In Silico Approach to Molecular Profiling of the Transition from Ovarian Epithelial Cells to Low-Grade Serous Ovarian Tumors for Targeted Therapeutic Insights.

This paper aims to elucidate the differentially coexpressed genes, their potential mechanisms, and possible drug targets in low-grade invasive serous ovarian carcinoma (LGSC) in terms of the biologic continuity of normal, borderline, and malignant LGSC. We performed a bioinformatics analysis, integrating datasets generated using the GPL570 platform from different studies from the GEO database to identify changes in this transition, gene expression, drug targets, and their relationships with tumor microenvironmental characteristics. In the transition from ovarian epithelial cells to the serous borderline, the FGFR3 gene in the "Estrogen Response Late" pathway, the ITGB2 gene in the "Cell Adhesion Molecule", the CD74 gene in the "Regulation of Cell Migration", and the IGF1 gene in the "Xenobiotic Metabolism" pathway were upregulated in the transition from borderline to LGSC. The ERBB4 gene in "Proteoglycan in Cancer", the AR gene in "Pathways in Cancer" and "Estrogen Response Early" pathways, were upregulated in the transition from ovarian epithelial cells to LGSC. In addition, SPP1 and ITGB2 genes were correlated with macrophage infiltration in the LGSC group. This research provides a valuable framework for the development of personalized therapeutic approaches in the context of LGSC, with the aim of improving patient outcomes and quality of life. Furthermore, the main goal of the current study is a preliminary study designed to generate in silico inferences, and it is also important to note that subsequent in vitro and in vivo studies will be necessary to confirm the results before considering these results as fully reliable.

Reference values for T and B lymphocyte subpopulations in Turkish children and adults

Background/aim: Established reference values are critical for the interpretation of immunologic assessments. In particular, the proportion and absolute counts of T- and B- cell subpopulations are subject to change with age and ethnicity. We aimed to establish age- specific reference values for lymphocyte subsets using updated immunophenotyping panels. Materials and methods: We studied a total of 297 healthy Turkish subjects aged 0 to 50 years, stratified into major age brackets in a cluster factor of 10 per age-group. The predetermined age intervals contained randomly allocated participants enrolled over a period of 6 months, who were homogenously distributed by sex. We analyzed a complete blood count test and simultaneously with detailed immunophenotyping enumerated the percent and absolute cell counts of lymphocyte subsets. Results: The percentage and absolute counts of lymphocyte subsets show a marked surge across the age-span. T helper, T cytotoxic, and the natural killer cell numbers were increasing from birth until 6 months, followed by a gradual decrease thereafter. B cell numbers were rising until 2 years, followed by a gradual decrease for the upcoming years, accompanied by a steady expansion of unclass-switched- and class-switched- B cells. Conclusion: We provide updated extensive reference intervals for lymphocyte subpopulations in Turkish people.

Carvacrol alters soluble factors in HCT-116 and HT-29 cell lines

Background/aim: Natural products are popular insights for researchers to investigate promising anti-cancer agents since some of these substances have lesser adverse effects restricting the treatment than traditional chemotherapeutic agents. A well-known monoterpene Carvacrol, widely consumed in Mediterranean cuisine and lower risks of cancer, has efficient anticancer effects. However, the mechanism of action is yet to be discovered. Materials and methods: The investigation aims to illuminate a new perceptive in the role of this substance on colorectal cancer treatment, by the means of differences in a well-defined range of soluble factors. Carvacrol effect on both HT-29 and HCT-116 cell lines was evaluated on proliferation and the IC50 values were calculated by the RTCA xCELLigence device. Then MAGPIX assay was performed to obtain the changes in soluble factors of the cell lines. Results: The Multiplexing assay suggests some of these factors were altered in favor of surviving and proliferation in aggressive cell line HCT-116 whereas they were altered against these characters in HT-29, were correlated with the increased IC50 concentration of HCT- 116 in carvacrol treatment. Conclusion: The current study indicates that differences in the levels of these soluble factors could modulate the anticancer effect related to carvacrol.

New treatment alternatives for primary and metastatic colorectal cancer by an integrated transcriptome and network analyses.

Metastatic colorectal cancer (CRC) is still in need of effective treatments. This study applies a holistic approach to propose new targets for treatment of primary and liver metastatic CRC and investigates their therapeutic potential in-vitro. An integrative analysis of primary and metastatic CRC samples was implemented for alternative target and treatment proposals. Integrated microarray samples were grouped based on a co-expression network analysis. Significant gene modules correlated with primary CRC and metastatic phenotypes were identified. Network clustering and pathway enrichments were applied to gene modules to prioritize potential targets, which were shortlisted by independent validation. Finally, drug-target interaction search led to three agents for primary and liver metastatic CRC phenotypes. Hesperadin and BAY-1217389 suppress colony formation over a 14-day period, with Hesperadin showing additional efficacy in reducing cell viability within 48 h. As both candidates target the G2/M phase proteins NEK2 or TTK, we confirmed their anti-proliferative properties by Ki-67 staining. Hesperadinin particular arrested the cell cycle at the G2/M phase. IL-29A treatment reduced migration and invasion capacities of TGF-ß induced metastatic cell lines. In addition, this anti-metastatic treatment attenuated TGF-ß dependent mesenchymal transition. Network analysis suggests IL-29A induces the JAK/STAT pathway in a preventive manner.

Association of Serum Hepatocyte Growth Factor Level with Systemic Inflammatory Biomarkers in Patients with Pancreatobiliary Cancer.

BACKGROUND: Hepatocyte growth factor is a cytokine secreted by the stromal cells in the tumor microenvironment. There is little information about the clinical significance of serum hepatocyte growth factor level in patients diagnosed with pancreatobiliary cancer. The objective of the current study was to investigate the relationship between serum hepatocyte growth factor level with inflammation markers and the clinical features of patients with pancreatobiliary cancer. METHODS: A total of 62 patients with pancreatobiliary cancer were included in this study. Serum hepatocyte growth factor concentrations were evaluated utilizing the enzyme-linked immunosorbent assay method. RESULTS: The median serum hepatocyte growth factor level was 329.1 ng/mL (1.4-1051.1). The patients were categorized into 2 groups as those below the median hepatocyte growth factor level (low hepatocyte growth factor) and those above the median hepatocyte growth factor level (high hepatocyte growth factor). While 40.9% of the patients without metastasis were observed to be in the high hepatocyte growth factor group, 72.2% of the metastatic patients were observed to be in the high hepatocyte growth factor group (P = .025). The median levels of monocyte, monocyte-to-lymphocyte ratio, C-reactive protein, and C-reactive protein-to-albumin ratio were found to be significantly higher in the high hepatocyte growth factor group as compared to the low hepatocyte growth factor group (P < .050). CONCLUSION: The significant relationship between serum hepatocyte growth factor level and systemic inflammation markers in patients with pancreatobiliary cancer is shown for the first time in our study. This study, which showed a significant relationship between the presence of metastasis and serum hepatocyte growth factor level, suggests that serum hepatocyte growth factor level may be a prognostic biomarker in patients who are diagnosed with pancreatobiliary cancer.

Evaluation of 25-hydroxyvitamin D (25(OH)D) levels before and during the COVID-19 pandemic: A cross-sectional study and trend analysis involving 86,772 samples.

BACKGROUND: The aim of this paper was to evaluate the change in 25-hidroxyvitamin D (25(OH)D) levels before and during the COVID-19 pandemic. METHODS: In this retrospective, cross-sectional and methodological study included 86,772 patients (18-75 years) samples who were admitted to the Izmir Dokuz Eylul University Hospital (latitude and longitude (Turkey): 27 E 09; 38 N 25, respectively) for various reasons and whose 25(OH)D levels were measured in the biochemistry unit between 2019-2020 and 2020-2021 (before and during the COVID-19 outbreak). A time series analysis of monthly averages for 25(OH)D was performed. For the purpose of seasonal study, the mean levels of 25(OH)D are grouped by years. Data were modeled in terms of 25(OH)D levels using the MATLAB Curve Fitting Toolbox. RESULTS: There was no significant difference between the sexes according to 25(OH)D levels (p>0.05). 25(OH)D levels were significantly higher in the summer months and lower in the winter months (p<0.001). When comparing the spring months, 25(OH)D levels in 2020 (18 ± 10) were found to be significantly lower than in 2019 (22 ± 12) (p<0.001); on the contrary, when examined based on the summer, autumn, and winter months, it was determined that 25(OH)D levels increased in 2020 (summer: 25 ± 13, autumn: 25 ± 14, and winter: 19 ± 10) compared to 2019 (summer: 23 ± 11, autumn: 22 ± 10, and winter: 19 ± 11) (p<0.001). In the estimates curve obtained with an error margin of 11% in the time series analysis, it was estimated that the 25(OH)D averages after the pandemic would be similar to those before the pandemic. CONCLUSIONS: Restrictions, partial or complete closures, and curfews can significantly affect individuals' 25(OH)D levels during the COVID-19 outbreak. There is a need for multicenter studies with larger populations covering different regions to strengthen and support our results.

The Prognostic Significance of Circulating Tumor Cells in Patients with Pancreatobiliary Cancer.

BACKGROUND: Circulating tumor cells (CTCs) are cancer cells which separate from the primary tumor and enter systemic circulation. In this study, it was aimed to examine the relationship between CTCs isolated and identified from the peripheral blood of patients with pancreatobiliary cancer, with the clinicopathological characteristics of the patients and their overall survival. METHODS: A total of 21 patients were included the study. Density gradient centrifugation with the OncoQuick® assay was performed for isolation of CTCs from peripheral blood. In order to identify CTCs, enriched samples underwent flow cytometric analysis. RESULTS: The rate of patients with positive surgical margin in the high CTC group (CTC <15) was identified to be statistically significantly high compared to the group with low CTC (CTC ≤15) (83.3% vs. 16.7%; P = .041). Median neutrophil/lymphocyte ratio (NLR) was found to be higher in the high CTC group compared to the low CTC group, which was close to statistical significance (2.37 vs. 1.41; P = .055). CONCLUSIONS: Circulating tumor cells were identified to have a significant relationship with surgical margin positivity in our study for the first time, suggesting that the CTCs count in peripheral blood in preoperative patients may be a biomarker predicting positive surgical margin. Due to the very low number of studies assessing the relationship between CTCs and NLR, our study which identified relationship close to statistical significance between CTCs and NLR, significantly contributes to the literature on the topic of the possible role of lymphocytes in CTC clearance.

Prognostic and predictive role of liquid biopsy in lung cancer patients.

Introduction: Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. Approximately 80% of LC cases are of the non-small cell lung cancer (NSCLC) type, and approximately two-thirds of these cases are diagnosed in advanced stages. Only systemic treatment methods can be applied to patients in the advanced stages when there is no chance of surgical treatment. Identification of mutations that cause LC is of vital importance in determining appropriate treatment methods. New noninvasive methods are needed to repeat and monitor these molecular analyses. In this regard, liquid biopsy (LB) is the most promising method. This study aimed to determine the effectiveness of LB in detecting EGFR executive gene mutations that cause LC. Methods: One hundred forty-six patients in stages IIIB and IV diagnosed with non-squamous cell non-small cell LC were included. Liquid biopsy was performed as a routine procedure in cases where no mutation was detected in solid tissue or in cases with progression after targeted therapy. Liquid biopsy samples were also obtained for the second time from 10 patients who showed progression under the applied treatment. Mutation analyses were performed using the Cobas® EGFR Test, a real-time PCR test designed to detect mutations in exons 18, 20, and 21 and changes in exon 19 of the EGFR gene. Results: Mutation positivity in paraffin blocks was 21.9%, whereas it was 32.2% in LB. Solids and LB were compatible in 16 patients. Additionally, while no mutation was found in solid tissue in the evaluation of 27 cases, it was detected in LB. It has been observed that new mutations can be detected not only at the time of diagnosis, but also in LB samples taken during the follow-up period, leading to the determination of targeted therapy. Discussion: The results showed that "liquid biopsy" is a successful and alternative non-invasive method for detecting cancer-causing executive mutations, given the limitations of conventional biopsies.

In silico identification of novel biomarkers for key players in transition from normal colon tissue to adenomatous polyps.

Adenomatous polyps of the colon are the most common neoplastic polyps. Although most of adenomatous polyps do not show malign transformation, majority of colorectal carcinomas originate from neoplastic polyps. Therefore, understanding of this transformation process would help in both preventive therapies and evaluation of malignancy risks. This study uncovers alterations in gene expressions as potential biomarkers that are revealed by integration of several network-based approaches. In silico analysis performed on a unified microarray cohort, which is covering 150 normal colon and adenomatous polyp samples. Significant gene modules were obtained by a weighted gene co-expression network analysis. Gene modules with similar profiles were mapped to a colon tissue specific functional interaction network. Several clustering algorithms run on the colon-specific network and the most significant sub-modules between the clusters were identified. The biomarkers were selected by filtering differentially expressed genes which also involve in significant biological processes and pathways. Biomarkers were also validated on two independent datasets based on their differential gene expressions. To the best of our knowledge, such a cascaded network analysis pipeline was implemented for the first time on a large collection of normal colon and polyp samples. We identified significant increases in TLR4 and MSX1 expressions as well as decrease in chemokine profiles with mostly pro-tumoral activities. These biomarkers might appear as both preventive targets and biomarkers for risk evaluation. As a result, this research proposes novel molecular markers that might be alternative to endoscopic approaches for diagnosis of adenomatous polyps.

Machine learning for differentiating metastatic and completely responded sclerotic bone lesion in prostate cancer: a retrospective radiomics study.

OBJECTIVE: Using CT texture analysis and machine learning methods, this study aims to distinguish the lesions imaged via 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/CT as metastatic and completely responded in patients with known bone metastasis and who were previously treated. METHODS: We retrospectively reviewed the 68Ga-PSMA PET/CT images of 75 patients after treatment, who were previously diagnosed with prostate cancer and had known bone metastasis. A texture analysis was performed on the metastatic lesions showing PSMA expression and completely responded sclerotic lesions without PSMA expression through CT images. Textural features were compared in two groups. Thus, the distinction of metastasis/completely responded lesions and the most effective parameters in this issue were determined by using various methods [decision tree, discriminant analysis, support vector machine (SVM), k-nearest neighbor (KNN), ensemble classifier] in machine learning. RESULTS: In 28 of the 35 texture analysis findings, there was a statistically significant difference between the two groups. The Weighted KNN method had the highest accuracy and area under the curve, has been chosen as the best model. The weighted KNN algorithm was succeeded to differentiate sclerotic lesion from metastasis or completely responded lesions with 0.76 area under the curve. GLZLM_SZHGE and histogram-based kurtosis were found to be the most important parameters in differentiating metastatic and completely responded sclerotic lesions. CONCLUSIONS: Metastatic lesions and completely responded sclerosis areas in CT images, as determined by 68Ga-PSMA PET, could be distinguished with good accuracy using texture analysis and machine learning (Weighted KNN algorithm) in prostate cancer. ADVANCES IN KNOWLEDGE: Our findings suggest that, with the use of newly emerging software, CT imaging can contribute to identifying the metastatic lesions in prostate cancer.