Bosnian Journal of Basic Medical Sciences 2021-04-19T18:49:03+02:00 Faruk Skenderi Open Journal Systems <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> Analysis of the diagnostic and prognostic value of miR-9-5p in carotid artery stenosis 2021-04-19T18:49:03+02:00 Hongxin Liu Juan Zhou Wei Jiang Feng Wang <p><span data-preserver-spaces="true">More and more evidence shows that microRNAs (miRNAs) play an important role in the diagnosis and prognosis of human diseases. In this study, we investigated the diagnostic value of miR-9-5p for asymptomatic carotid artery stenosis (CAS) and its predictive value for future cerebrovascular events within 5 years. A total of 88 asymptomatic CAS patients and 86 healthy individuals were recruited. The expression level of serum miR-9-5p was determined by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The diagnostic value of miR-9-5p in CAS was assessed by a receiving operator characteristic (ROC) curve. The predictive value of miR-9-5p for the occurrence of cerebrovascular events was evaluated by the Kaplan-Meier method. The serum level of miR-9-5p was significantly decreased in asymptomatic CAS patients. ROC curve had an AUC value of 0.910, with the sensitivity and specificity of 80.7% and 87.2% at the cut-off value of 0.72, respectively. A total of 25 patients had cerebrovascular events during the 5-year follow-up, including 3 strokes and 22 transient ischemic attacks</span><strong><span data-preserver-spaces="true">&nbsp;</span></strong><span data-preserver-spaces="true">(TIAs). Kaplan-Meier survival analysis revealed that the low expression level of miR-9-5p was an independent factor closely related to the occurrence of cerebrovascular events. Serum miR-9-5p could be used as a new biomarker for the diagnosis of CAS, and the low expression of miR-9-5p is associated with poor prognosis.</span></p> 2021-04-19T18:47:17+02:00 Copyright (c) 2021 Hongxin Liu, Juan Zhou, Wei Jiang, Feng Wang The preoperative HALP score (hemoglobin, albumin, lymphocyte and platelet) is a useful predictor in patients with resectable esophageal squamous cell carcinoma 2021-04-19T17:13:12+02:00 Ji-Feng Feng Liang Wang Xun Yang <p>The<strong>&nbsp;</strong>hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been confirmed as a prognostic factor in several types of cancers. The current study aimed to assess the prognostic value of preoperative HALP score, an inflammatory and nutritional based score, in predicting cancer-specific survival (CSS) in resectable patients undergoing curative resection for esophageal squamous cell carcinoma (ESCC).<strong>&nbsp;</strong>The clinical data of 355 consecutive patients with ESCC who underwent curative resection were retrospectively conducted and analyzed. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for preoperative HALP. The areas under the curve (AUC) for preoperative HALP and other variables were calculated and compared. Cox regression analyses and Kaplan-Meier methods were used to identify the factors associated with CSS. According to the ROC curve, the optimal cut-off value for preoperative HALP was 31.8. The 5-year CSS for preoperative HALP low (≤31.8) and high (&gt;31.8) was 15.1% and 47.5%, respectively (<em>p</em>&lt;0.001). Preoperative HALP had reliable abilities to predict CSS in resectable ESCC patients in any stage or gender, according to the subgroup analysis based on the patients' cancer stage and gender. Multivariate analyses confirmed that preoperative HALP was an independent prognostic score regarding CSS in patients with resectable ESCC (<em>p</em>&lt;0.001). This study confirmed that the preoperative HALP score could be regarded as a potential independent prognostic factor for CSS in patients with resectable ESCC.</p> 2021-04-15T15:50:38+02:00 Copyright (c) 2021 Ji-Feng Feng, Liang Wang, Xun Yang Integrated profiling identifies ITGB3BP as prognostic biomarker for hepatocellular carcinoma 2021-04-16T13:23:15+02:00 Qiuli Liang Chao Tan Feifei Xiao Fuqiang Yin Meiliang Liu Lei Lei Liuyu Wu Yu Yang Hui Juan Jennifer Tan Shun Liu Xiaoyun Zeng <p>Hepatocellular carcinoma (HCC) is a highly malignant tumor. In this study, we sought to identify a novel biomarker for HCC by analyzing transcriptome and clinical data. The R software was used to analyze the differentially expressed genes (DEGs) in the datasets GSE74656 and GSE84598 downloaded from the Gene Expression Omnibus database, followed by a functional annotation. A total of 138 shared DEGs were screened from two datasets. They were mainly enriched in the “Metabolic pathways” pathway (Padj = 8.21E-08) and involved in the carboxylic acid metabolic process (Padj = 0.0004). The top 10 hub genes were found by protein-protein interaction analysis and were upregulated in HCC tissues compared to normal tissues in The Cancer Genome Atlas database. Survival analysis distinguished 8 hub genes CENPE, SPDL1, Hyaluronan-mediated motility receptor, Rac GTPase activating protein 1, Thyroid hormone receptor interactor 13, cytoskeleton-associated protein (CKAP) 2, CKAP5, and Integrin subunit beta 3 binding protein (ITGB3BP) were considered as prognostic hub genes. Multivariate cox regression analysis indicated that all the prognostic hub genes were independent prognostic factors for HCC. Furthermore, the receiver operating characteristic curve revealed that the 8-hub genes model had better prediction performance for overall survival compared to the T stage (<em>p </em>= 0.008) and significantly improved the prediction value of the T stage (<em>p </em>= 0.002). The Human Protein Atlas showed that the protein expression of ITGB3BP was upregulated in HCC, so the expression of ITGB3BP was further verified in our cohort. The results showed that ITGB3BP was upregulated in HCC tissues and was significantly associated with lymph node metastasis.</p> 2021-04-12T10:17:27+02:00 Copyright (c) 2021 Qiuli Liang, Chao Tan, Feifei Xiao, Fuqiang Yin, Meiliang Liu, Lei Lei, Liuyu Wu, Yu Yang, Hui Juan Jennifer Tan, Shun Liu, Xiaoyun Zeng Chronic mechanical irritation and oral squamous cell carcinoma: A systematic review and meta-analysis 2021-04-19T14:03:03+02:00 Archana A. Gupta Supriya Kheur Saranya Varadarajan Sameena Parveen Harisha Dewan Yaser Ali Alhazmi Thirumal A. Raj Luca Testaralli Shankargouda Patil <p>The objective of the present article was to qualitatively and quantitatively review the association between chronic mechanical irritation and oral squamous cell carcinoma (OSCC). PubMed, SCOPUS, and Web of Science databases were searched using the keyword combinations “chronic trauma and oral squamous cell carcinoma; chronic irritation and oral squamous cell carcinoma; chronic irritation and oral cancer; and chronic trauma and oral cancer.” Duplicates and irrelevant articles were excluded after the title and abstract screening. The full texts of the remaining articles were assessed using selection criteria. A total of 375 (PubMed-126; SCOPUS-152; WOS-97) articles were screened, and 343 duplicates and irrelevant articles were excluded from the study. Only 9 of the remaining 32 articles met the selection criteria and were included in the qualitative analysis. Buccal mucosa and tongue, being highly prone to chronic irritation through the dental prosthesis, were the common sites for OSCC. Edentulous subjects with ill-fitting dentures were at a high risk of developing chronic irritation associated-OSCC. According to the Joanna Briggs Institute of risk assessment, eight of the nine included studies had a low risk of bias. The quantitative analysis showed a significant association (<em>p </em>&lt; 0.00001) between the chronic oral mucosal irritation and OSCC with an overall risk ratio of 2.56 at a confidence interval of 1.96-3.35. Chronic oral mucosa irritation has a significant association with OSCC, and the nature of association could be that of a potential co-factor (dependent risk factor) rather than an independent risk factor.</p> 2021-04-02T19:51:15+02:00 Copyright (c) 2021 Supriya Kheur, Saranya Varadarajan, Sameena Parveen, Harisha Dewan, Yaser Ali Alhazmi, Thirumal A. Raj , Luca Testaralli, Shankargouda Patil Cisplatin inhibits the proliferation of Saos-2 osteosarcoma cells via the miR-376c/TGFA pathway 2021-03-20T17:29:01+01:00 Yuan Wang Yichao Wu Awei Cai Chengxiao Ma Shang Cai Hao Wang Yukang Que Shenglin Xu Tangbing Xu Yong Hu <p>The transforming growth factor alpha (<em>TGFA</em>) gene is involved in the proliferation and metastasis of various tumors, but its role in cell sensitivity to cisplatin chemotherapy is unclear. In this study, we investigated the mechanism underlying inhibitory effects of cisplatin on growth and proliferation of osteosarcoma cells. Osteosarcoma and normal skeletal muscle tissues were collected from 26 patients by biopsy. <em>TGFA</em> was silenced or overexpressed in Saos-2 osteosarcoma cells by transfection with <em>TGFA</em>-shRNA or <em>TGFA</em> ORF clone, respectively. MiR-376c was inhibited or overexpressed by transfection of Saos-2 cells with miR-376c sponge or miR-376c mimics, respectively. Cell growth was analyzed by MTT assay and cell proliferation by BrdU assay. MiR-376c and <em>TGFA</em> mRNA expression was detected by quantitative reverse transcription PCR and <em>TGFA</em> protein expression by Western blot. The target relationship between miR-376c and <em>TGFA</em> was assessed by luciferase reporter assay. Both in osteosarcoma tissues and Saos-2 cells, miR-376c expression was significantly decreased and <em>TGFA</em> mRNA expression was significantly increased compared with control. Transfection of Saos-2 cells with <em>TGFA</em>-shRNA silenced <em>TGFA</em> expression and significantly inhibited cell growth and proliferation. <em>TGFA</em> mRNA and protein expression in Saos-2 cells significantly decreased with increasing cisplatin concentrations (2.5–10 mg/L). Transfection with <em>TGFA</em> ORF clone reversed the inhibitory effects of cisplatin on Saos-2 cell proliferation. Compared with cisplatin (10 mg/L) treatment alone, the combined treatment with cisplatin and miR-376c mimics inhibited the proliferation of Saos-2 cells more significantly. MiR-376c suppressed <em>TGFA</em> expression by directly interacting with its 3' UTR region. Overall, cisplatin inhibited the proliferation of Saos-2 cells by upregulating miR-376c and downregulating <em>TGFA</em> expression.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Yuan Wang, Yichao Wu, Awei Cai, Chengxiao Ma, Shang Cai, Hao Wang, Yukang Que, Shenglin Xu, Tangbing Xu, Yong Hu Neural stem cell-conditioned medium ameliorates Aβ25–35-induced damage in SH-SY5Y cells by protecting mitochondrial function 2021-03-20T17:29:34+01:00 Guoyong Jia Zengyan Diao Ying Liu Congcong Sun Cuilan Wang <p>Inhibition of amyloid β (Aβ)-induced mitochondrial damage is considered crucial for reducing the pathological damage in Alzheimer’s disease (AD). We evaluated the effect of neural stem cell-conditioned medium (NSC-CDM) on Aβ<sub>25–35</sub>-induced damage in SH-SY5Y cells. An <em>in</em><em> vitro</em> model of AD was established by treating SH-SY5Y cells with 40 µM Aβ<sub>25–35</sub> for 24 h. SH-SY5Y cells were divided into control, Aβ<sub>25–35</sub> (40 µM), Aβ<sub>25–35</sub> (40 µM) + NSC-CDM, and Aβ<sub>25–35</sub> (40 µM) + neural stem cell-complete medium (NSC-CPM) groups. Cell viability was detected by CCK-8 assay. Apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were detected by flow cytometry. Malondialdehyde content was detected by ELISA assay. Western blot analysis was used to detect cytochrome c release and apoptosis-related proteins. Transmission electron microscopy was used to observe mitochondrial morphology. Cell viability significantly decreased and apoptosis significantly increased in SH-SY5Y cells treated with Aβ<sub>25–35</sub>, and both effects were rescued by NSC-CDM. In addition, NSC-CDM reduced ROS production and significantly inhibited the reduction of MMP caused by Aβ<sub>25–35</sub>. Furthermore, NSC-CDM ameliorated Aβ<sub>25–35</sub>-induced reduction in Bcl-2 expression levels and increased the expression levels of cytochrome c, caspase-9, caspase-3, and Bax. Moreover, Aβ<sub>25–35</sub> induced the destruction of mitochondrial ultrastructure and this effect was reversed by NSC-CDM. Collectively, our findings demonstrated the protective effect of NCS-CDM against Aβ<sub>25–35</sub>-induced SH-SY5Y cell damage and clarified the mechanism of action of Aβ<sub>25–35</sub> in terms of mitochondrial maintenance and mitochondria-associated apoptosis signaling pathways, thus providing a theoretical basis for the development of novel anti-AD treatments.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Guoyong Jia, Zengyan Diao, Ying Liu, Congcong Sun, Cuilan Wang Long non-coding RNA PVT1 regulates the migration of hepatocellular carcinoma HepG2 cells via miR-3619-5p/MKL1 axis 2021-03-20T17:29:51+01:00 Hua Liu Yan Yin Ting Liu Yanying Gao Qing Ye Junqing Yan Fushuang Ha <p>Hepatocellular carcinoma (HCC) is the third most common malignant tumor of the digestive system. Plasma cell tumor heterotopic gene 1 (PVT1) is an intergenic long non-coding RNA that is aberrantly expressed in different cancers. Myocardin-related transcription factor A or megakaryoblastic leukemia 1 (MKL1) is a transcriptional coactivator of serum response factor that has been shown to promote cancer cell migration and invasion. In this study, we investigated the relationship between PVT1 and MKL1 as a novel regulatory mechanism underlying HCC progression. We used HepG2 and Cos‑7 cell lines. Transfection experiments with miR-3619-5p mimics/inhibitor, PVT1, siRNA-PVT1, MKL1, or siRNA-MKL1 were performed. RNA and protein levels were analyzed by quantitative reverse transcription PCR and Western blot, respectively. Cell migration was assessed by transwell assay. Luciferase assays, RNA-FISH, RNA immunoprecipitation, and chromatin immunoprecipitation assays were performed to confirm the interaction between PVT1, miR-3619-5p, and MKL1 in HCC cells. Overexpression of PVT1 was positively correlated with MKL1 upregulation, which promoted HepG2 cell migration. miR-3619-5p inhibited MKL1 expression in HCC cells by acting on its 3′-UTR. Furthermore, PVT1 promoted MKL1 expression and migration in HCC cells by directly binding to miR-3619-5p. In a positive feedback loop, MKL1 could activate PVT1 transcription by binding to the CArG box in the promoter region. Our findings may provide a basis for the development of novel targeted therapies in HCC.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Hua Liu, Yan Yin, Ting Liu, Yanying Gao, Qing Ye, Junqing Yan, Fushuang Ha Progress in research on childhood T-cell acute lymphocytic leukemia, Notch1 signaling pathway, and its inhibitors: A review 2021-03-20T17:27:53+01:00 Zhong Fang-Fang Yang You Liu Wen-Jun <p>Childhood leukemia is cancer that seriously threatens the life of children in China. Poor sensitivity to chemotherapy and susceptibility to drug resistance are the reasons for the treatment of T-cell acute lymphocytic leukemia (T-ALL) being extremely difficult. Moreover, traditional intensive chemotherapy regimens cause great damage to children. Therefore, it is highly important to search for targeted drugs and develop a precise individualized treatment for child patients. There are activating mutations in the <em>NOTCH1</em> gene in more than 50% of human T-ALLs and the Notch signaling pathway is involved in the pathogenesis of T-ALL. In this review, we summarize the progress in research on T-ALL and Notch1 signaling pathway inhibitors to provide a theoretical basis for the clinical treatment of T-ALL.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Zhong Fang-Fang, Yang You, Liu Wen-Jun Respiratory depression in the post-anesthesia care unit: Mayo Clinic experience 2021-03-20T17:30:51+01:00 Mariana L. Laporta Juraj Sprung Toby N. Weingarten <p>The anesthesia recovery is a complex physiologic process as systems recover from the effects of surgery and anesthesia. Inadequate recovery of respiratory physiology can lead to severe hypoxemia-induced end-organ damage and even death. Emerging evidence suggests that signs of respiratory depression during early anesthesia recovery may portend increased risk for future severe adverse events. This article briefly reviews the Mayo Clinic research experience and advances in clinical practice. From the implementation of a step-down model of discharge criteria in the post-anesthesia care unit (PACU), consisting of PACU nurses monitoring patients in predetermined periods for signs of respiratory depression, and delaying PACU discharge for patients who exhibit signs of respiratory depression, and early intervention in high-risk patients. Subsequent studies found that even a single episode of respiratory depression in the PACU was strongly associated with subsequent respiratory complications. Further, patient baseline characteristics found to be associated with respiratory depression included obstructive sleep apnea and low body weight, and surgical factors associated with increased risk included the use of preoperative sustained-release opioids, perioperative gabapentinoid use, higher intraoperative opioids, isoflurane as the volatile anesthetic, and longer surgical duration. Based in part of Mayo Clinic research, the FDA issued a warning in 2019 on gabapentinoids use and respiratory complications, increasing the recommended level of respiratory vigilance in patients using this medication. Understanding the complex nature of postoperative respiratory events requires a range of translational and clinical research and constant update of practice.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Mariana L. Laporta, Juraj Sprung, Toby N. Weingarten 2020 consensus guideline for optimal approach to the diagnosis and treatment of HER2-positive breast cancer in Bosnia and Herzegovina 2021-03-20T17:27:21+01:00 Semir Bešlija Zdenka Gojković Timur Cerić Alma Mekić Abazović Inga Marijanović Semir Vranić Jasminka Mustedanagić–Mujanović Faruk Skenderi Ivanka Rakita Aleksandar Guzijan Dijana Koprić Alen Humačkić Danijela Trokić Jasmina Alidžanović Alma Efendić Ibrahim Šišić Harun Drljević Vanesa Bešlagić Božana Babić Azra Pašić Anela Ramić Dijana Mikić Zlatko Guzin Dragana Karan Teo Buhovac Dragana Miletić Senad Šečić Azra Đozić Šahmić Lejla Mujbegović Alisa Kubura Mensura Burina Nenad Lalović Nikolina Dukić Jelena Vladičić Mašić Mirjana Ćuk Rajna Stanušić <p>The HERe2Cure project, which involved a group of breast cancer experts, members of multidisciplinary tumor boards from healthcare institutions in Bosnia and Herzegovina, was initiated with the aim of defining an optimal approach to the diagnosis and treatment of HER2 positive breast cancer. After individual multidisciplinary consensus meetings were held in all oncology centers in Bosnia and Herzegovina, a final consensus meeting was held in order to reconcile the final conclusions discussed in individual meetings. Guidelines were adopted by consensus, based on the presentations and suggestions of experts, which were first discussed in a panel discussion and then agreed electronically between all the authors mentioned. The conclusions of the panel discussion represent the consensus of experts in the field of breast cancer diagnosis and treatment in Bosnia and Herzegovina. The objectives of the guidelines include the standardization, harmonization and optimization of the procedures for the diagnosis, treatment and monitoring of patients with HER2-positive breast cancer, all of which should lead to an improvement in the quality of health care of mentioned patients. The initial treatment plan for patients with HER2-positive breast cancer must be made by a multidisciplinary tumor board comprised of at least: a medical oncologist, a pathologist, a radiologist, a surgeon, and a radiation oncologist/radiotherapist.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Semir Bešlija, Zdenka Gojković, Timur Cerić, Alma Mekić Abazović, Inga Marijanović, Semir Vranić, Jasminka Mustedanagić–Mujanović; Faruk Skenderi; Ivanka Rakita, Aleksandar Guzijan, Dijana Koprić, Alen Humačkić, Danijela Trokić, Jasmina Alidžanović, Alma Efendić, Ibrahim Šišić, Harun Drljević, Vanesa Bešlagić, Božana Babić, Azra Pašić, Anela Ramić, Dijana Mikić, Zlatko Guzin, Dragana Karan, Teo Buhovac, Dragana Miletić, Senad Šečić, Azra Đozić Šahmić, Lejla Mujbegović, Alisa Kubura, Mensura Burina, Nenad Lalović, Nikolina Dukić, Jelena Vladičić Mašić, Mirjana Ćuk, Rajna Stanušić Combined inhibition of ACK1 and AKT shows potential toward targeted therapy against KRAS-mutant non-small-cell lung cancer 2021-03-20T17:30:12+01:00 Xiangjing Yu Jie Liu Huawei Qiu Huiting Hao Jinhong Zhu Shiyun Peng <p>Non-small-cell lung cancer (NSCLC) with Kirsten RAt Sarcoma 2 viral oncogene homolog (<em>KRAS</em>) mutation has become a clinical challenge in cancer treatment as <em>KRAS</em>-mutant tumors are often resistant to conventional anti-tumor therapies. Activated CDC42-associated kinase 1 (ACK1), an activator of protein kinase B (AKT), is a promising target for <em>KRAS</em>-mutant tumor therapy, but the downstream ACK1 signaling remains poorly understood. The aim of this study was to evaluate the effectiveness of combined ACK1/AKT inhibition on the proliferation, migration, invasion, and apoptosis of <em>KRAS</em>-mutant NSCLC cell lines (NCI-H23, NCI-H358, and A549). The cells were treated with an inhibitor of either ACK1 (dasatinib or sunitinib) or AKT (MK-2206 or GDC-0068), and the optimal concentrations of the two yielding synergistic tumor-killing effects were determined by applying the Chou-Talalay equation for drug combinations. We showed that combined administration of ACK1 and AKT inhibitors at the optimal concentrations effectively suppressed NSCLC cell viability and promoted apoptosis while inducing cell cycle arrest at the G2 phase. Moreover, NSCLC cell migration and invasion were inhibited by combined ACK1/AKT inhibition. These phenomena were associated with the reduced phosphorylation levels of ACK1 and AKT (at Ser473 and Thr308), as well as alterations in caspase-dependent apoptotic signaling. Collectively, our results demonstrate the promising therapeutic potential of combined ACK1/AKT inhibition as a strategy against <em>KRAS</em>-mutant NSCLC. Our findings provide the basis for the clinical translation of biological targeted drugs (ACK1 and AKT inhibitors) and their rational combination in cancer treatment.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Xiangjing Yu The role of cytoreductive nephrectomy in renal cell carcinoma patients with liver metastasis 2021-03-20T17:31:10+01:00 Boda Guo Shengjing Liu Miao Wang Huimin Hou Ming Liu <p>It is widely accepted that renal cell carcinoma (RCC) with liver metastasis (LM) carries a dismal prognosis. We aimed to explore the value of cytoreductive nephrectomy among these patients. Patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. The univariate and multivariate Cox proportional hazards models were conducted to select the prognostic predictors of survival. Patients were divided into nephrectomy and non-nephrectomy groups. Propensity score-matching (PSM) analyses were applied to reduce the above factors’ differences between the groups. Overall survival (OS) was compared by Kaplan–Meier analyses. Data from 683 patients were extracted from the database. The univariate Cox regression and multivariate Cox regression revealed that factors including age, histologic type, T and N stages, lung metastasis, brain metastasis, and nephrectomy were significant predictors of survival in the patients. After the PSM analyses, we found that nephrectomy prolonged OS. Nephrectomy can prolong OS in eligible RCC patients with LM.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Boda Guo, Shengjing Liu, Miao Wang, Huimin Hou, Ming Liu Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use 2021-03-20T17:28:20+01:00 Fitri Fareez Ramli <p>Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of <em>ABCB1</em> single-nucleotide polymorphism (SNP) 1236C&gt;T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, <em>ABCB1</em> SNP 1236C&gt;T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and <em>ABCB1</em> 3435C&gt;T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, <em>ABCB1</em> diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C&gt;T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of <em>CYP2B6</em> genotypes *4(G/G) and *9(T/T) among Jewish patients, <em>CYP2B6</em>*9 genotype (T/T) and haplotypes (TA/TG); and <em>CYP2C19</em> <em>(*2/*2</em>,<em>*2/*3</em>, and <em>*3/*3</em>; Han Chinese). Higher methadone dose was observed in <em>CYP2C19</em>*1 allelic carriers (Han Chinese) and <em>CYP2D6</em> ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in <em>CYP2B6</em> SNPs, haplotypes TTT, and AGATAA (Han Chinese), <em>CYP2C19</em> genotype *1/*1 (Han Chinese), allelic carrier <em>*1xN</em> (Caucasian), and <em>CYP3A4</em> genotype *1/*1 (Caucasian). Carriers of <em>CYP2B6</em> genotype <em>*6/*6</em> (Caucasian), <em>CYP2B6</em> haplotypes ATGCAG and ATGCTG (Han Chinese), and <em>CYP3A4</em> genotype <em>*1/*1B</em> (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Fitri Fareez Ramli The value of lymphocyte count in determining the severity of COVID-19 and estimating the time for nucleic acid test results to turn negative 2021-03-20T17:31:31+01:00 Yuanchao Li Tuoyun Yang Sicong Wang Junbo Zheng Jing Zhou Min Jiang Tong Zhou Yang Cao Hongliang Wang <p>Peripheral blood lymphocyte count is shown to be decreased in patients with COVID-19 in the early stage of the disease. The degree of lymphocyte count reduction is related to COVID-19 severity and could be used as an indicator to reflect the disease severity. Our aim was to investigate the value of lymphocyte count in determining COVID-19 severity and estimating the time for SARS-CoV-2 nucleic acid test results to turn negative. We retrospectively analyzed clinical data of 201 patients with severe and critical COVID-19. The patients were admitted to the West Campus of Union Hospital of Tongji Medical College of Huazhong University of Science and Technology. The data included age, gender, chronic disease, lymphocyte count, and SARS-CoV-2 nucleic acid test results. The age of patients in critically ill group was higher than in severely ill group (<em>p</em> = 0.019). The lymphocyte count of critically ill patients was lower than of severely ill patients. The cutoff value of lymphocyte count to distinguish between the critically ill and the severely ill was 0.735 × 10<sup>9</sup>/L (<em>p</em> = 0.001). The cutoff value of lymphocyte count for SARS-CoV-2 nucleic acid test results turning negative in severely and critically ill patients with chronic diseases (hypertension, diabetes, and coronary heart disease) was 0.835 × 10<sup>9</sup>/L (<em>p</em> = 0.017). The cutoff value of lymphocyte count for SARS-CoV-2 nucleic acid test results turning negative in severely and critically ill male patients was 0.835 × 10<sup>9</sup>/L (<em>p</em> &lt; 0.0001). Lymphocyte count could be an effective indicator to predict COVID-19 severity. It may also be useful in determining the time for nucleic acid test results to turn negative in COVID-19 patients with underlying chronic diseases or male COVID-19 patients with severe and critical conditions.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Yuanchao Li, Tuoyun Yang, Sicong Wang, Junbo Zheng, Jing Zhou, Min Jiang, Tong Zhou, Yang Cao, Hongliang Wang An insight into osteoarthritis susceptibility: Integration of immunological and genetic background 2021-03-20T17:28:37+01:00 Debora Stefik Vladimir Vranic Nemanja Ivkovic Dzihan Abazovic Dusan Maric Danilo Vojvodic Gordana Supic <p>Osteoarthritis (OA) is a progressive degenerative disease that affects all synovial joints, causing the disability of the main locomotor diarthrodial joints. OA pathogenesis is caused by a complex interplay between a number of genetic and environmental risk factors, involved in the early onset and progression of this chronic inflammatory joint disease. Uncovering the underlying immunological and genetic mechanisms will enable an insight into OA pathophysiology and lead to novel and integrative approaches in the treatment of OA patients, together with a reduction of the disease risk, or a delay of its onset in susceptible patients.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Debora Stefik, Vladimir Vranic, Nemanja Ivkovic, Dzihan Abazovic, Dusan Maric, Danilo Vojvodic, Gordana Supic Increasing the efficiency of mechanical ventilators during pandemics through additive manufacturing 2021-03-20T17:31:53+01:00 Abdullatif Alwasel Jean Zaky Khalid Alhussaini Bandr Alossimi Turki Alharbi <p>The COVID-19 pandemic tested medical facilities’ readiness in terms of the number of available mechanical ventilators. Most countries raced to stock up on ventilators, which created a surge in demand and short in supply. Furthermore, other means of coping with the demand were proposed, such as using additive manufacturing. The purpose of this paper was to test whether the addition of 3D-printed splitters would help deliver required tidal volume to each patient, while supporting four patients on a single ventilator for 24 hours on pressure mode at 25-cm H<sub>2</sub>O, and to determine whether a fifth patient can be ventilated. The ventilation of four human lungs was simulated using 3D printed parts, a single ventilator, four test-lungs, and standard tubing. Peak pressure, positive end-expiratory pressure, total tidal volume, individual tidal volume, total minute volume, and individual tidal volume data were collected. Usage of a 3D printed small size splitter enabled a 26% increase in individual tidal volume compared to standard tubing and a series of two-way splitters. The ventilator was able to supply the required pressure and tidal volume for 24 hours. A single ventilator with a four-way splitter can ventilate four patients experiencing respiratory failure for at least 24 hours without interruption. The equipment cannot sustain ventilating a fifth patient owing to minute volume limitation. This study expands on an earlier study that tested similar circuitry and reveals that the desired individual tidal volume is achieved. However, further research is required to provide the monitoring ability of individual patient parameters and prevention of cross-contamination.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Abdullatif Alwasel, Khalid Alhussaini, Bandr Alossimi, Turki Alharbi Cryptic t(15;17) acute promyelocytic leukemia with a karyotype of add(11)(p15) and t(13,20)- A case report with a literature review 2021-03-20T17:32:19+01:00 Siyu Gu Jie Zi Jinlong Ma Zheng Ge <p>Most acute promyelocytic leukemia (APL) are characterized by reciprocal translocations t(15;17)(q22;21), which results in the fusion of PML gene at 15q22 with RARα gene at 17q21. However, several complex variant translocations also have been reported. Here we report a 62-year-old man with typical morphology and clinical features of APL with a complex karyotype including add(11)(p15) and t(13,20)(q12;q11.2) without typical t(15;17) assayed by the G-banding analysis. FISH with a PML/RARα dual-color DNA probe showed an atypical fusion signal, RT-qPCR analysis showed PML/RARα fusion transcripts, and NGS detected<em> FLT3</em>, <em>WT1, </em>and <em>KRAS</em> mutations. The patient achieved complete remission after treatment with conventional chemotherapy combined ATRA and ATO. Although the mechanism of this kind of cryptic variant remains unknown, we conclude that the cryptic PML/RARα fusion with add(11)(p15), t(13,20)(q12;q11.2) seems not to alter the effectiveness of chemotherapy combined with ATRA and ATO.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Siyu Gu, Jie Zi, Jinlong Ma, Zheng Ge Kawasaki-like disease and acute myocarditis in the SARS-CoV-2 pandemic – reports of three adolescents 2021-03-20T17:32:46+01:00 Vladislav Vukomanovic Stasa Krasic Predrag Minic Gordana Petrovic Dejan Nesic Aleksandra Paripovic Milena Vasiljevic Borko Gobeljic <p>The novel coronavirus disease (COVID-19) may induce multisystem inflammatory syndrome (MIS) in children, which may be associated with Kawasaki-like disease and cardiac injury. In this study, we presented three male adolescents with MIS and myocardial injury admitted to the hospital during the peak of COVID-19 pandemic. All of the three patients had a history of fever, gastrointestinal symptoms, polymorph rash, non-exudative&nbsp; onjunctivitis, and signs of acute myocarditis (AM). One of them had renal failure. Previously, they did not have an acute infection. Upon admission, they were hypotensive and tachycardic. A nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on reverse transcription-polymerase chain reaction (PCR) assay was negative, but neutralizing viral antibodies were positive. In combination with blood tests,&nbsp; lectrocardiogram, echocardiography, and computerized tomography, a MIS associated with acute myocarditis with mild to moderate systolic dysfunction and dilated coronary arteries were diagnosed. Two of three patients had shock syndrome andrequired inotropic support. All patients were treated with intravenous imunoglobulins (Ig). The second patient had a fever up to 102.2°F (39°C) 3 days after intravenous Ig. Further, he was treated according to protocols for refractory Kawasaki disease, with an intravenous methylprednisolone pulse therapy and aspirin. After a few hours, he became afebrile and the clinical signs disappeared. The favorable short-term<br>outcome may reflect early recognition and adequate therapy; however, the long-term outcomes are currently unknown.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Stasa Krasic, Sergej Prijic, Predrag Minic, Gordana Petrovic, Dejan Nesic, Vladislav Vukomanovic The Ki-67 proliferation index predicts recurrence-free survival in patients with dermatofibrosarcoma protuberans 2021-03-20T17:29:18+01:00 Deligonul Adem Serkan Yazici Mine Ozsen Sibel Kahraman Cetintas Ulviye Yalcinkaya Ahmet Bilgehan Şahin Ozgur Tanrıverdi Sibel Oyucu Orhan Birol Ocak Erdem Cubukcu Ramazan Kahveci Turkkan Evrensel <p>Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue sarcoma that originates from the dermis or subcutaneous tissue in the skin. While its prognosis is generally favorable, disease recurrence is relatively frequent. Because morbidity after repeated surgery may be significant, an optimized prediction of recurrence-free survival (RFS) has the potential to improve current management strategies. The purpose of this study was to investigate the prognostic value of the Ki-67 proliferation index with respect to RFS in patients with DFSP. We retrospectively analyzed data from 45 patients with DFSP. We calculated the Ki-67 proliferation index as the percentage of immunostained nuclei among the total number of tumor cell nuclei regardless of the intensity of immunostaining. We constructed univariate and multivariate Cox proportional hazards regression models to identify predictors of RFS. Among the 45 patients included in the study, 8 developed local recurrences and 2 had lung metastases (median follow-up: 95.0 months; range: 5.2−412.4 months). The RFS rates at 60, 120, and 240 months of follow-up were 83.8%, 76.2%, and 65.3%, respectively. The median Ki-67 proliferation index was 14%. Notably, we identified the Ki-67 proliferation index as the only independent predictor for RFS in multivariate Cox proportional hazards regression analysis (hazard ratio = 1.106, 95% confidence interval = 1.019−1.200, p = 0.016). In summary, our results highlight the potential usefulness of the Ki-67 proliferation index for facilitating the identification of patients with DFSP at higher risk of developing disease recurrences.</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 Deligonul Adem, Serkan Yazici, Mine Ozsen, Sibel Kahraman Cetintas, Ulviye Yalcinkaya, Ahmet Bilgehan Şahin, Ozgur Tanrıverdi, Sibel Oyucu Orhan, Birol Ocak, Erdem Cubukcu, Ramazan Kahveci, Turkkan Evrensel A plea for extension of the anatomical nomenclature: Vessels 2021-03-20T17:30:33+01:00 David Kachlik Vladimir Musil Alzbeta Blankova Zuzana Marvanova Jakub Miletin Daniela Trachtova Vlasta Dvorakova Vaclav Baca <p>This article is the fourth and last part of a series aimed at extending and correcting the anatomical nomenclature. Because of the rapid development of internet and the use of electronic formats in communication in anatomy, embryology, histology, medical education, and clinical medicine, an appropriate, precise, and concise anatomical nomenclature is required. Such tool enables to avoid any potential confusion and possible scientific/medical mistakes. The up-to-date official anatomical terminology, Terminologia Anatomica, is available longer than 20 years and needs to be refined and extended. The authors have collected and listed 210 terms and completed them with definitions and/or explanations. We aimed to start a discussion about their potential incorporation into the new revised version of the Terminologia Anatomica. This article is primarily focused on the vessels of the human body (arteries, veins, and lymphatic system).</p> 2021-04-01T00:00:00+02:00 Copyright (c) 2020 David Kachlik, Vladimir Musil, Alzbeta Blankova , Zuzana Marvanova , Jakub Miletin, Daniela Trachtova , Vlasta Dvorakova , Vaclav Baca