Bosnian Journal of Basic Medical Sciences (BJBMS)
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Six RNA binding proteins (RBPs) related prognostic model predicts overall survival for clear cell renal cell carcinoma and is associated with immune infiltration
Get PDFThe aim of this article was to construct an accurate prognostic model by using RNA-binding proteins (RBPs) to predict overall survival (OS) for patients with clear cell renal cell carcinoma (ccRCC) as well as to reveal its associations with immune infiltration. Expression profiles based on RNA-binding proteins (RBPs) and clinical follow-up parameters were obtained from the Cancer Genome Atlas (TCGA) and the ArrayExpress databases. Through univariate COX and LASSO regression analyses, the RBPs based signature was developed. A total of six RBPs (CLK2, IGF2BP2, RNASE2, EZH2, PABPC1L, RPL22L1) were eventually used to establish a prognostic signature. Based on this signature, ccRCC patients were classified into high-risk and low-risk subgroups and significant OS was obtained in both the internal and external datasets (p<0.05). AUCs of its ROC curve were all above 0.70 and this signature was an independent prognostic factor of OS for ccRCC (p<0.05). Nomograms were also constructed to visualize the relationships among individual predictors and 1-, 3- and 5-year OS for ccRCC. Furthermore, the established RBPs based signature was strongly related to critical clinicopathologic characteristics such as grade (p=8.921e−12), stage (p=1.421e−11), M (p=1.662e−05), and T stage (p=7.907e−10). Moreover, 12 kinds of tumor-infiltrating immune cells were significantly linked to high-risk and low-risk groups classified by our constructed model (all p<0.05). Our study successfully identified six RBPs as a robust prognostic signature in ccRCC by both external and internal verification. Besides, our established model displayed significant associations with immune infiltration. In addition to original clinical parameters, our findings may further help clinicians in predicting patients’ survival status and creating individualized treatment plans
Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers
Get PDFAntibody-drug conjugates (ADCs) represent a new class of highly potent antineoplastic drugs built by attaching a small molecule of an anticancer drug (payload) or another therapeutic agent to an antibody recognizing an epitope on the targeted cells. Trophoblast cell-surface antigen-2 (Trop-2) was originally described in trophoblasts and fetal tissues, but subsequently, its overexpression has been demonstrated in various solid malignancies. Sacituzumab govitecan, a conjugate of anti-Trop-2 antibody and SN-38 payload (an active metabolite of irinotecan), is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021). In the current review, we summarize and critically appraise the most recent advances with Sacituzumab govitecan, emphasizing the predictive biomarker analysis
EWSR1 rearrangement in papillary thyroid microcarcinoma is related to classic morphology and the presence of small-cell phenotype
Get PDFThe EWSR1 rearrangements with unknown genes were detected in a high percentage of classic variants of papillary thyroid carcinoma. The small-cell carcinoma of the thyroid with Ewing family tumor elements (CEFTE) typically presents with EWSR1-FLI1 rearrangement suggesting the possible role of EWSR-FLI1 translocation in the loss of thyroid differentiation and acquisition of a small-cell phenotype. In order to determine the frequency and association of EWSR1 rearrangements, particularly the EWSR1-FLI1 fusion with clinicopathological features of papillary thyroid microcarcinoma (m-PTC) and the presence of small cells, we analyzed a series of 99 m-PTCs using the fluorescence in situ hybridization method. Ninety cases (90.9%) of m-PTC were positive for small cells. This group of m-PTC has shown more often invasive growth, lymphatics invasion, and moderate/extended intratumoral fibrosis. Three cases out of 99 were inconclusive for EWSR1 rearrangement. Eighty-nine (92.7%) and twenty-seven (28.1%) out of 96 m-PTC cases were positive for EWSR1 rearrangement and EWSR1-FLI1 fusion, respectively. m-PTC with classical architectural pattern presented more frequently with EWSR1 rearrangement relative to m-PTC with other patterns (p = 0.005). Other clinicopathological features were not related to the presence of EWSR1 rearrangement or EWSR1-FLI1 fusion. The percentage of small cells present significantly correlated with the percentage of cells positive for EWSR1-FLI1 fusion (p = 0.05) and EWSR1 rearrangement (p <0.001). EWSR1-FLI1 fusion is not rare in m-PTC and it is associated with the acquisition of small-cell phenotype. The EWSR1 gene rearrangement is a frequent event in m-PTC and is related to the classical pattern of m-PTC
CircFOXM1 promotes the proliferation, migration, invasion, and glutaminolysis of glioblastoma by regulating the miR-577/E2F5 axis
No full textCircular RNA (circRNA) is a key regulator of tumor progression. However, the role of circFOXM1 in glioblastoma (GBM) progression is unclear. The aim of this study was to investigate the role of circFOXM1 in GBM progression. The expression levels of circFOXM1, miR-577, and E2F transcription factor 5 (E2F5) were examined by real-time quantitative polymerase chain reaction. Cell counting kit 8 assay, EdU staining, and transwell assay were used to detect cell proliferation, migration, and invasion. The levels of glutamine, glutamate, and α-ketoglutarate were determined to evaluate the glutaminolysis ability of cells. Protein expression was tested by Western blot analysis. Dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation assay were employed to verify the interaction between miR-577 and circFOXM1 or E2F5. Mice xenograft model for GBM was constructed to perform in vivo experiments. Our results showed that circFOXM1 was highly expressed in GBM tumor tissues and cells. Silencing of cir FOXM1 inhibited GBM cell proliferation, migration, invasion, glutaminolysis, as well as tumor growth. MiR-577 could be sponged by circFOXM1, and its inhibitor could reverse the suppressive effect of circFOXM1 downregulation on GBM progression. E2F5 was a target of miR-577, and the effect of its knockdown on GBM progression was consistent with that of circFOXM1 silencing. CircFOXM1 positively regulated E2F5 expression, while miR-577 negatively regulated E2F5 expression. In conclusion, our data confirmed that circFOXM1 could serve as a sponge of miR-577 to enhance the progression of GBM by targeting E2F5, which revealed that circFOXM1 might be a biomarker for GBM treatment
Serum glial fibrillary acidic protein as a biomarker of brain injury in premature neonates
Get PDFNeonatal brain injury is a serious adverse outcome of prematurity. Early detection of high risk premature neonates to develop neonatal brain injury is not currently feasible. The predictive value of many biomarkers has been tested, but none is used currently in clinical practice. The purpose of this study was to determine the levels and predictive value of serum glial fibrillary acidic protein (GFAP) in a prospective longitudinal case-control study during the first three days of life in premature neonates (<34 weeks of gestation) that later developed either intraventricular hemorrhage or periventricular leukomalacia. Each case (n=29) was matched according to birth weight and gestational age to one neonate with normal head ultrasound scans. No significant difference on GFAP levels was observed between the groups. Nevertheless, neonates with brain injury presented more frequently GFAP levels above the lowest detection limit (0.056 ng/ml) and this trend was significantly different during all days. The effectiveness of GFAP as an early biomarker of neonatal brain injury in premature neonates seems to be limited
Risk and prognosis of secondary bladder cancer after post-operative radiotherapy for gynecological cancer
Get PDFThe aim of this study was to investigate the impacts of radiation therapy (RT) on the occurrence risk of secondary bladder cancer (SBC) and on the patients’ survival outcome after being diagnosed with gynecological cancer (EC). The data was obtained from the SEER database between 1973 and 2015. Chi-squared test was used to compare the clinicopathological characteristics among the different groups. Fine and Gray’s competing risk model was used to assess the cumulative incidence and occurrence risk of SBC in GC survivors. Kaplan-Meier method was utilized for survival analysis. A total of 123,476 GC patients were included, among which 31,847 (25.8%) patients received RT while 91629 (74.2%) patients did not. The cumulative incidence of SBC was 1.59% or 0.73% among patients who had received prior GC specific RT or not, respectively. All EBRT (standardized incidence ratio (SIR) =2.49, 95% CI [2.17-2.86]), brachytherapy (SIR =1.96, 95% CI [1.60-2.38]), and combinational RT modality groups (SIR =2.73, 95% CI [2.24-3.28]) had dramatically higher SBC incidence as compared to the US general population. Receiving EBRT (HR = 2.83, 95% CI [2.34–3.43]), brachytherapy (HR = 2.17, 95% CI [1.67–2.82]), and combinational RT modality (HR = 2.97, 95% CI [2.34–3.77]) were independent risk factors for SBC development. Survival detriment was observed in SBC patients who received RT after GC diagnosis, as compared to those who did not receive RT. In conclusion, patients who underwent RT after GC had an increased risk of developing bladder as a secondary primary cancer. A long-term surveillance for SBC occurrence is necessary for GC patients who have received prior RT
The expression of VISTA on CD4+ T cells associate with poor prognosis and immune status in non-small cell lung cancer patients
No full textBesides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres
miR-212-3p attenuates neuroinflammation of rats with Alzheimer\u27s disease via regulating the SP1/BACE1/NLRP3/Caspase-1 signaling pathway
Get PDFAlzheimer\u27s disease (AD) ranks as the leading cause of dementia. MicroRNA (miR)-212-3p has been identified to exert neuroprotective effects on brain disorders. The current study analyzed the protective role of miR-212-3p in AD rats via regulating the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/Caspase-1 signaling pathway. The AD rat model was established via injection of amyloid-β 1-42 (Aβ1-42), followed by the Morris water maze test. The morphology and functions of neurons were observed. Furthermore, miR-212-3p, NLRP3, cleaved Caspase-1, gasdermin D N-terminus, interleukin (IL)-1β and IL-18 expressions were measured. H19-7 cells were treated with Aβ1-42 to establish the AD cell model, followed by an assessment of cell viability and pyroptosis. Downstream targets of miR-212-3p and specificity protein 1 (SP1), as well as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) were predicted by databases and testified using dual-luciferase and chromatin immunoprecipitation assays. miR-212-3p was weakly expressed in AD rats. miR-212-3p overexpression was linked to improved learning and memory capacities of AD rats and reduced neuronal pyroptosis linked to neuroinflammation attenuation. In vitro, miR-212-3p improved viability and suppressed pyroptosis of neurons via inhibiting NLRP3/Caspase-1. Overall, miR-212-3p inhibited SP1 expression to block BACE1-induced activation of NLRP3/Caspase-1, thereby attenuating neuroinflammation of AD rats
Untangling the relationship between hemoglobin, peak troponin level, and mortality in patients with myocardial infarction
Get PDFPatients with a history of myocardial infarction (MI) and lower admission hemoglobin (aHb) levels have a worse outcome than patients with higher aHb, but lower or similar peaks in enzymatic infarct size. Hemoglobin levels are positively correlated with body surface area (BSA), which is positively correlated with cardiac mass. We hypothesized that patients with lower aHb suffer comparatively greater myocardial injury. We examined the relationships between aHb, and troponin (Tn) normalized to BSA (Tn/BSA) and its association with 30-day mortality. Data from 6055 patients, who were divided into seven groups based on their aHb at 10g/L intervals, were analyzed, and the groups were compared. The relationships between aHb and Tn/BSA and between Tn/BSA and 30-day mortality were assessed. Patients with higher aHb levels had greater BSA (p<0.0001). A negative relationship between aHb and log10Tn/BSA was observed in the entire group, and in men and women separately (p<0.0001, p<0.0001, and p=0.013, respectively). The log10Tn/BSA value was associated with 30-day mortality in the entire group, and in men and women separately (p<0.0001, p=0.014, and p<0.0001, respectively). Our finding suggests that a similar peak Tn value in patients with lower aHb means comparatively greater myocardial injury relative to cardiac mass. This hypothesis helps to explain the worse outcomes in patients with lower aHb. According to our findings, troponin should be indexed to BSA to provide comparable information on cardiac injury relative to cardiac mass. Whether this relationship is causal remains to be clarified
Comparison of the vitality tests used in the dental clinical practice and histological analysis of the dental pulp
Get PDFIn dentistry, indirect diagnostic methods such as electrical sensibility testing and pulse oximetry are used to assess the status of the pulp. Our study aimed to determine the correlation between hemoglobin oxygen saturation and vascular volume density (Vvasc). We also wanted to examine an electrical sensibility test and the volume density of myelinated nerve fibers (Vnerv). Twenty-six intact permanent premolars were included in the study. For histological analysis, the pulp tissue was stained with hematoxylin-eosin and immunohistochemically for von Willebrand factor and S100 to detect blood vessels and myelinated nerve fibers, respectively. The stereological analysis was used to determine the Vvasc and Vnerv. Statistical analysis was done using the Pearson correlation test and Welch’s ANOVA test. Histological analysis showed that the pulp tissue was strongly vascularized and innervated. A significant positive correlation was found between Vvasc and hemoglobin oxygen saturation levels (p=0.030). A significant negative correlation was found between Vnerv and the lowest electrical voltage that patient felt (p=0.033). According to the maturity of the dental apex, teeth were divided into a group with open (N=6, OA group) and closed apex (N=20, CA group). We found that pulps in the CA group had higher Vnerv than the OA group (p=0.037). In contrast, there were no significant differences in Vvasc of the pulp tissue (p=0.059), oxygen saturation (p=0.907), or electrical voltage (p=0.113) between both groups. We can conclude that the measurement of pulse oximetry and electrical sensibility test reflect the morphology of healthy pulp tissue independently of the maturity of the dental apex