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> en-US (Faruk Skenderi) (Armin Sehovic) Fri, 08 Nov 2019 23:37:03 +0100 OJS 60 Galectin-1 reduces the severity of ulcerative colitis induced by dextran sulfate sodium via suppressing inflammatory and oxidative mediators <p>Ulcerative colitis is an inflammatory bowel disease and many people suffers from this disease across the word. Dextran sulfate sodium (DSS) is a synthetic sulfated polysaccharide that is used to produce ulcerative colitis in rodents. Galectin-1 is a β-galactoside binding animal lectin which plays key roles in many biological events. In this study, we investigated the role of galectin-1 on colon morphology, cell proliferation, oxidative stress, anti-oxidant system, inflammatory and anti-inflammatory mediators in the model of experimental ulcerative colitis induced by DSS in mice. C57BL/6&nbsp; mice were fed orally 3% DSS in their drinking water for 5 days for acute colitis induction. Animals were injected with 1 mg/kg recombinant human galectin-1 for 7 consecutive days. Oral DSS application resulted in colitis injury by causing histopathological changes; an increase in disease activity index (DAI), lipid peroxidation (MDA), myeloperoxidase (MPO) and TNF-α levels; a decrease in body weight, colon length, cell proliferation index, catalase (CAT), glutahione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities, gluathione (GSH) and IL-10 levels. However, treatment with galectin-1 prevented DSS-induced colitis injury through the reduction of DAI, MDA, MPO and TNF-α levels, and the increase of body weight, colon length, cell proliferation, antioxidant enzymes activities, GSH and IL-10 levels. As a result, this study showed that galectin-1 has proliferative, anti-oxidant, anti-inflammatory, and cytoprotective effects against DSS-induced colitis in mice. In addition, galectin-1 reduces the severity of ulcerative colitis via suppressing inflammatory and oxidative mediators.</p> Pelin Arda-Pirincci, Guliz Aykol-Celik Copyright (c) 2020 Pelin Arda-Pirincci, Guliz Aykol-Celik Sun, 26 Jan 2020 13:07:44 +0100 Overexpression of microRNA-129-5p in glioblastoma inhibits cell proliferation, migration, and colony-forming ability by targeting ZFP36L1 <p>Glioblastoma multiforme (GBM) is a highly invasive cancer with a high recurrence rate. The prognosis of GBM patients remains poor, even after standard surgical resection combined with chemoradiotherapy. Thus, there is an urgent need for new therapeutic targets in GBM. In recent years, microRNAs have received considerable attention due to their important role in tumor development and progression. In this study, we investigated the role of miR-129-5p and miR-129-5p/ZFP36L1 axis in GBM tumorigenesis. Analysis of GSE103228 microarray data from the GEO database showed that miR-129-5p was significantly downregulated in GBM vs. normal brain tissues. Quantitative reverse transcription PCR analysis of miR-129-5p expression in seven GBM cell lines (LN229, A172, U87, T98G, U251, H4, and LN118) vs. normal human astrocytes (NHA) showed miR-129-5p was significantly downregulated in GBM cells. Overexpression of miR-129-5p in LN229 and A172 cells significantly suppressed cell proliferation, migration, invasion, and colony-forming ability. Target Scan analysis identified <em>ZFP36L1</em> as the target of miR-129-5p. UALCAN dataset analysis found that <em>ZFP36L1</em> was significantly upregulated in GBM vs. normal brain tissues, and high <em>ZFP36L1</em> expression was positively associated with the poor survival of GBM patients. Western blot analysis demonstrated that ZFP36L1 was significantly upregulated in seven GBM cell lines vs. NHA. Overexpression of miR-129-5p in LN229 and A172 cells significantly inhibited ZFP36L1 mRNA and protein expression, while overexpression of ZFP36L1 in LN229 and A172 cells reversed miR-129-5p-mediated inhibition on GBM tumorigenesis. Our results revealed an important role of miR-129-5p in the negative regulation of <em>ZFP36L1</em> expression in GBM, suggesting new candidates for targeted therapy in GBM patients.</p> Xu Guo, Haozhe Piao, Ye Zhang, Peixin Sun, Bing Yao Copyright (c) 2019 Xu Guo, Haozhe Piao, Ye Zhang, Peixin Sun, Bing Yao Sat, 28 Dec 2019 01:12:55 +0100 Concordance of PD-L1 expression and CD8+ TIL intensity between NSCLC and synchronous brain metastases <p>Programmed death-ligand 1 (PD-L1) is suggested to be a predictive biomarker in non-small-cell lung carcinoma (NSCLC). However, the differential expression of PD-L1 in primary lung tumor vs. synchronous metastases, especially brain metastasis (BM), remains unclear. This study assessed the concordance of PD-L1 expression on tumor cells and tumor infiltrating lymphocytes (TILs) and CD8<sup>+</sup> TIL intensity between primary lung tumors and synchronous BMs from 24 NSCLC patients. PD-L1, CD3, and CD8 positivity was determined by immunohistochemistry (IHC). PD-L1 scoring was based on the proportion of tumor cells with membranous expression of PD-L1 and the cutoff values &lt;1%, 1–49%, and ≥50%. CD3 and CD8 positivity in TILs was evaluated semi-quantitatively and the proportion of CD3<sup>+</sup>/CD8<sup>+</sup> TILs was determined. PD-L1 expression on tumor cells and TILs was evaluated in relation to CD3<sup>+</sup>/CD8<sup>+</sup> TIL proportions and the intensity of CD8<sup>+</sup> TILs between the paired primary lung and BM tissues. In the primary lung tumors, PD-L1 positivity was observed in 25%, 37.5%, and 37.5% cases for the cutoff values &lt;1%, 1–49%, and ≥50%, respectively. PD-L1 expression on tumor cells was strongly correlated between the paired primary lung and BM tissues, in all cutoff groups. However, PD-L1 expression on TILs and the proportion of CD3<sup>+</sup>/CD8<sup>+</sup> TILs were not strongly correlated in all three groups between the paired primary lung tumors and BMs. The intensity of CD8<sup>+</sup> TILs was concordant in only 54.16% of the paired primary lung tumors and BMs. This study showed a high concordance of PD-L1 expression in neoplastic cells between primary NSCLC and synchronous BMs.</p> Sebnem Batur, Onur Dulger, Sermin Durak, Perran Fulden Yumuk, Hale Basak Caglar, Emine Bozkurtlar, Suheyla Bozkurt, Ebru Tastekin, Irfan Cicin, Rengin Ahiskali, Rashad Rzazade, Asli Cakir, Buge Oz Copyright (c) 2019 Sebnem Batur, Onur Dulger, Buge Oz Sat, 28 Dec 2019 01:01:13 +0100 Androgen effect on connexin expression in the mammalian female reproductive system: a systematic review <p>The functions of androgen and connexin in the mammalian female reproductive system are suggested to be related. Previous research has shown that androgen affects connexin expression and localization in the female reproductive system, altering its function. However, no definitive conclusion on their cause-effect relationship has been drawn yet. In addition, a high prevalence of women with polycystic ovary syndrome (PCOS), who are characterized by elevated androgen levels and failure of ovulation, has prompted the studies on the relationship between androgen and connexin in the ovaries. This systematic review aims to investigate the effect of androgen on connexin expression in the mammalian female reproductive system. The literature search was conducted using the MEDLINE, EBSCOhost, and Scopus databases and the following keywords: “androgen” or “testosterone” or “androgen blocker” or “anti-androgen” or “androstenedione” or “dehydroepiandrosterone” or “flutamide AND connexin” or “gap junction” or “cell junction”. We only considered <em>in vitro</em> and <em>in vivo</em> studies that involved treatment by androgen or androgen receptor blockers and measured connexin expression as one of the parameters. Our review showed that the exposure to androgen or androgen blocker affects connexin expression but not its localization in the mammalian ovary. However, it is not clear whether androgen downregulates or upregulates connexin expression. Additionally, it is inconclusive whether the upregulation of connexin positively contributes to the ovarian function.</p> Datu Agasi Mohd Kamal, Siti Fatimah Ibrahim, Mohd Helmy Mokhtar Copyright (c) 2019 Association of Basic Medical Sciences Mon, 09 Dec 2019 13:10:29 +0100 Serum patterns of mir-23a and mir-181b in irritable bowel syndrome and colorectal cancer - A pilot study <p>Emerging evidence demonstrates that microRNAs (miRNAs) could serve as reliable biomarkers of inflammation and oncogenesis. The aim of this study was to determine whether miR-23a and miR-181b were suitable as biomarkers of irritable bowel syndrome (IBS) and colorectal cancer (CRC). Forty patients with IBS (29 females, 11 males), 33 with CRC (14 females, 19 males), and 33 healthy controls (17 females, 16 males) were prospectively included. Serum levels of miRNAs were evaluated by quantitative real-time PCR. The serum levels of miR-23a and miR-181b were significantly higher in the IBS group (<em>p</em>&nbsp;=&nbsp;0.0009 and 0.004, respectively) and CRC group (<em>p</em>&nbsp;=&nbsp;0.002 and 0.029, respectively) than in the control group. Serum levels of miR-23a and miR-181b were upregulated in CRC vs. IBS, but the differences did not reach statistical significance (<em>p</em>&nbsp;=&nbsp;0.169 and 0.179, respectively). The miRNet and Reactome databases identified phosphatase and tensin homolog as a major common pathway, indicating inflammation as a central hallmark. Although miRNAs could serve as reliable biomarkers in clinical practice, future studies are needed to establish appropriate cut-off limits.</p> Alexandra Chira, Mihai-Stefan Muresan, Cornelia Braicu, Liviuta Budisan, Lajos Raduly, Romeo Ioan Chira, Dan Lucian Dumitrascu, Ioana Berindan-Neagoe Copyright (c) 2019 Association of Basic Medical Sciences Sat, 07 Dec 2019 00:28:50 +0100 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 a phosphate buffer solution. 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 the vancomycin revealed the 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 i. p. 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.</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 Fri, 29 Nov 2019 14:55:27 +0100 Expression of the anti-Mullerian hormone, kisspeptin 1, and kisspeptin 1 receptor in polycystic ovary syndrome and controlled ovarian stimulation rat models <p>Polycystic ovary syndrome represents a significant cause of female infertility. The aim of this study was to investigate the expression of anti-Mul­lerian hormone (AMH), kisspeptin 1 (KISS-1), and kisspeptin 1 receptor (KISS1r) in rat models of polycystic ovary syndrome (PCOS) and controlled ovarian stimulation (COS). For this purpose, 28 rats were assigned into four groups. Estrus and Diestrus groups consisted of rats in estrus and diestrus phases, respectively, while COS and PCOS groups consisted of rats with induced COS and PCOS, respectively. The serum AMH, KISS-1, and estradiol levels, and ovarian KISS1r levels were analyzed by enzyme-linked immunosorbent assay. Furthermore, histopathological analysis of the ovary tissue was done and ovarian KISS-1 expression was determined by immunohistochemical assay. The results revealed that ovarian KISS1r levels were higher in the Estrus (1271.43±51.98 pg/mL) and COS (1191.43±85.67 pg/mL) groups, compared to Diestrus and PCOS groups. The highest level of AMH was found in the Estrus group (16.91±2.12 ng/mL). The results indicate that AMH had no effect on the development of COS and PCOS, while KISS-1 was found to affect the development of COS in rats.</p> Ali Risvanli, Halis Ocal, Necati Timurkaan, Pinar Ipek, Ibrahim Seker, Burak Karabulut Copyright (c) 2019 BJBMS Fri, 29 Nov 2019 00:00:00 +0100 Percutaneous coronary intervention assisted by invasive mechanical ventilation and intra-aortic balloon pump for acute myocardial infarction with cardiogenic shock: Retrospective cohort study and meta-analysis <p>The aim of this study was to compare the mortality outcome in patients with acute myocardial infarction and cardiogenic shock who were treated with percutaneous coronary intervention (PCI) assisted by intra-aortic balloon pump (IABP) + invasive mechanical ventilation (IMV) with historical controls. From January 1, 2016 to June 1, 2017, 60 patients were retrospectively enrolled at Tianjin Chest Hospital. Out of these, 88.3% of patients achieved thrombolysis in myocardial infarction flow 3 after PCI. The all-cause mortality rate in-hospital and at 1 year was 25% (95% CI: 0.14–0.36) and 33.9% (0.22–0.46), respectively. A systematic review followed by meta-analysis was performed with 4 historical studies of patients treated by PCI + IMV with partial IABP, which found an in-hospital mortality rate of 66.0% (95% CI: 0.62–0.71). Recently, a meta-analysis of patients receiving PCI + IABP with partial IMV showed that the 1 year mortality rate was 52.2% (95% CI: 0.47–0.58). In Cox regression analysis of patient data from the current study, lactic acid level ≥4.5 mmol/L, hyperuricemia, and thrombolysis in myocardial infarction flow &lt;3 were independent predictors of death at 1 year. All-cause mortality, in-hospital and at 1 year, in patients with acute myocardial infarction and cardiogenic shock treated with PCI + IABP and IMV was lower than in those treated with PCI + partial IABP or IMV. Larger, longer-term direct comparisons are warranted.</p> Yin Liu, Chang-Ping Li, Peng-Ju Lu, Xu-Ying Wang, Jian-Yong Xiao, Ming-Dong Gao, Ji-Xiang Wang, Xiao-Wei Li, Nan Zhang, Chun-Jie Li, Jun Ma, Jing Gao Copyright (c) 2019 BJBMS Wed, 27 Nov 2019 15:40:27 +0100 Human brucellosis in pregnancy – an overview <p>Human brucellosis during pregnancy is characterized by significantly less pronounced adverse obstetric outcomes than in animals, but with remarkably more adverse obstetric outcomes when compared to healthy pregnant women. Seroprevalence of brucellosis in pregnancy and cumulative incidence of brucellosis cases per 1000 delivered obstetrical discharges in endemic regions were reported to be 1.5–12.2% and 0.42–3.3, respectively. Depending on the region, frequency of pregnant women in the cohorts of patients with brucellosis was from 1.5% to 16.9%. The most common and the most dramatic unfavorable outcomes during brucellosis in pregnancy are the obstetric ones, manifested as abortions (2.5–54.5%), intrauterine fetal death (0–20.6%) or preterm deliveries (1.2–28.6%), depending on the stage of pregnancy. Other unfavorable outcomes due to brucellosis are addressed to infant (congenital/neonatal brucellosis, low birth weight, development delay or even death), the clinical course of disease in mother and delivery team exposure. When diagnosed in pregnant women, brucellosis should be treated as soon as possible. Early administration of adequate therapy significantly reduces the frequency of adverse outcomes. Rifampicin in combination with trimethoprim-sulfamethoxazole for 6 weeks is the most commonly used and recommended regimen, although monotherapies with each of these two drugs are also widely used while waiting for the results from prospective randomized therapeutic trials. As no effective human vaccine exists, screening of pregnant women and education of all women of childbearing age about brucellosis should be compulsory preventive measures in endemic regions.</p> Mile Bosilkovski, Jurica Arapović, Fariba Keramat Copyright (c) 2019 BJBMS Wed, 27 Nov 2019 15:02:07 +0100 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 Fri, 15 Nov 2019 13:06:41 +0100 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 Thu, 14 Nov 2019 10:52:05 +0100 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 Wed, 13 Nov 2019 08:56:51 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100 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 Fri, 08 Nov 2019 00:00:00 +0100