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.

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.

An endoscopic approach providing near-infrared laser-induced coagulation with accurate depth limits.

This article investigates an endoscopic approach that utilizes negative pressure to achieve laser-induced thermal coagulation limited to the esophageal wall's mucosal and superficial submucosal layers. The study was built upon a series of studies combining numerical simulation based on the Monte-Carlo technique and ex vivo porcine tissue experiments, including apparatus design and histology analysis. An endoscopy apparatus was developed using 3D printing to validate the tissue stretching-based approach. A fiber-pigtailed diode was used as the near-infrared source, emitting 208.8 W/cm2 laser irradiance at 1.5 µm. Simulation results suggested that the approach successfully created a local heat well to prevent residual thermal effects (>65°C) from penetrating the deeper submucosal layer. Histology analysis of ex vivo tissues showed that at a fluence of 5.22 kJ/cm2, the depth of thermal coagulation was reduced by half compared to the control. With further preclinical studies, including endoscopy apparatus design, the approach can be applied to the larger esophageal surface.

Beta-Hydroxybutyrate Augments Oxaliplatin-Induced Cytotoxicity by Altering Energy Metabolism in Colorectal Cancer Organoids.

Deregulation of cellular metabolism has recently emerged as a notable cancer characteristic. This reprogramming of key metabolic pathways supports tumor growth. Targeting cancer metabolism demonstrates the potential for managing colorectal cancer. Beta-hydroxybutyrate (BOHB) acts as an acetyl-CoA source for the tricarboxylic acid (TCA) cycle, possibly redirecting energy metabolic pathways towards the TCA cycle that could enhance sensitivity to oxaliplatin, through the generation of reactive oxygen species (ROS). This study explores the potential of BOHB to enhance oxaliplatin's cytotoxic effect by altering the energy metabolism in colorectal cancer. The study employed advanced in vitro organoid technology, which successfully emulates in vivo physiology. The combination treatment efficacy of BOHB and oxaliplatin was evaluated via cell viability assay. The levels of key proteins involved in energy metabolism, apoptotic pathways, DNA damage markers, and histone acetylation were analyzed via Western Blot. ROS levels were evaluated via flow cytometer. Non-toxic doses of BOHB with oxaliplatin significantly amplified cytotoxicity in colorectal cancer organoids. Treatment with BOHB and/or melatonin resulted in significantly decreased lactate dehydrogenase A and increased mitochondrial carrier protein 2 levels, indicating inhibited aerobic glycolysis and an increased oxidative phosphorylation rate. This metabolic shift induced apoptotic cell death mediated by oxaliplatin, owing to high levels of ROS. Melatonin counteracted this effect by protecting cancer cells from high oxidative stress conditions. BOHB may enhance the efficacy of chemotherapeutics with a similar mechanism of action to oxaliplatin in colorectal cancer treatment. These innovative combinations could improve treatment outcomes for colorectal cancer patients.

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.

Overexpressions of RHOA, CSNK1A1, DVL2, FZD8, and LRP5 genes enhance gastric cancer development in the presence of Helicobacter pylori.

BACKGROUND AND STUDY AIMS: Intestinal metaplasia (IM), and Helicobacter pylori (HP) infection can be shown as risk factors in the development of gastric cancer (GC). WNT signaling pathway plays a critical role in carcinogenesis. However, the literature studies are limited on the significance of this pathway for the transition from IM to GC. PATIENTS AND METHODS: We aimed to investigate the importance of the genes of WNT signaling pathways diagnostic and prognostic markers in the presence and absence of HP in conversion from IM to GC. 104 patients, (GC group n = 35, IM group n = 45, control group n = 25) were included in this case-control study. Expression of genes in WNT signalling were searched in study groups with qRT-PCR array and qRT-PCR method. Data were analysed using PCR array data analysis software. RESULTS: Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was detected in the GC and IM groups compared to the control group (p < 0.05). Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was observed in patients with metastatic GC compared to patients with GC without metastasis (p < 0.05). It was found that the RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes were statistically significantly over-expressed in diffuse GC patients compared to non-diffuse GC patients (p < 0.05). Statistically significant overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes was detected in HP positive IM patients compared to HP negative IM patients (p < 0.05). CONCLUSION: Overexpression of RHOA, CSNK1A1, DVL2, FZD8 and LRP5 genes in IM may suggest that these genes are important markers in the development of IM and inflammation with HP. In addition, these genes are linked to tumor burden in the GC group. Consequently, we can conclude that these genes are poor prognosis biomarkers for GC and have the potential to be used as markers for future treatment monitoring.

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.