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) Mon, 02 Nov 2020 00:00:00 +0100 OJS 60 Expression of NEDD9 and connexin-43 in neoplastic and stromal cells of gastric adenocarcinoma <p>Gastric cancer is related to high mortality rates and advanced disease stage at the time of diagnosis. Its carcinogenesis is extensively studied and is associated with genetic and epigenetic changes, changed the interaction between tumor and adjacent stromal cells, and changes in the microenvironment molecule status. NEDD9 affects different signaling proteins and pathways, apoptosis, adhesion, cell migration, and invasiveness. Connexin-43 also assists in intercellular communications and has several channel-independent functions. Aberrant expression of those two gap junction proteins plays an essential role in metastatic processes. Our scope was to detect the expression of connexin-43 and NEDD9 in epithelial and stromal gastric cancer compartments and its relation to tumor progression and lymph node metastases. Cancer tissue from 53 cases of node-negative and 55 cases of node-positive primary gastric carcinoma patients was analyzed for connexin-43 and NEDD9 expression by immunohistochemical assay, and the results were correlated with the remaining clinical and pathological findings and survival. In our cohort of patients with lymph node metastases, we detected higher expression of epithelial connexin-43 in the primary tumor and stromal connexin-43 expression correlated with both epithelial NEDD9 (rho=0.453) and stromal NEDD9 (rho=0.484). Higher epithelial connexin-43 and NEDD9 expression were associated with higher mortality (HR 1.54, 95% CI 1.01 -2.37, <em>p</em>=0.048). Epithelial connexin-43 expression, both epithelial and stromal NEDD9 expression, T and N status were all independently associated with shorter survival. In summary, our findings suggest that increased expression of both epithelial and stromal NEDD9 and epithelial connexin-43 could potentially be used as prognostic gastric cancer biomarkers.</p> Ivan Lerotić, Petra Vuković, Davor Hrabar, Zvonimir Misir, Ivan Kruljac, Tajana Pavić, Jelena Forgač, Petra Čačić, Monika Ulamec Copyright (c) 2021 Ivan Lerotić, Petra Vuković, Davor Hrabar, Zvonimir Misir, Ivan Kruljac, Tajana Pavić, Jelena Forgač, Petra Čačić, Monika Ulamec Mon, 11 Jan 2021 19:56:32 +0100 Development and validation of a SEER-based prognostic nomogram for cervical cancer patients below the age of 45 years <p>This study aimed to establish a nomogram for the prognostic prediction of patients with early-onset cervical cancer (EOCC) in both overall survival (OS) and cancer-specific survival (CSS). The 10,079 patients diagnosed with EOCC between 2004 and 2015 were captured within the Surveillance, Epidemiology, and End Results (SEER) database and further were divided into training and validation sets randomly. The independent prognostic factors were identified in a retrospective study of 7,055 patients training sets randomly. Besides, the prognostic nomogram was developed using R software according to multivariable Cox regression analysis. Furthermore, the model was externally validated using the data of 3,024 patients diagnosed at different times enrolled in the SEER database. In training set, the C-indexes for OS and CSS prediction were 0.831 (95% confidence interval [CI]: 0.815-0.847) and 0.855(95%CI:0.839-0.871). The results of ROC indicated that nomograms possessed better predict performance compared with TNM-stage and SEER-stage. And the areas under the curve (AUC) of the nomogram for OS and CSS prediction in ROC analysis were 0.855(95%CI:0.847-0.864) and 0.782(95%CI:0.760-0.804), respectively. In addition, calibration curves presented perfect agreements between the nomogram-predicted and actual 1-, 3-, and 5-year in the validation cohort, in OS rate and CSS rate. This study established and validated a prognostic nomogram that provided an accurate prediction of 3-, 5-, and 10-year OS and CSS of EOCC patients, which contributed to clinicians to be useful for patients’ counseling and clinical trial designing.</p> Qunlong Liu, Wenxia Li, Ming Xie, Ming Yang, Mei Xu, Lei Yang, Bing Sheng, Yanna Peng, Li Gao Copyright (c) 2020 Qunlong Liu, Wenxia Li, Ming Xie, Ming Yang, Mei Xu, Lei Yang, Bing Sheng, Yanna Peng, Li Gao Thu, 31 Dec 2020 18:21:02 +0100 Machine learning as the new approach in understanding biomarkers of suicidal behavior <p>In psychiatry, compared to other medical fields, the identification of biological markers that would complement current clinical interview, and enable more objective and faster clinical diagnosis, implement accurate monitoring of treatment response and remission, is grave. Current technological development enables analyses of various biological marks in high throughput scale at reasonable costs, and therefore ‘omic’ studies are entering the psychiatry research. However, big data demands a whole new plethora of skills in data processing, before clinically useful information can be extracted. So far the classical approach to data analysis did not really contribute to identification of biomarkers in psychiatry, but the extensive amounts of data might get to a higher level, if artificial intelligence in the shape of machine learning algorithms would be applied. Not many studies on machine learning in psychiatry have been published, but we can already see from that handful of studies that the potential to build a screening portfolio of biomarkers for different psychopathologies, including suicide, exists.</p> Alja Videtič Paska, Katarina Kouter Copyright (c) 2020 Alja Videtič Paska, Katarina Kouter Thu, 31 Dec 2020 01:02:02 +0100 Significance of chromogranin A and synaptophysin in medullary thyroid carcinoma <p>Medullary thyroid carcinoma (MTC) is a relatively rare thyroid carcinoma of C-cell deviation and produces and secrete calcitonin (CT) and chromogranin A (CgA) into the blood. Thus, both CT and CgA are immunohistochemical and serum markers for MTCs. MTC occurs in both sporadic and inheritable cases and the hallmark of inheritable cases in multiple endocrine neoplasm 2 (NEN2) is MTC. MEN2 cases represent 30% of MTCs through germline RET protooncogene mutation and occur in younger ages involving bilateral thyroid lobes. Sporadic cases are 70% of cases of solitary tumor and occur in older ages. CgA and synaptophysin (SPY) are the two, most widely used and reliable immunohistochemical markers for neuroendocrine tumors including MTCs. This study aimed to detect different immunohistochemical staining patterns for CgA and SPY between non-symptomatic small, microscopic lesions and invading larger aggressive tumors in both MEA2 cases and sporadic cases. There was different CgA and SPY immunostaining in MEA2 cases where small tumors (≤ 0.3 cm) were lesser immunostained for CgA and SPY, despite strong staining for CT, compared to the larger (≥ 0.5cm) tumors, stronger immunostained for CgA. There was also different CgA and SPY immunohistochemical staining in sporadic cases between small lesion (≤ 0.5 cm) and larger tumors (≥ 1.0cm). One small sporadic tumor (0.5 x 0.3 cm) was strongly and weakly, patchy (about 10% of tumor tissue) stained for CgA and SPY, respectively, while larger sporadic tumors were diffusely, stronger stained for CgA and SPY. Therefore, stronger CgA and SPY immunostaining for larger tumors in both MEA2 and sporadic cases may be used as independent aggressive immunohistochemical markers for MTCs.</p> Tatsuo Tomita Copyright (c) 2020 Tatsuo Tomita Wed, 30 Dec 2020 00:00:00 +0100 Clinical significance of miR-129-5p in patients with neonatal sepsis and its regulatory role in the LPS-induced inflammatory response <p>Neonatal sepsis (NS) occurs in neonates within 28 days, especially preterm infants. The dysregulation of miRNAs is widely detected in NS. The study investigated the expression changes and clinical significance of miR-129-5p in NS patients and further explored the regulatory role of miR-129-5p in the LPS-induced inflammatory response in monocytes. A total of 75 neonates with NS and 84 neonates without NS were recruited. qRT-PCR was used for the measurement of miR-129-5p expression. The receiver operating characteristic (ROC) curve was constructed for diagnostic value analysis. ELISA was used to detect the concentration of inflammatory cytokines. Monocytes were isolated from the blood of neonates to investigate the role of miR-129-5p in the LPS-induced inflammatory response in vitro. miR-129-5p was low expressed in the serum of NS cases compared with controls. Serum miR-129-5p had a diagnostic value for NS with a sensitivity of 82.7% and specificity of 79.8%. There was close association for serum miR-129-5p with TNF-α (r = -0.652,<em> p</em> &lt; 0.001) and IL-8 (r = -0.700, <em>p</em> &lt; 0.001) levels in NS patients. Overexpression of miR-129-5p reversed the increasing trend of TNF-α and IL-8 induced by LPS, whereas miR-129-5p downregulation aggravated the increase of TNF-α and IL-8 induced by LPS in monocytes. MiR-129-5p was downregulated in the serum of NS patients, and it might be a promising biomarker for disease diagnosis. Overexpression of miR-129-5p alleviated the inflammatory response of NS.</p> Meng Li, Xiaoyang Huang, Qingcui Zhuo, Jinghui Zhang, Xiuli Ju Copyright (c) 2020 Meng Li, Xiaoyang Huang, Qingcui Zhuo, Jinghui Zhang, Xiuli Ju Tue, 29 Dec 2020 00:00:00 +0100 A novel homozygous exon2 deletion of TRIM32 gene in a Chinese patient with sarcotubular myopathy: A case report and literature review <p>Sarcotubular myopathy (STM) is a rare autosomal recessive myopathy caused by <em>TRIM32</em> gene mutations. It is predominantly characterized by the weakness of the proximal limb and mild to moderate elevation of creatine kinase (CK) levels. In this study, we describe a 50-year-old Chinese man who exhibited a <em>proximal</em>-to-<em>distal</em> weakness in the muscles of the lower limbs and who had difficulty standing up from a squat position. The symptoms gradually became more severe. He denied a history of cognitive or cardiological problems. The patient’s parents and children were healthy. Histopathological examination revealed dystrophic changes and irregular slit-shaped vacuoles containing amorphous materials. Whole-exome sequencing consisting of protein-encoding regions of 19,396 genes was performed, the results of which identified one novel homozygous 2kb deletion chr9.hg19: g.119460021_119461983del (exon2) in the <em>TRIM32 </em>gene. This was confirmed at the homozygous state with quantitative real-time PCR. Here, we present a Chinese case of STM with one novel mutation in <em>TRIM32</em> and provide a brief summary of all known pathogenic mutations in <em>TRIM32</em>.</p> Xiao-Jing Wei, Jing Miao, Zhi-Xia Kang, Yan-Lu Gao, Zi-Yi Wang, Xue-Fan Yu Copyright (c) 2020 Xiao-Jing Wei, Jing Miao, Zhi-Xia Kang, Yan-Lu Gao, Zi-Yi Wang, Xue-Fan Yu Tue, 29 Dec 2020 00:00:00 +0100 Dishevelled family proteins (DVL1-3) expression in intrauterine growth restriction (IUGR) placentas <p>Dishevelled family proteins (DVL1, DVL2, and DVL3) are cytoplasmic mediators involved in canonical and non-canonical Wnt signaling important in embryonic development. The role of DVL proteins in the placental tissue remains mostly unknown. In the current study, we explored the role of Dishevelled proteins in naturally invasive tissue, trophoblast. Formalin-fixed paraffin-embedded samples of 15 term placentas from physiologic term pregnancies and 15 term placentas from pregnancies complicated with intrauterine growth restrictions (IUGR) were used the study. Expression levels of mRNA for <em>DVL1</em>, <em>DVL2,</em> and <em>DVL3</em> in placentas were analyzed by quantitative real-time PCR (qRT-PCR). DVL1, DVL2, and DVL3 protein expression were semi-quantitatively analyzed using immunohistochemistry. The expression of DVL2 and DVL3 proteins was significantly higher in trophoblasts in placental villi from IUGR pregnancies than in the control group of term placentas. In contrast, DVL3 protein expression was significantly higher in endothelial cells in placental villi from IUGR pregnancies than normal term placentas. The observed differences at protein levels between normal and IUGR placentas were not confirmed at the mRNA levels of <em>DVL</em> genes. Our data indicate the active involvement of DVL proteins in IUGR-related placentas. No significant changes were observed in <em>DVL</em> mRNA levels between the two groups of placentas. Further studies are required to explore the clinical relevance of these observations.</p> Ida Marija Sola, Alan Serman, Valentina Karin-Kujundzic, Frane Paic, Anita Skrtic, Paula Slatina, Luka Kakarigi, Semir Vranic, Ljiljana Serman Copyright (c) 2020 Ida Marija Sola, Alan Serman, Valentina Karin-Kujundzic, Frane Paic, Anita Skrtic, Paula Slatina, Luka Kakarigi, Semir Vranic, Ljiljana Serman Sat, 26 Dec 2020 04:15:11 +0100 Assessment of Wnt pathway selected gene expression levels in peripheral blood mononuclear cells (PBMCs) of postmenopausal patients with low bone mass <p>The purpose of the study was to assess the expression of selected genes of the Wnt pathway: <em>APC, AXIN1, CTNNB1, DKK1, GSK3β, KREMEN1, SFRP1, </em>and <em>WNT1</em> in peripheral blood mononuclear cells (PBMC) of patients, selected in consideration of their bone mineral density (BMD), and the occurrence of low-energy fractures. The study involved 45 postmenopausal women, divided into four groups, according to BMD and fracture history. Measurements of laboratory parameters and RNA expression in PBMC cells were carried out in material, collected once at the inclusion visit. The densitometric examination was performed on all participants. In the analysis of the relative expression levels (RELs) of the studied genes in the entire population, we observed an overexpression for SFRP1 in 100% of samples and <em>WNT1</em>. In addition, the REL of <em>DKK1, APC,</em> and <em>GSK3β</em> genes were slightly elevated versus the calibrator. In contrast, <em>CTNNB1</em> and <em>AXIN1</em> presented with a slightly decreased RELs. Analysis did not show any significant differences among the groups in the relative gene expression levels (<em>p </em>&lt; 0.05) of particular genes. However, we have observed quite numerous interesting correlations between the expression of the studied genes and BMD, the presence of fractures, and laboratory parameters, both in the whole studied population as well as in selected groups. In conclusion, the high level of <em>CTNNB1</em> expression maintains normal BMD and/or protects against fractures. It also appears that the changes in expression levels of the Wnt pathway genes in PBMCs reflect the expected changes in bone tissue.</p> Michal Stuss, Monika Migdalska-Sek, Ewa Brzezianska-Lasota, Marta Michalska-Kasiczak, Pawel Bazela, Ewa Sewerynek Copyright (c) 2020 Michal Stuss, Monika Migdalska-Sęk, Ewa Brzezianska-Lasota, Marta Michalska-Kasiczak, Pawel Bazela, Ewa Sewerynek Mon, 21 Dec 2020 18:24:15 +0100 Trends of incidence and prognosis of upper tract urothelial carcinoma <p>The purpose of this study was to investigate trends in the incidence of upper tract urothelial carcinoma (UTUC) in patients and to establish a reliable and practical nomogram based on significant clinical factors to predict the overall survival (OS) and cancer-specific survival (CSS) of UTUC patients. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract data on UTUC patients between 1988 and 2015. Incidence was calculated using Joinpoint regression software, and trends were quantified by annual percentage change (APC). A nomogram was constructed using R software to predict the OS and CSS probabilities for individual patients. From 1988 to 2015, the incidence of UTUC showed a downward trend (1988: 1.57/100,000 to 2015: 1.51/100,000; APC=-0.1). After stratification according to sex, age and primary site, we found that the incidences of UTUC in males, patients 70+ years old and the renal pelvis were higher than those in females, patients &lt;70 years old and ureter cancer patients. In the training cohort, the nomogram established based on multivariate Cox regression results showed better OS and CSS accuracy (OS: C-index=0.701, AUC=0.736; CSS: C-index=0.729, and AUC=0.688) than SEER stage. In addition, the calibration curves showed good consistency between the predicted and actual 3-, 5- and 10-year OS and CSS rates of the nomogram. In the past 30 years, the incidence of UTUC has shown a general downward trend, and the prognostic nomogram we established can provide a personalized risk assessment for the survival of UTUC patients.</p> Jianping Wu, Shuqiu Chen, Xiaoli Wu, Weipu Mao, Yali Wang, Bin Xu, Donghui Zheng, Ming Chen Copyright (c) 2020 Ming Chen, Jianping Wu, Shuqiu Chen, Xiaoli Wu, Weipu Mao, Yali Wang, Bin Xu, Donghui Zheng Fri, 18 Dec 2020 18:58:14 +0100 Computed tomography in the diagnosis of intraperitoneal effusions: The role of texture analysis <p>The morphological changes advocating for peritoneal carcinomatosis are inconsistent and may be visible only in later stages of the disease. However, malignant ascites represents an early sign, and this fluid exhibits specific histological characteristics. This study aimed to quantify the fluid properties on computed tomography (CT) images of intraperitoneal effusions through texture analysis and evaluate its utility in differentiating benign and malignant collections. Fifty-two patients with histologically proven benign (n=29) and malignant (n=23) intraperitoneal effusions who underwent CT examinations were retrospectively included. Texture analysis of the fluid component was performed on the non-enhanced phase of each examination using dedicated software. Fisher and the probability of classification error and average correlation coefficients were used to select two sets of ten texture features, whose ability to distinguish between the two types of collections were tested using a k-nearest-neighbor classifier. Also, each of the selected feature’s diagnostic power was assessed using univariate and receiver operating characteristics analysis with the calculation of the area under the curve. The k-nearest-neighbor classifier was able to distinguish between the two entities with 71.15% accuracy, 73.91% sensitivity, and 68.97% specificity. The highest-ranked texture parameter was Inverse Difference Moment (<em>p</em>=0.0023; area under the curve=0.748), based on which malignant collections could be diagnosed with 95.65% sensitivity and 44.83% specificity. Although successful, the texture assessment of benign and malignant collections most likely does not reflect the cytological differences between the two groups.</p> Csaba Csutak, Paul-Andrei Ștefan, Roxana-Adelina Lupean, Lavinia Manuela Lenghel, Carmen Mihaela Mihu, Andrei Lebovici Copyright (c) 2020 Csaba Csutak, Paul-Andrei Ștefan, Roxana-Adelina Lupean, Lavinia Manuela Lenghel, Carmen Mihaela Mihu, Andrei Lebovici Thu, 17 Dec 2020 15:58:00 +0100 MPTP-induced mouse model of Parkinson’s disease: A promising direction of therapeutic strategies <p>Amongst the popular animal models of Parkinson’s disease (PD) commonly used in researches are those that employ neurotoxins, especially the 1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). MPTP neurotoxin exerts its neurotoxicity by causing a barrage of insults such as oxidative stress, mitochondrial apoptosis, inflammation, excitotoxicity, and formation of inclusion bodies acting singly and in concert. All of this ultimately leads to dopaminergic neuron damage in substantia nigra pars compacta and striatum. The selective neurotoxicity induced by MPTP in the nigrostriatal dopaminergic neuron of the mouse brain brought a new dawn in our perspectives about PD. For decades now MPTP-induced mouse model of PD has become the gold standard in PD research despite its shortcoming in fully recapitulating PD symptomatology. It has the advantage of easy practicability, affordability, less ethical consideration, and more clinical correlation over the other toxin models of PD. The model has rejuvenated researches in PD and has also opened new frontiers in the quest for more novel therapeutic and adjuvant agents for PD. Hence, this review summarizes the MPTP’s role in producing Parkinson-like symptoms in mice, the MPTP-induced mouse model’s experimental role, and the recent development in PD therapeutics using this model to enrich our existing knowledge on this neurotoxin. Furthermore, our review promotes the use of this model by researchers for developing more promising therapeutic strategies.</p> Che Norma Mat Taib, Musa Mustapha Copyright (c) 2020 Che Norma Mat Taib, Musa Mustapha Mon, 14 Dec 2020 21:57:02 +0100 Prevalence, clinical features and prognosis of malignant solid tumors in infants: a 14-year study <p>The onset of malignant solid tumors in infants is insidious and difficult to diagnose on time. The purpose of our study is to provide a theoretical basis for clinical diagnosis by retrospective analysis of the data in the past 14 years. Here, we retrospectively collected the clinical data of infants aged 0-12 months with malignant solid tumors in Beijing Tongren Hospital Affiliated to Capital Medical University from May 2005 to May 2019. The epidemiology, clinical characteristics, treatments and prognosis were statistically analyzed. A total of 496 infants (294 males and 202 females) with malignant solid tumors were analyzed. The main period of onset was 1-11 months. The most common tumor was retinoblastoma (RB, 51.8%), followed by hepatoblastoma (HB, 26.6%), neuroblastoma (NB, 10.5%), rhabdomyosarcoma (RMS, 3.4%), malignant renal tumors (3.2%), infantile fibrosarcoma (IFS, 1.6%), malignant teratoma (1.2%), Ewing’s sarcoma (ES, 0.8%), medulloblastoma (MB, 0.4%) and inflammatory myofibroblastic tumor (IMT, 0.4%). The median follow-up time was 32 months (range 2-162 months). The 1-year, 3-year, and 5-year overall survival of all patients were 97.3%, 89.2%, and 81.1%, respectively, and event-free survival was 94.7%, 84.8%, and 75.8%, respectively. In conclusion, as a special group, malignant solid tumors in infants are complex, heterogeneous, and relatively rare. The prognosis of RB, HB, NB, RMS, malignant renal tumors, IFS, malignant teratoma, ES, MB, and IMT, were excellent duo to timely diagnosis and rational treatment.</p> Tian Zhi, Wei-Ling Zhang, Yi Zhang, Yi-Zhuo Wang, Dong-Sheng Huang Copyright (c) 2020 Tian Zhi, Wei-Ling Zhang, Yi Zhang, Yi-Zhuo Wang, Dong-Sheng Huang Tue, 01 Dec 2020 23:57:48 +0100 The association between serine hydroxymethyl transferase 1 gene hypermethylation and ischemic stroke <p>This study aimed to determine the correlation between serine hydroxymethyl transferase 1 (<em>SHMT1</em>) gene methylation and ischemic stroke. A total of 202 age- and sex-matched individuals were included. Quantitative methylation-specific polymerase chain reaction (qMSP-PCR) was used to analyze the DNA methylation level. The plasma homocysteine (Hcy) concentration was much higher in ischemic cases than in controls (<em>p</em> = 0.009), while the high-density lipoprotein (HDL) levels in stroke cases were considerably lower than in controls (<em>p</em> = 0.005). A significantly higher level of <em>SHMT1</em> methylation was observed in the ischemic strokes (58.82 ± 17.83%) compared to that in the controls (42.59 ± 20.76%, <em>p</em> &lt; 0.001). The <em>SHMT1</em> methylation level was strongly correlated with HDL concentration in the healthy controls (r = 0.517, <em>p</em> &lt; 0.001), while the high plasma level of Hcy showed strong association with <em>SHMT1</em> methylation in ischemic strokes (r = 0.346, <em>p</em> &lt; 0.001). Receiver operating characteristic (ROC) analysis of curve indicated that <em>SHMT1</em> methylation has been an acceptable indicator for ischemic stroke in female patients [all sexes, area under the curve (AUC) = 0.71, <em>p</em> &lt; 0.001; male patients AUC = 0.62, <em>p</em> = 0.032; and female patients AUC = 0.79, <em>p</em> &lt; 0.001] and in all ages (AUC = 0.71, <em>p</em> &lt; 0.001). In our samples, DNA methylation levels of the <em>STHMI</em> gene were significantly correlated with ischemic stroke in Han Chinese. <em>STHMI</em> hypermethylation was significantly associated with the high Hcy concentration in ischemic stroke and had value as a potential indicator for female ischemic stroke.</p> Junnan Wang, Junqing Gu, Yi Huang, Yuanjian Fang, Jinhui Lin Copyright (c) 2020 Junnan Wang, Junqing Gu, Yi Huang, Yuanjian Fang, Jinhui Lin Mon, 30 Nov 2020 11:56:51 +0100 Accelerated atherosclerosis in premenopausal women with rheumatoid arthritis – 15-year follow-up <p>Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased mortality and morbidity due to the higher cardiovascular risk in these patients. Traditional risk factors are not the only answer for the accelerated atherosclerosis. In a long-term prospective study, we investigated the relationship between asymptomatic atherosclerosis and traditional risk factors and inflammatory markers in patients with RA and matched healthy controls. We studied the laboratory test results, the concentrations of inflammatory mediators, matrix metalloproteases (MMP), and inflammation markers in a total of 70 (60 at follow-up) premenopausal healthy women with RA and 40 (34 at follow-up) matched controls. We used the B-mode ultrasound imaging of carotid arteries for the detection of asymptomatic atherosclerosis. Correlation with different factors was evaluated. Statistically significant higher values of inflammatory markers such as selective adhesion molecules ICAM and VCAM, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and MMP-3 in the patients group were found in the follow-up study. More plaques were found in the patients group (42.4% vs. 12.9%; <em>p</em>=0.005), as compared with the controls group. The patients had also higher values of cIMT (<em>p</em>=0.001). Using bivariate regression analysis only VCAM was found as a prognostic factor for plaque occurrence (r= 0. 341, <em>p</em>=0.016), but not for cIMT (r= -0.130, <em>p</em>=0.327) in premenopausal female patients with RA after the follow-up. Therefore, asymptomatic atherosclerosis is accelerated in premenopausal women with RA. The results of our follow-up study showed the association between inflammation and accelerated atherosclerosis. Furthermore, VCAM was found to have a statistically significant correlation with plaque occurrence in these patients.&nbsp;</p> Metka Koren Krajnc, Radovan Hojs, Iztok Holc, Željko Knez, Artur Pahor Copyright (c) 2020 Metka Koren Krajnc, Radovan Hojs, Iztok Holc, Željko Knez, Artur Pahor Wed, 25 Nov 2020 00:29:35 +0100 Stomach-specific c-Myc overexpression drives gastric adenoma in mice through AKT/mammalian target of rapamycin signaling <p>Gastric cancer (GC) is one of the most common malignant cancers in the world.<em> c-Myc</em>, a well-known oncogene, is commonly amplified in many cancers, including gastric cancer. However, it is still not completely understood how<em> c-Myc</em> functions in GC. Here, we generated a stomach-specific <em>c-Myc</em> transgenic mouse model to investigate its role in GC. We found that overexpression of <em>c-Myc </em>in <em>Atp4b<sup>+</sup></em> gastric parietal cells could induce gastric adenoma in mice. Mechanistically, <em>c-Myc</em> promoted tumorigenesis via the AKT/mTOR pathway. Furthermore, AKT inhibitor (MK-2206) or mTOR inhibitor (Rapamycin) inhibited the proliferation of <em>c-Myc</em> overexpressing gastric cancer cell lines. Thus, our findings highlight that gastric tumorigenesis can be induced by <em>c-Myc</em> overexpression through activation of the AKT/mTOR pathway.</p> Jing Liu, Wenxin Feng, Min Liu, Hanyu Rao, Xiaoxue Li, Yan Teng, Xiao Yang, Jin Xu, Weiqiang Gao, Li Li Copyright (c) 2020 Jing Liu, Wenxin Feng, Min Liu, Hanyu Rao, Xiaoxue Li, Yan Teng, Xiao Yang, Jin Xu, Weiqiang Gao, Li Li Thu, 19 Nov 2020 23:45:46 +0100 Raloxifene inhibits the overexpression of TGF-β1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis <p>Overexpression of transforming growth factor-beta 1 (TGF-β1) and subchondral bone remodelling play key roles in osteoarthritis (OA). Raloxifene (RAL) reduces the serum level of TGF-β1 in postmenopausal women. However, the effect of RAL on TGF-β1 expression in articular cartilage is still unclear. Therefore, we aimed to investigate the protective effect of RAL on osteoporotic osteoarthritis via affecting TGF-β1 expression in cartilage and the metabolism of subchondral bone. Osteoporotic osteoarthritis was induced by a combination of anterior cruciate transection (ACLT) and ovariectomy (OVX). Rats were divided into five groups (n = 12): The sham group, the ACLT group, the OVX group, the ACLT + OVX group, and the RAL group (ACLT + OVX + RAL, 6.25 mg/kg/day for 12 weeks). Assessment was performed by histomorphology, microcomputed tomography (micro-CT) scan, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining. We found that severe cartilage degeneration was shown in the ACLT + OVX group. The histomorphological scores, the levels of TGF-β1, and its related catabolic enzymes and osteoclasts numbers in the ACLT + OVX group were higher than those in other groups (<em>p </em>&lt; 0.05). Furthermore, structure model index (SMI) and trabecular spacing (Tb.Sp) were decreased (<em>p </em>&lt; 0.05), while bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) were increased by RAL compared with the ACLT + OVX group (<em>p </em>&lt; 0.05). Our findings demonstrated that RAL in clinical doses retards the development of osteoporotic osteoarthritis by inhibiting the overexpression of TGF-β1 in cartilage and regulating the metabolism of subchondral bone. These results provide support for RAL in the expansion of clinical indication for prevention and treatment in postmenopausal osteoarthritis.</p> Shao-Hua Ping, Fa-Ming Tian, Hao Liu , Qi Sun, Li-Tao Shao, Qiang-Qiang Lian, Liu Zhang Copyright (c) 2020 Shao-Hua Ping, Fa-Ming Tian, Hao Liu , Qi Sun, Li-Tao Shao, Qiang-Qiang Lian, Liu Zhang Thu, 19 Nov 2020 00:49:50 +0100 A plea for extension of the anatomical nomenclature: Vessels <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> David Kachlik, Vladimir Musil, Alzbeta Blankova , Zuzana Marvanova , Jakub Miletin, Daniela Trachtova , Vlasta Dvorakova , Vaclav Baca Copyright (c) 2020 David Kachlik, Vladimir Musil, Alzbeta Blankova , Zuzana Marvanova , Jakub Miletin, Daniela Trachtova , Vlasta Dvorakova , Vaclav Baca Tue, 17 Nov 2020 00:00:00 +0100 Bioinformatics analysis reveals TSPAN1 as a candidate biomarker of progression and prognosis in pancreatic cancer <p>Pancreatic cancer (PCC) is a common malignant tumor of the digestive system that is resistant to traditional treatments and has an overall 5-year survival rate of &lt;7%. Transcriptomics research provides reliable biomarkers for diagnosis, prognosis, and clinical precision treatment, as well as the identification of molecular targets for the development of drugs to improve patient survival. We sought to identify new biomarkers for PCC by combining transcriptomics and clinical data with current knowledge regarding molecular mechanisms. Consequently, we employed weighted gene co-expression network analysis and differentially expressed gene analysis to evaluate genes co-expressed in tumor versus normal tissues using pancreatic adenocarcinoma data from The Cancer Genome Atlas and dataset GSE16515 from the Gene Expression Omnibus. Twenty-one overlapping genes were identified, with enrichment of key Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways, including epidermal growth factor receptor signaling, cadherin, cell adhesion, ubiquinone, and glycosphingolipid biosynthesis pathways, and retinol metabolism. Protein-protein interaction analysis highlighted 10 hub genes, according to Maximal Clique Centrality. Univariate and multivariate COX analyses indicated that TSPAN1 serves as an independent prognostic factor for PCC patients. Survival analysis distinguished TSPAN1 as an independent prognostic factor among hub genes in PCC. Finally, immunohistochemical staining results suggested that the TSPAN1 protein levels in the Human Protein Atlas were significantly higher in tumor tissue than in normal tissue. Therefore, TSPAN1 may be involved in PCC development and act as a critical biomarker for diagnosing and predicting PCC patient survival.</p> Chenhui Ma, ZeLong Cui, YiChao Wang , Lei Zhang, JunYe Wen , HuaiBin Guo, Na Li, WanXing Zhang Copyright (c) 2020 Chenhui Ma, ZeLong Cui, YiChao Wang , Lei Zhang, JunYe Wen , HuaiBin Guo, Na Li, WanXing Zhang Sat, 14 Nov 2020 15:23:27 +0100 Epigenetically inactivated RASSF1A as a tumor biomarker <p><em>RASSF1A</em> represents one of the eight isoforms of the <em>RASSF1</em> gene. <em>RASSF1A</em> is a tumor suppressor gene whose inactivation influences tumor initiation and development. In cancer, <em>RASSF1A</em> is frequently inactivated by mutations, loss of heterozygosity and, most commonly, by promoter hypermethylation. As epigenetic inactivation of <em>RASSF1A</em> was detected in various cancer types, it was extensively investigated and nowadays, the research on <em>RASSF1A</em> promoter methylation proceeds in the light of an epigenetic tumor biomarker. Analyses of DNA methylation of genes involved in carcinogenesis such as<em> RASSF1A</em> are currently done mostly on genomic DNA (gDNA). Simultaneously, cell-free DNA (cfDNA) from liquid biopsies has lately been developed as an early cancer diagnostic tool.&nbsp; This review discusses the evidence on aberrantly methylated <em>RASSF1A</em> in gDNA and cfDNA from different cancer types and its utility for early cancer diagnosis, prognosis, and surveillance. Furthermore, methylation frequencies of <em>RASSF1A</em> in gDNA and cfDNA were compared in various cancer types. The weaknesses and strengths of the investigations mentioned above are discussed. In conclusion, although the importance of <em>RASSSF1A</em> methylation in relation to cancer was established, and it became included in several diagnostic panels, the evidence of its diagnostic utility is still experimental and not yet implemented in standard clinical health care.</p> Dora Raos, Monika Ulamec, Ana Katusic Bojanac, Floriana Bulic-Jakus, Davor Jezek, Nino Sincic Copyright (c) 2020 Dora Raos, Monika Ulamec, Ana Katusic Bojanac, Floriana Bulic-Jakus, Davor Jezek, Nino Sincic Wed, 11 Nov 2020 21:50:06 +0100 Can NLR, PLR and LMR be used as prognostic indicators in patients with pulmonary embolism? Author’s reply on commentary <p>We appreciate the comments made by Dr Bedel and colleagues. NLR, PLR and LMR are affected by various diseases such as oncological, collagen tissue, inflammatory, or severe renal/liver diseases [1]. Because of this, we have listed some of the above-mentioned disorders in the tables. Hematological diseases, collagen tissue disease, inflammatory diseases, congenital heart disease, or severe renal/liver disease were therefore excluded from the study. However, the presence of malignancy did not affect our results in regression analysis.<br>Platelets swell until 120 minutes in ethylene diamine tetra acetic (EDTA) and until 60 minutes in citrate [2]. Authors suggest that optimal measuring time should not exceed 120 minutes. The blood samples of the patients were taken within 1 hour after their emergency admission. All blood samples in our study were tested within 1 hour of collection [3]. We used EDTA for whole blood anticoagulation. The mean duration of symptoms prior to admission was 5.04 ± 6.9 days. <br>The drugs such as corticosteroids affect inflammatory parameters. Therefore, we excluded inflammatory diseases without emphasizing corticosteroids or other anti-inflammatory drugs.</p> Nuri Kose, Tarık Yıldırım, Fatih Akın, Seda Elçim Yıldırım, Ibrahim Altun Copyright (c) 2020 Nuri Kose, Tarık Yıldırım, Fatih Akın, Seda Elçim Yıldırım, Ibrahim Altun Fri, 06 Nov 2020 01:56:50 +0100