Potential Tumor Research Articles

Consensus molecular subtyping of colorectal carcinoma brain metastases reveals a metabolic signature associated with poor patient survival.

The transcriptomic classification of primary colorectal cancer (CRC) into distinct consensus molecular subtypes (CMSs) is a well-described strategy for patient stratification. However, the molecular nature of CRC metastases remains poorly investigated. To this end, this study aimed to identify and compare organotropic CMS frequencies in CRC liver and brain metastases. Compared to reported CMS frequencies in primary CRC, liver metastases from CRC patients were CMS4-enriched and CMS3-depleted, whereas brain metastases mainly clustered as CMS3 and rarely as CMS4. Regarding overall survival rates, CMS4 was the most favorable subtype for patients with hepatic lesions, followed by CMS1 and CMS2. The survival of patients with brain metastases did not correlate with CMS. However, we identified a CMS3-related metabolic gene signature, specifically upregulated in central nervous system (CNS)-infiltrating CRC, as a negative prognostic marker and potential tumor progressor. In summary, subtyping of CRC metastases revealed an organotropic CMS distribution in liver and brain with impact on patient survival. CNS-infiltrating CRC samples were enriched for CMS3 and predictive metabolic biomarkers, suggesting metabolic dysregulation of CRC cells as a prerequisite for metastatic colonization of the brain.

DPP4, a potential tumor biomarker, and tumor therapeutic target: review.

Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target.

Combined replacement of lnc-MEG3 and miR-155 elicit tumor suppression in multiple myeloma.

To investigate the biological impact of simultaneous overexpression of lncRNA MEG3 and miR-155, termed a "double hit," on multiple myeloma (MM) cells compared to individual biomarker substitution. Human MM cells were transfected with MEG3-overexpressed plasmids and miR-155 mimics. Cell cytotoxicity, apoptosis, and gene expression were evaluated in transfected cells and clinical samples. MEG3 and miR-155 were significantly downregulated in MM patients, with lower expression levels correlating with advanced disease stages and poorer survival. Dual overexpression induced potent cytotoxic effects in MM cells. MEG3 and miR-155 are potential tumor suppressors in MM. Simultaneous overexpression of both biomarkers could represent a novel therapeutic strategy, and their levels could serve as diagnostic and prognostic markers.

A Comprehensive Analysis of the Role of PAX9 in Head and Neck Squamous Cell Carcinoma.

Paired box 9 (PAX9) has been linked to several human disorders; however, its relevance in Head And Neck Squamous Cell Carcinoma (HNSCC) remains unknown. The difference in PAX9 mRNA expression in pan-cancer was analyzed utilizing The Cancer Genome Atlas (TCGA), and the level of PAX9 protein expression across various types of cancer was assessed utilizing the Human Protein Atlas (HPA) and UALCAN databases, as well as the cellular localization of PAX9. UALCAN studied the methylation levels of PAX9 in pan-cancer. The predictive significance of PAX9 in pan-cancer was assessed utilizing the Kaplan-Meier Plotter website. Functional enrichment analysis was carried out with the "cluster Profiler" program. By employing CCK8 and colony formation methods, the influence of PAX9 on the growth of HNSCC cells was evaluated. By conducting a transwell experiment, we assessed the influence of PAX9 on the migration of HNSCC cells. Western blotting was used to determine the levels of Bax and Bcl-2, two proteins involved in the regulation of apoptosis. A nude mouse model was established to study the impact of PAX9 overexpression on the growth of subcutaneous HNSCC tumors. In HNSCC, the expression of PAX9 was found to be low, while levels of promoter methylation rose considerably. Low PAX9 expression has been linked to a decrease in overall survival (OS) rates among individuals with HNSCC. Furthermore, overexpressing the PAX9 gene decreased HNSCC cell proliferation, migration, and invasion while boosting apoptosis rates. The abnormal expression of PAX9 is linked to various cancers. In HNSCC, PAX9 is a potential tumor suppressor, inhibiting tumor invasion and migration. The results reveal a potentially significant new therapeutic target for HNSCC.

Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53

The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3R97H mutation, which not only fails to activate p53 but also impedes NR2E3WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies.

Identification of critical biomarkers and immune landscape patterns in glioma based on multi-database

PurposeGlioma is the most prevalent tumor of the central nervous system. The poor clinical outcomes and limited therapeutic efficacy underscore the urgent need for early diagnosis and an optimized prognostic approach for glioma. Therefore, the aim of this study was to identify sensitive biomarkers for glioma.Patients and methodsDifferentially expressed genes (DEGs) of glioma were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The potential biomarkers were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. The prognostic ability of the potential biomarkers was evaluated by Cox regression and survival curve. CellMiner was used to access the correlation between the expression of potential biomarkers and anticancer drug sensitivity. We then explored the association of potential biomarkers and tumor immune infiltration by single-sample GSEA (ssGSEA) and CIBERSORT. Immune staining in glioma patient samples and cell experiments of potential biomarkers further verified their expression and function.ResultsUltimately, we identified three potential biomarkers: SLC8A2, ATP2B3, and SRCIN1. These 3 genes were found significantly correlated with clinicopathological features (age, WHO grade, IDH mutation status, 1p19q codeletion status). Furthermore, the overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were found to be positively correlated with high expression of these 3 potential biomarkers. Besides, there was a substantial relationship between the sensitivity of anticancer drugs and these biomarkers expression. More importantly, the negative association between the 3 genes with most tumor immune cells was also established. Moreover, the decreased expression of the biomarkers was also verified in glioma patient samples. Finally, we confirmed that these 3 genes might promotes glioma proliferation and migration in vitro.ConclusionSLC8A2, ATP2B3, and SRCIN1 were identified as underlying biomarkers for glioma associated with prognosis assessments and personal immunotherapy.Graphical

Comprehensive analysis of DNA methylation and gene expression to identify tumor suppressor genes reactivated by MLN4924 in acute myeloid leukemia.

This study investigated whether the neddylation inhibitor MLN4924 induces aberrant DNA methylation patterns in acute myeloid leukemia and contributes to the reactivation of tumor suppressor genes. DNA methylation profiles of Kasumi-1 and KU812 acute myeloid leukemia cell lines before and after MLN4924 treatment were generated using the 850K Methylation BeadChip. RNA sequencing was used to obtain transcriptomic profiles of Kasumi-1 cells. Target genes were identified through a combined analysis of methylation and transcriptome data. Methylation-specific PCR and quantitative PCR validated the changes in methylation and expression. Prognostic analysis of target genes was performed using databases, and Pearson correlation was used to examine the relationship between methylation and expression levels. In Kasumi-1 and KU812 cells, 301 and 469 differentially methylated sites, respectively, were identified. A total of 4310 differential expression genes were detected in Kasumi-1. Combined analysis revealed that TRIM58 exhibited significant demethylation and upregulation after MLN4924 treatment, as confirmed by quantitative and methylation-specific PCR. Furthermore, database analysis revealed that both down-expression and promoter hypermethylation of TRIM58 were correlated with poor prognosis in acute myeloid leukemia. A negative correlation was observed between TRIM58 methylation and expression levels. This study suggests that MLN4924 alters DNA methylation patterns in acute myeloid leukemia and reactivates TRIM58, a potential tumor suppressor gene, through demethylation.

Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells.

Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor. Glioblastoma cells usually lack GLS2 while they express high GLS. We investigated how GLS2 expression modifies the metabolism of glioblastoma cells, looking for changes that may explain GLS2's potential tumour suppressive role. We developed LN-229 glioblastoma cells stably expressing GLS2 and performed isotope tracing using U-13C-glutamine and metabolomic quantification to analyze metabolic changes. Treatment with GLS inhibitor CB-839 was also included to concomitantly inhibit endogenous GLS. GLS2 overexpression resulted in extensive metabolic changes, altering the TCA cycle by upregulating part of the cycle but blocking the synthesis of the 6-carbon intermediates from acetyl-CoA. Expression of GLS2 caused downregulation of PDH activity through phosphorylation of S293 of PDHA1. GLS2 also altered nucleotide levels and induced the accumulation of methylated metabolites and S-adenosyl methionine. These changes suggest that GLS2 may be a key regulator linking glutamine and glucose metabolism, also impacting nucleotides and epigenetics. Future research should ascertain the mechanisms involved and the generalizability of these findings in cancer or physiological conditions.

Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors.

The genomic landscape of esophageal squamous cell carcinoma (ESCC) has been characterized extensively, but there remains a significant need for actionable targets and effective therapies. Here, we perform integrative analysis of genome-wide loss of heterozygosity and expression to identify potential tumor suppressor genes. The functions and mechanisms of one of the candidates, TACC2, are then explored both invitro and invivo, leading to the proposal of a therapeutic strategy based on the concept of synthetic lethality. We reveal that the inactivation of TACC2, due to copy number loss and promoter hypermethylation, is associated with poor prognosis in ESCC patients. TACC2 depletion enhances ESCC tumorigenesis and progression, as demonstrated in Tacc2 knockout mouse models and by increased growth abilities of ESCC cells. Mechanistically, TACC2 interacts with components of the NuRD and CoREST co-repressor complexes, including MTA1, MBD3, and HMG20B, in the cytoplasm. TACC2 loss leads to the translocation of these proteins into the nucleus, facilitating the formation of functional NuRD and CoREST complexes and the epigenetic repression of CDKN1A. This repression results in elevated CDK1/2 activation. Furthermore, TACC2-deficient cells and ESCC patient-derived organoids with reduced TACC2 expression show increased sensitivity to CDK inhibitors, particularly dinaciclib, which is currently in a phase III trial. Notably, the combination of TACC2-specific RNAi and dinaciclib in subcutaneous ESCC models significantly impairs tumor growth. The findings suggest a strategy for cancer treatment based on synthetic lethality. Funded by NKRDP, NSFC, GDIIET, GDBABRF, GDECISTP, and SYSUTP.

EP-0108A is a moderation selectively BRD4 BD2 inhibitor with potential AML tumor suppression.

Acute myeloid leukemia is the most common type of acute leukemia in adults. The epigenetic molecule BRD4 is a member of the bromodomain and extra-terminal family and plays an important role in the occurrence and development of tumors. BRD4 is essential for oncogene expression, including c-Myc. So, BRD4 inhibition is considered as an effective strategy for the treatment of hematological and solid malignancies. In recent years, several small molecule inhibitors targeting BRD4 have been developed. However, these inhibitors had excessive hematological toxicity due to the lack of specific binding to BD1 and BD2 domains of BRD4, while other inhibitors with high selectivity lose their antitumor efficacy. To balance the relationship between efficacy and safety, we developed EP-0108A, a BRD4 inhibitor with moderate selectivity for the BD2 domain over BD1 domain of BRD4. Our results show that EP-0108A has antitumor effects in MV4-11 and Kasumi-1 cell line-derived xenograft mouse models without significant effects on heart or breathing safe in rats and Beagle dogs. In repeated dose toxicity studies, EP-0108A showed reversible hematological and gastrointestinal toxicity in both rats and dogs. Our findings indicate that EP-0108A has the potential to be a new therapeutic agent for the treatment of cancer.

Unraveling the mechanism of microRNA-134 in colon cancer progression: Targeting KRAS and PIK3CA for cell cycle control and histone deacetylase regulation.

Colon cancer is the leading cause of cancer-related deaths worldwide. MicroRNAs (miRNAs) are key regulators of gene expression, often dysregulated in colon cancer. This study aims to elucidate the therapeutic role of miR-134-5p as a tumor suppressor miRNA in colon cancer cells. We analyzed miRNA expression profiles in primary and metastatic colon cancer cells. The clinical significance of miR-134-5p was evaluated using the TCGA database. Bioinformatics tools (HADDOCK) predicted miRNA-mRNA interactions and the molecular docking of miRNA-mRNA-AGO2 complexes. Luciferase reporter assays, cell proliferation, immunofluorescence, colony forming unit assays, and qRT-PCR analysis assessed miR-134-5p effects on KRAS, PIK3CA, and downstream signaling pathways in primary and metastatic colon cancer cells. miR-134-5p was downregulated in colon cancer cells. Bioinformatics analysis suggested KRAS, PIK3CA, EGFR, and HDAC5 as potential targets. HADDOCK analysis revealed strong binding affinity and structural stability between KRAS, PIK3CA, miR-134-5p, and AGO2. Gene-reporter assays confirmed miR-134-5p-mediated degradation of KRAS and PIK3CA. miR-134-5p transfection reduced KRAS and PI3K protein levels, suppressed EGFR/RTK signaling and its downstream targets, and inhibited HDAC expression, ultimately reducing colon cancer cell proliferation. The results of this study confirm that miR-134-5p acts as a potential tumor suppressor miRNA in colon cancer cells by inhibiting KRAS and PI3K expression through AGO2-mediated gene silencing. It deregulates downstream EGFR signaling and HDACs, thereby reducing colon cancer cell proliferation. These findings highlight miR-134-5p as a promising therapeutic target for miRNA-mediated anticancer therapy.

Intratumoral Fusobacterium nucleatum in Pancreatic Cancer: Current and Future Perspectives

The intratumoral microbiome plays a significant role in many cancers, such as lung, pancreatic, and colorectal cancer. Pancreatic cancer (PC) is one of the most lethal malignancies and is often diagnosed at advanced stages. Fusobacterium nucleatum (Fn), an anaerobic Gram-negative bacterium primarily residing in the oral cavity, has garnered significant attention for its emerging role in several extra-oral human diseases and, lately, in pancreatic cancer progression and prognosis. It is now recognized as oncobacterium. Fn engages in pancreatic tumorigenesis and metastasis through multifaceted mechanisms, including immune response modulation, virulence factors, control of cell proliferation, intestinal metabolite interactions, DNA damage, and epithelial–mesenchymal transition. Additionally, compelling research suggests that Fn may exert detrimental effects on cancer treatment outcomes. This paper extends the perspective to pancreatic cancer associated with Fn. The central focus is to unravel the oncogenomic changes driven by Fn in colonization, initiation, and promotion of pancreatic cancer development. The presence of Fusobacterium species can be considered a prognostic marker of PC, and it is also correlated to chemoresistance. Furthermore, this review underscores the clinical research significance of Fn as a potential tumor biomarker and therapeutic target, offering a novel outlook on its applicability in cancer detection and prognostic assessment. It is thought that given the role of Fn in tumor formation and metastasis processes via its FadA, FapA, Fap2, and RadD, new therapies for tumor treatment targeting Fn will be developed.

Investigating LETd optimization strategies in carbon ion radiotherapy for pancreatic cancer: a dosimetric study using an anthropomorphic phantom.

Clinical carbon ion beams offer the potential to overcome hypoxia-induced radioresistance in pancreatic tumors, due to their high dose-averaged Linear Energy Transfer (LETd), as previous studies have linked a minimum LETd within the tumor to improved local control. Current clinical practices at the Heidelberg Ion-Beam Therapy Center (HIT), which use two posterior beams, do not fully exploit the LETd advantage of carbon ions, as the high LETd is primarily focused on the beams' distal edges. Different LETd-boosting strategies, such as Spot-scanning Hadron Arc (SHArc), could enhance LETd distribution by concentrating high-LETd values in potential hypoxic tumor cores while sparing organs at risk. This study aims to investigate and verify different LETd-boosting strategies using an anthropomorphic pancreas phantom. Various LETd-boosting strategies were investigated for a cylindrical and a pancreas-shaped target in an anthropomorphic pancreas phantom. Treatment plans were optimized using single field optimization (SFO) or multi field optimization (MFO), with objective functions based on either physical dose (Phys), relative biological effectiveness(RBE)-weighted dose, or a combination of RBE and LETd-based objectives (LETopt). The LETd-boosting planning strategies were optimized with the goal of increasing the minimum LETd in the tumor without compromising its homogeneous dose coverage. Beam configurations investigated included the two-beam in-house clinical standard (2-SFOPhys, 2-SFORBE and 2-MFORBE-LETopt), a three-beam configuration (3-MFORBE and 3-MFORBE-LETopt) and SHArc (SHArcPhys, SHArcRBE and SHArcRBE-LETopt) using step-and-shoot delivery. The different plans were verified using an anthropomorphic pancreas phantom at HIT and compared to treatment planning system (TPS) predictions. All investigated LETd-boosting strategies altered the LETd distribution while meeting optimization goals and constraints, resulting in varying degrees of LETd enhancement. For the cylindrical volume, the SHArc plan resulted in the highest LETd concentration in the tumor core, with the minimum LETd in the GTV scaling up to 91keV/µm. For the pancreas-shaped volume, however, the 3-MFORBE-LETopt achieved a higher minimum LETd in the GTV than SHArcRBE (75.6 and 62.3keV/µm, respectively). When combining SHArc with LETd optimization, a minimum LETd of 76.3keV/µm was achieved, suggesting a potential benefit from this combined approach. Most dosimetric verifications showed dose deviations to the TPS within a 5% range, for both beam-per-beam and total dose. LETd-optimized and SHArc plans exhibited slightly higher mean dose deviations (2.0%-4.6%) compared to the standard RBE-based plans (<1.5%). This study demonstrated the feasibility of enhancing LETd in pancreatic tumors using carbon ion arc delivery coupled with LETd optimization. The possibility of delivering these plans was verified through irradiation of an anthropomorphic pancreas phantom, which showed agreement between dose measurements and predictions.

Diagnostic value of digital breast tomosynthesis in suspicious lesions detected in screening mammogram

BackgroundDigital mammography (DM) serves as the primary breast imaging technique for early cancer detection and diagnosis. However, it faces certain limitations, particularly in imaging dense breasts. DM exhibits reduced sensitivity and specificity in women with radiographically dense breast tissue due to diminished contrast between potential tumors and surrounding tissue, as well as tissue summation potentially obscuring lesions. The aim of this study was to assess the diagnostic efficacy of digital breast tomosynthesis compared to digital mammography in evaluating suspicious breast lesions. The study included 60 female patients eligible for mammography. All participants underwent full-field digital mammography and 3d tomosynthesis. Written informed consent was obtained from all subjects after explaining the research’s purpose and benefits. The Ethics Committee of the Faculty of Medicine, Menoufia University approved the study under code no. 10/2022RADI24.ResultsRegarding BIRADS classification: All 60 patients were categorized using the BIRADS lexicon for both mammography and digital breast tomosynthesis. Mammography results showed BIRADS 3 in 10% (6/60), BIRADS 4a in 33.3% (20/60), 4b in 10% (6/60), BIRADS 4c in 26.7% (16/60), and BIRADS 5 in 20% (12/60) of cases. In comparison, tomosynthesis classified cases as BIRADS 3 in 13.3% (8/60), 4b in 16.7% (10/60), BIRADS 4c in 23.3% (14/60), and BIRADS 5 in 46.7% (28/60) of cases.ConclusionsDigital breast tomosynthesis (DBT) has established itself as a significant advancement in three-dimensional breast imaging for both screening and diagnostic purposes. It exhibits enhanced performance in identifying breast abnormalities and generates images of superior diagnostic quality with improved precision compared to conventional digital mammography. This improvement is particularly notable when examining dense breast tissue, which has traditionally been one of the most challenging aspects of breast imaging.

Design of a novel complex 99mTc-Nilutamide as a tracer for prostate cancer disorder detection in mice

Abstract Male prostate cancer (PCa) is considered among the most fatal illnesses. Despite the recent decrease in prostate cancer incidence attributed to advancements in early detection and therapy, these reductions have not effectively mitigated the elevated fatality rate linked to this disease. The drug Nilutamide was effectively radiolabeled with technetium-99m, producing a radiochemical yield of 96 ± 0.14 % under optimal conditions. In our study, two cohorts of mice were utilized, namely the control group and the group with prostate cancer. Various biochemical parameters, including PSA levels in serum, were assessed, revealing a significantly elevated value in the group with prostate cancer, indicating potential tumor development. Furthermore, the activities of antioxidant enzymes (CAT, SOD) were notably lower in the group with prostate cancer compared to the healthy control group, while the oxidative activity reflected by MDA levels, the final product of lipid peroxidation, was higher in the prostate cancer group than in the healthy control group. The biodistribution analysis showed rapid localization of 99mTc-Nilutamide in prostate cancer tissue after 2 h post-injection, with a substantial value of 11.4 ± 1.1 % I. D/g tissue. Consequently, it was deduced that radiolabeled 99mTc-Nilutamide can serve as an effective imaging tool for prostate cancer.

Depletion of ELMOD3 inhibits the growth and migration of gastric cancer cells by disrupting the β-catenin signaling and the F-actin cytoskeleton.

ELMOD3 (encoding ELMO domain containing 3) is a causative gene associated with human autosomal dominant nonsyndromic and progressive hearing loss. However, the role of ELMOD3 in the occurrence and development of tumors remains unknown. Herein, we observed that inactivation of ELMOD3 in gastric cancer cells significantly inhibited their proliferation, migration, and invasion, and altered cell cycle progression. A xenograft tumor model showed that knockout of ELMOD3 suppressed the tumorigenicity of BGC823 gastric cancer cells in nude mice. Further investigation demonstrated that the ELMO domain of ELMOD3 interacts with β-catenin, which increases the levels of β-catenin, promoting downstream target gene expression. Deletion of ELMOD3 in gastric cells decreased the β-catenin signaling, elevated E-cadherin levels, suppressed RAF/MEK/ERK signal pathway, and disrupted the formation of F-actin cytoskeleton. These results led us to propose that ELMOD3 may participate in multiple biological processes in promoting the tumorigenesis of gastric cancer. It exerts a positive role in the regulation of gastric cancer cell proliferation and progression. Thus, ELMOD3 was identified as a potential tumor target, which deserves further investigation.

Synthesis and Relaxivity study of amino acid-branched radical dendrimers as MRI contrast agents for potential brain tumor imaging.

This study introduces a series of water-soluble radical dendrimers (G0 to G5) as promising magnetic resonance imaging (MRI) contrast agents that could potentially address clinical safety concerns associated with current gadolinium-based contrast agents. By using a simplified synthetic approach based on a cyclotriphosphazene core and lysine-derived branching units, we successfully developed a G5 dendrimer containing up to 192 units of 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO) radical. This synthesis offers advantages including ease of preparation, purification, and tunable water solubility through the incorporation of glutamic acid anion residues. Comprehensive characterization using 1H NMR, FT-IR, and SEC-HPLC confirmed the dendrimers' structures and purity. Electron paramagnetic resonance (EPR) spectroscopy revealed that TEMPO groups in higher generation dendrimers exhibited decreased mobility and stronger spin exchange in their local environments. In vitro MRI showed that relaxivity (r1) increased with higher dendrimer generations, with G5 exhibiting an exceptionally high r1 of over 24 mM-1s-1. Molecular dynamics simulations provided crucial insights into structure-property relationships, revealing the importance of water accessibility to TEMPO groups for enhancing relaxivity. Vero cell viability assay demonstrated G3 and G3.5 have good biocompatibility. In vivo MRI experiments in mice demonstrated that G3.5 was excreted through the kidneys and selectively accumulated in glioblastoma tumors. STATEMENT OF SIGNIFICANCE: This study explores a class of MRI contrast agents based on organic radical dendrimers as a potential alternative to gadolinium-based agents. We present a simplified synthesis method for water-soluble dendrimers containing up to 192 TEMPO radical units-the highest number achieved to date for this class of compounds-resulting in record-high relaxivity values. Our approach offers easier preparation, purification, and tunable water solubility, representing an improvement over existing methods. Through combined experimental and computational studies, we provide insights into the structure-property relationships governing relaxivity. In vivo experiments demonstrate the dendrimers' potential for glioblastoma imaging, with predominantly renal excretion. This work represents a step towards developing metal-free MRI contrast agents with promising relaxivity and biocompatibility, potentially opening new avenues for diagnostic imaging research.

3D bioprinting of multicellular tumor spheroids in photocrosslinkable hyaluronan-gelatin for engineering pancreatic cancer microenvironment

3D bioprinting can be utilized to fabricate cancer-like tissue that models complex interactions within the cancer microenvironment. In human pancreatic ductal adenocarcinoma (PDAC), these interactions involve the extracellular matrix (ECM), cancer cells, and pancreatic stellate cells. Hyaluronan (HA) is a major component of ECM supporting tumor progression and chemoresistance in PDAC. In the current study, an in vitro PDAC-like tissue platform was developed by embedding multicellular pancreatic tumor-like spheroids within a novel 3D bioprinting HA-gelatin photocrosslinked hydrogel (GHP). This optimized GHP bioink (7 wt% gelatin and 0.2 wt% phenolic HA) achieved a modulus (∼5.46 kPa) closely resembling that of clinical PDAC tissue, with a dense and uniform structure superior to gelatin-only hydrogel (GN). The bioprinted 3D tumor-like spheroids within GHP exhibited distinct invasive and metastatic behavior, along with up-regulated expression of epithelial-mesenchymal transition (EMT) markers. Furthermore, gene expression analysis also revealed a ∼290-fold increase in CD44 gene and a 7.3-fold rise in S100A9 (a novel pancreatic cancer biomarker for early diagnosis). These tumor-like spheroids within 3D-bioprinted GHP constructs further demonstrated substantial chemoresistance, maintaining remarkable 98.5% viability after 48 h of exposure to a Gemcitabine and Abraxane combination, in contrast to significantly lower resistance observed in spheroids alone or co-cultured monolayers. An in-depth investigation of HA distribution within the 3D-bioprinted PDAC-like construct revealed a pattern consistent with clinical PDAC, indicating enhanced malignancy and potential tumor reprogramming. This 3D-bioprinted PDAC model holds significant potential for advancing pancreatic cancer research and preclinical drug testing.

GNAO1: A Novel Tumor Suppressor Gene in Colorectal Cancer Pathogenesis.

This study examined the role of GNAO1 as a potential tumor suppressor gene in colorectal cancer (CRC). RNA-seq data analysis revealed a significant GNAO1 down-regulation in colon cancer tissues compared to normal colon tissues. GNAO1 over-expression in CRC cell lines inhibited cell proliferation, migration, and tumor formation both in vitro and in vivo. This study suggests that GNAO1 exerts its tumor-suppressive effects by inhibiting the mTOR/S6K signaling pathway. The observed correlation between GNAO1 expression and cancer progression highlights its potential as a prognostic marker and therapeutic target in CRC. This study provides a foundation for further exploration of the molecular mechanisms by which GNAO1 influences CRC pathogenesis, with significant implications for its application in clinical settings.

Distinctive genomic features of human T-lymphotropic virus type 1-related adult T-cell leukemia-lymphoma in Western populations.

Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy driven by human T-cell leukemia virus type 1 (HTLV-1). Although patients from the Western hemisphere (Afro-Caribbean and South American) face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletions and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-sequencing, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest that ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with chronic cases with unfavorable outcomes. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.