SMAD4–201 transcript as a putative biomarker in colorectal cancer

Background Transcripts with alternative 5′-untranslated regions (UTRs) result from the activity of alternative promoters and they can determine gene expression by influencing its stability and translational efficiency, thus executing complex regulation of developmental, physiological and pathological processes. Transcriptional regulation of human SMAD4, a key tumor suppressor deregulated in most gastrointestinal cancers, entails four alternative promoters. These promoters and alternative transcripts they generate remain unexplored as contributors to the SMAD4 deregulation in cancer. The aim of this study was to investigate the relative abundance of the transcript SMAD4–201 in colorectal cell lines and tissues in order to establish if its fluctuations may be associated with colorectal cancer (CRC). Methods Relative abundance of SMAD4–201 in total SMAD4 mRNA was analyzed using quantitative PCR in a set of permanent human colon cell lines and tumor and corresponding healthy tissue samples from patients with CRC. Results The relative abundance of SMAD4–201 in analyzed cell lines varied between 16 and 47%. A similar relative abundance of SMAD4–201 transcript was found in the majority of analyzed human tumor tissue samples, and it was averagely 20% lower in non-malignant in comparison to malignant tissue samples (p = 0.001). Transcript SMAD4–202 was not detectable in any of the analyzed samples, so the observed fluctuations in the composition of SMAD4 transcripts can be attributed to transcripts other than SMAD4–201 and SMAD4–202. Conclusion The expression profile of SMAD4–201 in human tumor and non-tumor tissue samples may indicate the translational potential of this molecule in CRC, but further research is needed to clarify its usability as a potential biomarker for early diagnosis.

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner–Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

3D bioprinted tumor model with extracellular matrix enhanced bioinks for nanoparticle evaluation

The traditional evaluation of nanoparticles (NPs) is mainly based on 2D cell culture and animal models. However, these models are difficult to accurately represent human tumor microenvironment (TME) and fail to systematically study the complex transportation of NPs, thus limiting the translation of nano-drug formulations to clinical studies. This study reports a tumor model fabricated via 3D bioprinting with decellularized extracellular matrix (adECM) enhanced hybrid bioink. Compared with 2D cultured cells, the 3D printed tumor models with multicellular spheroids formation are closer to real tumor in protein, gene expression and tumorigenicity both in vitro and in vivo. Two characteristics of TME, ECM remodeling and epithelial-mesenchymal transition (EMT), are tracked simultaneously under 3D conditions. Furthermore, the cellular uptake efficiency of two different NPs is significantly lower in the printed 3D tumor model than the 2D individual cells, and higher drug resistance is observed in 3D group, which suggest the ECM barrier of tumor can significantly affect the permeability of NPs. These results suggest that this 3D printed tumor model is capable of mimicking the multiple TME, potentially providing a more accurate platform for the design and development of NPs before moving into animal and clinical trials.

The Oncogenic Role of γ-Aminobutyrate Aminotransferase in Human Tumor: A Pan-Cancer Analysis

Emerging evidence supports the correlation between γ-aminobutyrate aminotransferase (ABAT) and tumors, but few research groups used pan-cancer analysis to verify it previously. Therefore, this study used the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) to obtain information about the correlations between ABAT and tumor development, and to explore its potential effectiveness for genetic alterations in tumor prognosis. The reduced expression level of ABAT in a majority of tumors is significantly associated with the poor prognosis. The genetic alteration of ABAT seems linked to the favorable prognosis of Uterine Corpus Endometrial Carcinoma (UCEC). Immune infiltration analysis showed a significantly positive correlation between ABAT and cancer-associated fibroblasts in the majority of tumors, but a highly negative correlation with Kidney renal clear cell carcinoma (KIRC), Kidney Renal Papillary cell carcinoma (KIRP), and Prostate adenocarcinoma (PRAD). Enrichment analysis showed that cell junction organization, amino acids metabolism, and neuronal system-involved behaviors might affect the pathogenesis or etiology of cancer. This study is the first pan-cancer analysis that offers a detailed, comprehensive study of the process of the oncogenic roles of ABAT across different human tumors.

Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis

Patients with malignant pleural mesothelioma (MPM) have very poor prognoses, and pemetrexed plus platinum is the standard first-line therapy. However, the second-line therapy for relapsed MPM remains controversial. A comprehensive search was performed to identify randomized controlled trials (RCTs) evaluating various second-line regimens in patients with relapsed MPM. Indirect comparisons of overall survival (OS) and progression-free survival (PFS) were performed using network meta-analysis. Surface under the cumulative ranking curve (SUCRA) values were used to rank the included treatments according to each outcome. Nivolumab alone or nivolumab plus ipilimumab provided significantly longer OS than placebo (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55–0.94 for nivolumab alone; HR: 0.54, 95% CI: 0.31–0.92 for nivolumab plus ipilimumab). The best SUCRA ranking for OS was identified for nivolumab plus ipilimumab (SUCRA: 90.8%). Tremelimumab, vorinostat, nivolumab alone, chemotherapy (CTX), asparagine–glycine–arginine–human tumor necrosis factor plus CTX, and nivolumab plus ipilimumab all produced noticeable PFS benefits compared with placebo. Nivolumab plus ipilimumab had the best PFS ranking (SUCRA: 92.3%). Second-line treatment with nivolumab plus ipilimumab provided the OS and PFS outcomes for patients with relapsed MPM.

Newly-Obtained Two Organic-Inorganic Hybrid Compounds Based on Potassium Peroxidomolybdate and Dicarboxypyridinic Acid: Structure Determination, Catalytic Properties, and Cytotoxic Effects of Eight Peroxidomolybdates in Colon and Hepatic Cancer Cells

Two new organic-inorganic hybrid compounds containing dicarboxylic pyridine acids have been obtained and characterized. Both compounds are potassium oxidodiperoxidomolybdates with 2,6-dicarboxylicpyridine acid or 3,5-dicarboxylicpyridine acid moieties, respectively. The chemical formula for the first one is C14H7K3Mo2N2O18 denoted as K26dcpa, the second C7H4K1Mo1N1O11.5—K35dcpa. Their crystal structures were determined using single crystal (K26dcpa) or XRPD—X-ray powder diffraction techniques (K35dcpa). The purity of the compounds was confirmed by elemental analysis. Their thermal stability was determined with the use of non-ambient XRPD. In addition, they were examined by IR spectroscopy methods and catalytic activity studies were performed for them. Catalytic tests in the Baeyer–Villiger reaction and biological activity have been performed for eight compounds: K26dcpa, K35dcpa, and six peroxidomolybdates previously obtained by our group. The anti-proliferative activity of peroxidomolybdenum compounds after 24 h of incubation was studied in vitro against three selected human tumor cell lines (SW620, LoVo, HEP G2) and normal human cells (fibroblasts). The data were expressed as IC50 values. The structure of the investigated oxodiperoxomolybdenum compounds was shown to have influence on the biological activity and catalytic properties. It has been shown that the newly-obtained compound, K35dcpa, is a very efficient catalyst in the Baeyer–Villiger reaction. The best biological activity results were obtained for Na-picO (previously obtained by us), which is a very effective anti-cancer agent towards SW 620 colorectal adenocarcinoma cells.

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

Hyaluronic acid fuels pancreatic cancer cell growth

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

Phytochemical analysis and antiproliferative properties of Pistacia atlantica leaves

The medicinal plants may serve as potential sources for the development of new drugs and more effective anticancer agents for future therapy. Pistacia atlantica (Vahl.) Masters (Anacardiaceae) is an important plant used in traditional medicine practice in Algeria, and North Africa countries. The present study has the objective to estimate the in vitro antiproliferative (on the RD and Hep2 human tumor cell lines using the3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) assay) properties of the aqueous extracts of P. atlantica leaves, offering a phytochemical characterization of its aqueous extracts, by spectrophotometry methods. evealed by HPLC, phenolic compounds present among the five different flavonoids identified such as: ((epi)catechin, myricetin, quercetin and kaempferol glycoside derivatives). The MTT assay revealed that the tested extract had a good activity against Hep2 and RD cell lines with median inhibitory concentration (GI50)> 1000 μg/mL against Hep2 and (IC50) = 825,079 μg/mL against RD, (GI 50). The results showed a great bioactive potential for this species with a significant contribution of phenolic compounds, specially the flavonoids which makes it an interesting matrix in the development of novel pharmaceutical formulations. Planned future studies will involve the identification of different extract other than aqueous extract, determination of the mechanisms of action and the bioactive molecule of plant extracts. Keywords: Pistacia atlantica; aqueous extract; antiproliferative; MTT, HPLC.