical biopsy. The overall sensitivity and specificity of HPV genotyping for the detection of cervical intraepithelial neoplasia (CIN) 2-3 was 79% and 72%, respectively in patients with ASCUS, and 85% and 64%, respectively in patients with LSIL. For p16/Ki-67 test, sensitivity and specificity rate was 66% and 93%, respectively in ASCUS and 59% and 79%, respectively in LSIL group. The specificity of p16/Ki-67 staining was significantly higher in both groups in patients aged &lt;30 years compared to patients &gt;30 years old (<em>p</em> &lt; 0.001). Our results showed that p16/Ki-67 dual staining has a higher specificity compared to HPV genotyping, especially in patients under 30 years old. This indicates the usefulness of p16/Ki-67 testing in the triage of patients with ASCUS/LSIL and &lt;30 years old, prior to referral for colposcopy and biopsy.</p> Laurențiu Pirtea Cristina Secosan Madalin Margan Lavinia Moleriu Oana Balint Dorin Grigoras Ioan Sas Florin Horhat Adelina Jianu Răzvan Ilina Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 336 341 10.17305/bjbms.2018.3560 Effects of TCF7L2 rs7903146 variant on metformin response in patients with type 2 diabetes <p>The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C&gt;T within the transcription factor 7-like 2 gene (<em>TCF7L2</em>) is the strongest genetic risk factor associated with T2D to date. In this study, we explored the effects of the <em>TCF7L2</em> rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA<sub>1c</sub>, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of the <em>TCF7L2</em> rs7903146 was performed by the Sequenom MassARRAY<span class="st"><sup>®</sup></span> iPLEX<span class="st"><sup>®</sup></span> platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (<em>p</em> = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9–38.3%, <em>p</em> = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1–44.1%, <em>p</em> = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1–12.0%, <em>p</em> = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in the TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0–25.6%,<em> p</em> = 0.002) compared to the patients with CC genotype. Our results suggest that the <em>TCF7L2</em> rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.</p> Tanja Dujic Tamer Bego Maja Malenica Zelija Velija-Asimi Emma Ahlqvist Leif Groop Ewan R. Pearson Adlija Causevic Sabina Semiz Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 368 374 10.17305/bjbms.2019.4181 Characteristics and prognostic factors of age-stratified high-grade intracranial glioma patients: A population-based analysis <p>We evaluated characteristics and different prognostic factors for survival in age-stratified high-grade glioma in a U.S. cohort. Eligible patients were identified in the Surveillance, Epidemiology, and End Results (SEER) registries and stratified into 3 age groups: 20–39 years old (1,043 patients), 40–59 years old (4,503 patients), and <u>&gt;</u>60 years old (5,045 patients). Overall and cancer-related survival data were obtained. Cox models were built to analyze the outcomes and risk factors. It showed that race was a prognostic factor for survival in patients 40 to 59 years old and in patients ≥60 years old. Partial resection was associated with lower overall survival and cause-specific survival in all age groups (overall survival: 20–39 yr: HR = 6.41; 40–59 yr: HR = 4.84; <u>&gt;</u>60 yr: HR = 5.06; cause-specific survival: 20–39 yr: HR = 5.87; 40–59 yr: HR = 4.01; <u>&gt;</u>60 yr: HR = 3.36). The study highlights that, while some prognostic factors are universal, others are age-dependent. The effectiveness of treatment approaches differs for patients in different age groups. Results of this study may help to develop personalized treatment protocols for glioma patients of different ages.</p> Yun Sun Zhi-Yong Xiong Peng-Fei Yan Liang-Lei Jiang Chuan-Sheng Nie Xuan Wang Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 375 383 10.17305/bjbms.2019.4213 Postoperative pulmonary complications in contemporary cohort of patients with pulmonary hypertension <p>Patients with pulmonary hypertension are at increased risk for postoperative pulmonary complications (PPCs). Herein, we review PPCs in pulmonary hypertension patients undergoing non-cardiac procedures under general anesthesia. The medical records of pulmonary hypertension patients who underwent surgery with general anesthesia between 2010 and 2017 were reviewed for PPCs. In addition we reviewed nursing-documented respiratory depressive episodes in the post-anesthesia care unit to assess the associations between these episodes and later PPCs. There were 20 PPCs among 128 patients who underwent 197 procedures (10.2 per 100 surgeries) [95% CI 6.7–15.2]. Of these, 5 occurred during anesthesia recovery and 15 following anesthesia recovery. Three-quarters of the PPCs occurred within 24 postoperative hours. All the PPCs were severe. The frequency of PPCs was significantly higher in those who experienced respiratory depression during anesthesia recovery vs. in those who did not (5/17, 29% vs. 10/175, 6%; odds ratio 5.15, 95% CI 1.58–16.81, <em>p</em> = 0.007). Increased PPC rates were observed among patients who were current/previous smokers and who routinely use benzodiazepines, and among those undergoing emergent surgery. With treatment, all PPCs resolved. The rate of PPCs in the population of contemporary surgical pulmonary hypertension patients was 10.2%, and three-quarters occurred during first 24 postoperative hours. Patients who had respiratory depression during anesthesia recovery were 5-fold more likely to experience later PPCs.</p> S. Chandralekha Kruthiventi Garvan C. Kane Juraj Sprung Toby N. Weingarten Mary Ellen Warner Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 392 399 10.17305/bjbms.2019.4332 Recombinant deoxyribonucleoside kinase from Drosophila melanogaster can improve gemcitabine based combined gene/chemotherapy for targeting cancer cells <p>A recombinant deoxyribonucleoside kinase from <em>Drosophila melanogaster</em> with a deletion of the last 20 amino acid residues (named <em>Dm</em>dNKΔC20) was hypothesized as a potential therapeutic tool for gene therapy due to its broad substrate specificity and better catalytic efficiency towards nucleosides and nucleoside analogs. This study was designed to evaluate the effect of <em>Dm</em>dNKΔC20 for sensitizing human cancer cell lines to gemcitabine and to further investigate its role in reversal of acquired drug resistance in gemcitabine-resistant cancer cell line. The <em>DmdNKΔC20</em> gene was delivered to three different cancer cell lines, including breast, colon and liver cancer cells, using lipid-mediated transfection reagent. After transfection, gene expression of <em>DmdNKΔC20 </em>was confirmed by quantitative reverse transcription PCR (qRT-PCR) and the combined effect of <em>Dm</em>dNKΔC20 and gemcitabine based cytotoxicity was observed by cell viability assay. We further evolved a gemcitabine-resistant breast cancer cell line (named MCF7-R) through directed evolution in the laboratory, which showed 375-fold more resistance compared with parental MCF7 cells. Upon transfection with <em>DmdNKΔC20</em> gene, MCF7-R cells showed 83-fold higher sensitivity to gemcitabine compared with the control group of MCF7-R cells. Moreover, we observed 79% higher expression of p21 protein in transfected MCF7-R cells, which may indicate induction of apoptosis. Our findings highlight the importance and therapeutic potential of <em>DmdNKΔC20 </em>in combined gene/chemotherapy approach to target a wide range of cancers<em>,</em> particularly gemcitabine-resistant cancers.</p> Mahak Fatima Muhammad Mubashar Iqbal Ahmed Faiza Batool Anjum Riaz Moazzam Ali Birgitte Munch-Petersen Zeeshan Mutahir Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 342 349 10.17305/bjbms.2019.4136 Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer <p>Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in <em>EGFR</em>-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an <em>EGFR</em> exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the <em>FBXW7</em> gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from <em>EGFR</em>-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in <em>EGFR </em>mutation-positive NSCLC.</p> Moulid Hidayat Yoichiro Mitsuishi Fumiyuki Takahashi Ken Tajima Toshifumi Yae Katsumi Miyahara Daisuke Hayakawa Wira Winardi Hiroaki Ihara Yoshika Koinuma Aditya Wirawan Fariz Nurwidya Motoyasu Kato Isao Kobayashi Shinichi Sasaki Kazuya Takamochi Takuo Hayashi Yoshiyuki Suehara Mariko Moriyama Hiroyuki Moriyama Sonoko Habu Kazuhisa Takahashi Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 355 367 10.17305/bjbms.2019.4227 Association of serum chemerin and inflammatory factors with type 2 diabetes macroangiopathy and waist-to-stature ratio <p>Chemerin is an adipocytokine that participates in glycolipid metabolism; however, its association with type 2 diabetes (T2DM) with lower extremity macroangiopathy (T2DM-V) has rarely been reported. This study explored the association of chemerin and inflammatory factors with body fat parameters, glucolipid metabolism, and insulin resistance (IR) in T2DM and T2DM-V. Patients were classified into normal glucose regulation (NGR), T2DM, and T2DM-V groups. Serum chemerin, glucolipid metabolic parameters, transforming growth factor (TGF)-β, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and fasting insulin levels were measured along with HOMA-IR, body mass index (BMI), and waist-to-stature ratio (WSR). Serum chemerin, TGF-β, IL-6, and MCP-1 levels were significantly higher in T2DM groups than in NGR group, and BMI, WSR, fasting plasma glucose (FPG), 2hPG, glycated hemoglobin (HbA1c), triglycerides (TG), and HOMA-IR were higher in T2DM-V subgroups with moderate or severe lower extremity macroangiopathy than in NGR group, simple T2DM group, and T2DM-V subgroup with mild macroangiopathy. FPG, 2hPG, HbA1c, TG, and HOMA-IR were higher in T2DM-V subgroup with severe macroangiopathy than in T2DM-V with moderate macroangiopathy (<em>p</em> &lt; 0.05). In all groups, serum chemerin levels were positively correlated with BMI, WSR, FPG, 2hPG, HbA1c, fasting insulin, aspartate transaminase, TG, TGF-β, IL-6, and HOMA-IR (<em>p </em>&lt; 0.05) and negatively correlated with high-density lipoprotein cholesterol [HDL-c] (<em>p</em> &lt; 0.05). Multiple stepwise regression analysis showed that 2hPG, HbA1c, and HDL-c were independent predictors of serum chemerin levels (β = -0.768, -0.122, -0.115, and 3.261, respectively; <em>p</em> &lt; 0.01). Collectively, chemerin, factors associated with obesity, pathological and physiological changes in glucolipid metabolism, and inflammatory factors may promote the development of T2DM macroangiopathy.</p> Mengxue Yang Xue Zhou Jie Xu Bo Yang Jie Yu Qihai Gong Xuan Zhang Xiaohua Sun Qun Zhang Jinying Xia Jianhui Li Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 328 335 10.17305/bjbms.2019.4002 Adjunct corticosteroid treatment in patients with pneumonia: A precision medicine approach <p>Pneumonia is the leading infectious cause of death worldwide. While inflammation is critically important in host response to microbial invasion, exaggerated inflammation can damage the lungs, contributing to respiratory failure and mortality. Corticosteroids are effective in reducing inflammation and can also cause immune suppression. Presently, clinicians are unable to reliably distinguish between exaggerated and appropriate immune response and thus cannot rapidly identify patients most likely to benefit from adjunctive corticosteroids. In this review, we propose a biomarker-guided, precision medicine approach to corticosteroid treatment, aimed to give these medications at appropriate dose and time and only to patients who have exaggerated inflammation.</p> Srdjan Gavrilovic Ana Andrijevic Aida Mujakovic Yewande Odeyemi Belma Paralija Ognjen Gajic Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 315 320 10.17305/bjbms.2019.3977 Optogenetics: Therapeutic spark in neuropathic pain <p>Optogenetics is an emerging field, which uses light and molecular genetics to manipulate the activity of live cells by expressing light-sensitive proteins. With the discovery of bacteriorhodopsin, a light-sensitive bacterial protein, in 1971 Oesterhelt and Stoeckenius laid the pavement of optogenetics. However, the cross-integration of different disciplines is a little more than a decade old. The toolbox contains fluorescent sensors and optogenetic actuators that enable visualization of signaling events and manipulation of cellular activities, respectively. Neuropathic pain is pain caused either by damage or disease that affects the somatosensory system. The exact mechanism for neuropathic pain is not known, however proposed mechanisms include immune reactions, ion channel expressions, and inflammation. Current regimen for the disease provides about 50% relief for only 40–60% of patients. Recent <em>in vivo</em> and <em>in vitro</em> studies demonstrate the potential therapeutic applications of optogenetics by manipulating the activity of neurons. This review summarizes the basic concept, therapeutic applications for neuropathy, and potential of optogenetics to reach from bench to bedside in the near future.</p> Kang Liu Long Wang Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 321 327 10.17305/bjbms.2019.4114 Clear cell urothelial carcinoma of the urinary bladder - a rare pathological entity. A case report and a systematic review of the literature <p>The most common histological type of urinary bladder cancer is urothelial carcinoma (UC). In contrast, the clear cell variant of urothelial carcinoma (CCUC) is quite a rare neoplasm. In this study, we report a case of an 81-year-old male, presenting with gross hematuria and acute urinary retention, which was subsequently diagnosed with CCUC at our pathology department. Furthermore, we provide a short systematic review of the literature (PubMed, Scopus, and Science Citation Index) for this rare histopathological entity and a brief discussion about its morphological and immunohistochemical (IHC) characteristics.</p> Ioana Mihai Sorina Taban Alin Cumpanas Emilian Gh. Olteanu Mihaela Iacob Alis Dema Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 400 403 10.17305/bjbms.2019.4182 Making sense of subclinical cardiac alterations in patients with diabetes <p>Patients with diabetes are prone to develop a distinct primary myocardial condition, diabetic cardiomyopathy, placing them at an increased risk for heart failure [1-3]. This occurs independently of hypertension, coronary artery disease, and other established causes of heart failure. Pertinent findings include increased mass, concentric changes, and diastolic dysfunction of the left ventricle [4,5]. Such adverse remodeling is common among patients with diabetes and appears to be strongly associated with its duration, suggesting a role for persistent metabolic stress [6-8]. However, which exact components of the diabetic syndrome determine these cardiac alterations is not clear. Moreover, most studies have investigated patients with type 2 diabetes, and it is uncertain whether patients with type 1 diabetes experience similar myocardial changes.</p> <p><em>Continue reading the full text in the <strong><a href="">PDF</a></strong> version.</em></p> Manan Pareek Michael Hecht Olsen Copyright (c) 2019 Association of Basic Medical Sciences 2019-11-08 2019-11-08 19 4 312 314 10.17305/bjbms.2019.4349 The efficacy and safety of statin in combination with ezetimibe compared with double-dose statin in patients with high cardiovascular risk: A meta-analysis <p>Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk. Fourteen studies involving 3,105 participants were included in the final analysis; 1,558 (50.18%) participants received ezetimibe and statin combination therapy and 1,547 (49.82%) received double-dose statin monotherapy. Eight studies reported the percentages of changes in several lipid parameters from baseline to endpoint in both groups. Lipid parameters changed more significantly in patients co-administered with ezetimibe and statin (low-density lipoprotein cholesterol [LDL-C]: MD = -9.39, 95% CI -13.36 to -5.42; non-high-density lipoprotein cholesterol [non-HDL-C]: MD = -10.36, 95% CI -14.23 to -6.50; total cholesterol [TC]: MD = -8.11, 95% CI -10.95 to -5.26; and triglyceride [TG]: MD = -5.96, 95% CI -9.12 to -2.80), with moderate to high heterogeneity among the studies. Two out of fourteen studies investigated several different statins. Our subgroup analysis showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy significantly decreased LDL-C, non-HDL-C, TC, and TG levels by 14.16%, 14.01%, 11.06%, and 5.96%, respectively (<em>p </em>&lt; 0.001). No significant difference was found in the incidence of laboratory-related adverse events (AEs) between statin combination therapy and monotherapy. Overall, ezetimibe and statin combination therapy significantly decreased LDL-C, non-HDL-C, and TC levels in patients with high cardiovascular risk, among which ezetimibe combined with atorvastatin had the best therapeutic effect. Compared with ezetimibe and statin combination therapy, double-dose statin monotherapy did not increase the risk of AEs.</p> Yunyun Zhu Haochang Hu Jun Yang Qi Yao Hongyu Xu Yushan Yu Ting Liu Shaoyi Lin Copyright (c) 2019 Bosnian Journal of Basic Medical Sciences 2019-10-31 2019-10-31 19 4 10.17305/bjbms.2019.4437 Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy <p>Diabetic nephropathy (DN) is the most common complication of diabetes and is prone to kidney failure. Dihydromyricetin (DHM) has been reported to have a variety of pharmacological activities. This study aims to explore the effect of DHM on DN and the underlying molecular mechanism. An <em>in vivo</em> DN rat model was established. The degree of renal interstitial fibrosis (RIF) was detected by hematoxylin-eosin (HE) staining, Masson's trichrome staining, and immunohistochemistry (IHC). <em>In vitro</em>, NRK-52E cells were divided into four groups: normal glucose (NG), high glucose (HG), HG+DHM, and HG+rapamycin (autophagy inhibitor). The levels of autophagy- and fibrosis-related proteins were analyzed by western blotting. The expression of miR-155-5p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and their relationship were assessed by quantitative reverse transcription (qRT)-PCR and dual luciferase&nbsp;reporter gene assay. Our results showed that RIF was increased in DN rat model and in HG-induced NRK-52E cells. DHM treatment attenuated the increased RIF and also increased autophagy. MiR-155-5p expression was increased, while PTEN expression was decreased in DN rat and cell model, and DHM reversed both effects. Dual luciferase&nbsp;assay showed that PTEN was the target gene of miR-155-5p. DHM inhibited HG-induced fibrosis and promoted autophagy by inhibiting miR-155-5p expression in NRK-52E cells. In addition, DHM promoted autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, DHM promotes autophagy and attenuates RIF by regulating the miR-155-5p/PTEN signaling and PI3K/AKT/mTOR signaling pathway in DN.</p> Liming Guo Kuibi Tan Qun Luo Xu Bai Copyright (c) 2019 Bosnian Journal of Basic Medical Sciences 2019-10-31 2019-10-31 19 4 10.17305/bjbms.2019.4410 The effects of mutational profiles on phenotypic presentation of myeloproliferative neoplasm subtypes in Bosnia: 18 year follow-up <p>The identification of mutually exclusive somatic mutations shared among myeloproliferative neoplasm (MPN) subtypes&nbsp;has provided a powerful tool for studying disease evolution. Clinical features, gene mutations, and survival over 18 years were analyzed in MPN patients. One hundred thirty-eight MPN patients were subcategorized according to MPN subtypes: essential thrombocythemia (ET, n = 41), polycythemia vera (PV, n = 56), primary myelofibrosis (PMF, n = 10), and MPN unclassified (MPN-U, n = 31). Patient characteristics included clinical parameters, overall survival, and mutational status of the <em>JAK2</em>, <em>CALR</em>, and <em>MPL</em> genes. We compared hematologic and clinical features of <em>JAK2</em><sup>V617F</sup>-ET vs.&nbsp;<em>CALR</em>-mutated ET vs. <em>JAK2</em><sup>V617F</sup>-PV patients. <em>JAK2</em><sup>V617F</sup>-patients had higher values of erythrocytes, hemoglobin, and hematocrit compared to <em>CALR</em>-mutated patients (<em>p</em> &lt; 0.05). The mutant allele burden in <em>JAK2</em><sup>V617F</sup>-PV and <em>JAK2</em><sup>V617F</sup>-ET patients directly correlated with erythrocyte, hemoglobin, and hematocrit values, but it inversely correlated with platelet count. Thus, mutant allele burden was an indicator of the clinical phenotype in <em>JAK2</em><sup>V617F</sup>-MPN patients. OS was not affected by the mutational status. In general, mutated <em>JAK2</em>, <em>CALR</em>, and <em>MPL</em> genes left specific hematological signatures.</p> Amina Kurtovic-Kozaric Erna Islamagic Hana Komic Nurija Bilalovic Izet Eminovic Adnan Burekovic Amna Uzunovic Sabira Kurtovic Copyright (c) 2019 Bosnian Journal of Basic Medical Sciences 2019-10-30 2019-10-30 19 4 10.17305/bjbms.2019.4391 Inhibitory effect of microRNA-608 on lung cancer cell proliferation, migration, and invasion by targeting BRD4 through the JAK2/STAT3 pathway <p>Lung cancer is the leading cause of cancer-related mortality around the world. This malignancy has a 5-year survival rate of 21%, because most of the patients are diagnosed in the middle or late stage of the disease when local metastasis and tumor invasion have already progressed. Therefore, the investigation of the pathogenesis of lung cancer is an issue of crucial importance. MicroRNAs (miRNAs) seem to be involved in the evolution and development of lung cancer. MicroRNA-608 is likely to be downregulated in lung cancer tissues. Regarding this, the current study involved the determination of the fundamental mechanism of microRNA-608 in the development of lung cancer. Based on the results of quantitative&nbsp;reverse transcription&nbsp;polymerase chain reaction (RT-qPCR), the expression level of microRNA-608 was downregulated in 40 lung cancer tissues, compared to that in the adjacent normal tissues. The results of dual-luciferase reporter assay revealed that bromodomain-containing protein 4 (<em>BRD4</em>) was the direct target of microRNA-608. Accordingly, the lung cancer tissues had an elevated expression level of <em>BRD4,</em> in contrast to the adjacent normal tissues. The results of Cell Counting Kit 8 assay demonstrated that the high expression of microRNA-608 notably restrained lung cancer cell proliferation. The scratch wound and transwell assays showed that the upregulation of microRNA-608 suppressed the migration and invasion of lung cancer cells. Finally, the western blot assay showed that in the microRNA-608 mimics group, the expression levels of BRD4, p-JAK2, p-STATA3, CD44, and MMP9 were significantly decreased, compared with those in the negative control miRNA mimics group. Our results indicate that high expression of microRNA-608 inhibits the proliferation, migration, and invasion of lung cancer cells by targeting <em>BRD4</em> via the JAK2/STAT3 pathway.</p> Weigang Xu Dapeng Sun Yanqin Wang Xinlin Zheng Yan Li Yu Xia Ya'nan Teng Copyright (c) 2019 Bosnian Journal of Basic Medical Sciences 2019-10-17 2019-10-17 19 4 10.17305/bjbms.2019.4216 In vitro toxicity model: Upgrades to bridge the gap between preclinical and clinical research <p>The Centers for Disease Control and Prevention (CDC) provides extensive data that indicate our need for drugs to maintain human population health. Despite the substantial availability of drugs on the market, many patients lack specific drugs. New drugs are required to tackle this issue. Moreover, we need more reliable models for testing drug toxicity, as too many drug approval failures occur with the current models. This article briefly describes various approaches of the currently used models for toxicity screening, to justify the selection of <em>in vitro</em> cell-based models. Cell-based toxicity models have the best potential to reliably predict drug toxicity in humans, as they are developed using the cells of the target organism. However, currently, a large gap exists between <em>in vitro</em> cell-based approach to toxicity testing and the clinical approach, which may be contributing to drug approval failures. We propose improvements to<em> in vitro</em> cell-based toxicity models, which is often an insight approach, to better match this approach with the clinical homeostatic approach. This should enable a more accurate comparison of data between the preclinical as well as clinical models and provide a more comprehensive understanding of human physiology and biological effects of drugs.</p> Eneko Madorran Andraž Stožer Sebastjan Bevc Uroš Maver Copyright (c) 2019 Bosnian Journal of Basic Medical Sciences 2019-10-16 2019-10-16 19 4 10.17305/bjbms.2019.4378 Inflammatory cells in perivascular adipose tissue and the integrity of the tunica media in atherosclerotic coronary arteries <p>Obstructive coronary artery disease (CAD) is characterized by inflammation within the atherosclerotic coronary arteries. Infiltration of inflammatory cells into muscular media can lead to remodeling and weakening of the arterial wall. We examined the relationship between inflammatory infiltration in perivascular adipose tissue (PVAT), state of the external elastic membrane, and the intensity of inflammatory infiltration in the tunica media of coronary arteries obtained by endarterectomy from symptomatic patients with diffuse CAD. We analyzed endarterectomy sequesters from 22 coronary arteries that contained the intima, media, a part of the adventitia, and PVAT in at least one part of the sequester. The coronary arteries were divided into two groups according to the presence or absence of inflammatory infiltration in PVAT. Staining with hematoxylin-eosin and by the Movat's method showed atherosclerotic changes in the intima and media. Immunohistochemistry (anti-leukocyte common antigen [LCA] antibody) was used for the detection of leukocytes. We found a significant positive correlation between inflammatory infiltration in PVAT and preservation of the external elastic membrane of coronary arteries. Furthermore, we found a significant negative correlation between inflammatory infiltration in PVAT and the intensity of inflammatory infiltration in the media. It seems that the integrity of the external elastic membrane and the proinflammatory properties of PVAT restrain inflammatory cells within PVAT. Both effects may prevent the migration of inflammatory cells into the media and delay the development of CAD.</p> Ruda Zorc-Pleskovič Marjeta Zorc Dušan Šuput Aleksandra Milutinović Copyright (c) 2019 Bosnian Journal of Basic Medical Sciences 2019-09-27 2019-09-27 19 4 10.17305/bjbms.2019.4409