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NeuroImage. Clinical May 2024The main objective was to characterize the tracer uptake kinetics of [F]fluoromethylcholine ([F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling...
PURPOSE
The main objective was to characterize the tracer uptake kinetics of [F]fluoromethylcholine ([F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling approach. Secondarily, we aimed to explore the relationship between the PET uptake measures and the HGG molecular features.
MATERIALS AND METHODS
Twenty-four patients with a suspected diagnosis of HGG were prospectively included. They underwent a dynamic brain [F]F-CHO-PET/CT, from which a tumoral time-activity curve was extracted. The plasma input function was obtained through arterial blood sampling with metabolite correction. These data were fitted to 1- and 2-tissue-compartment models, the best of which was selected through the Akaike information criterion. We assessed the correlation between the kinetic parameters and the conventional static PET metrics (SUV, SUV and tumor-to-background ratio TBR). We explored the association between the [F]F-CHO-PET quantitative parameters and relevant molecular biomarkers in HGG.
RESULTS
Tumoral time-activity curves in all patients showed a rapid rise of [F]F-CHO uptake followed by a plateau-like shape. Best fits were obtained with near-irreversible 2-tissue-compartment models. The perfusion-transport constant K and the net influx rate K showed strong correlation with SUV (r = 0.808-0.861), SUV (r = 0.794-0.851) and TBR (r = 0.643-0.784), p < 0.002. HGG was confirmed in 21 patients, of which those with methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter showed higher mean K (p = 0.020), K (p = 0.025) and TBR (p = 0.001) than the unmethylated ones.
CONCLUSION
[F]F-CHO uptake kinetics in HGG is best explained by a 2-tissue-compartment model. The conventional static [F]F-CHO-PET measures have been validated against the perfusion-transport constant (K) and the net influx rate (K) derived from kinetic modeling. A relationship between [F]F-CHO uptake rate and MGMT methylation is suggested but needs further confirmation.
PubMed: 38763039
DOI: 10.1016/j.nicl.2024.103616 -
World Journal of Surgical Oncology May 2024Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant...
BACKGROUND
Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated.
METHODS
We initially conducted an analysis of the B7 family members' expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored.
RESULTS
Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs).
CONCLUSION
The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; TOR Serine-Threonine Kinases; ErbB Receptors; Cell Proliferation; Proto-Oncogene Proteins c-akt; Cell Movement; Epithelial-Mesenchymal Transition; Disease Progression; Prognosis; Macrophages; Tumor Cells, Cultured; Signal Transduction; Male; Biomarkers, Tumor; MAP Kinase Signaling System; Apoptosis; THP-1 Cells; Gene Expression Regulation, Neoplastic; Female; Immunoglobulins
PubMed: 38762741
DOI: 10.1186/s12957-024-03409-2 -
Scientific Reports May 2024According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial...
According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR) < 0.05, results showed that S100A16 was protective protein and S100A14 was risk protein for human epidermal growth factor receptor 2-positive (HER-positive) breast cancer, phosphodiesterase 5A (PDE5A) was risk protein for colorectal cancer, and melanoma inhibitory activity (MIA) was protective protein for non-small cell lung carcinoma (NSCLC). And there was no reverse causal association between them. Colocalization analysis showed that S100A14 (PP.H4.abf = 0.920) and S100A16 (PP.H4.abf = 0.932) shared causal variation with HER-positive breast cancer, and PDE5A (PP.H4.abf = 0.857) shared causal variation with colorectal cancer (CRC). The MR results of all pQTL of PDE5A and MIA were consistent with main results. In addition, the MR results of MIA and external outcome cohort were consistent with main results. In this study, genetic predictions indicate that circulating S100 calcium binding protein A14 (S100A14) and S100 calcium binding protein A16 (S100A16) are associated with increase and decrease in the risk of HER-positive breast cancer, respectively. Circulating PDE5A is associated with increased risk of CRC, while circulating MIA is associated with decreased risk of NSCLC. These findings suggest that four proteins may serve as biomarkers for cancer prevention and as potential drug targets that could be expected for approval.
Topics: Humans; Mendelian Randomization Analysis; Neoplasms; Genome-Wide Association Study; Quantitative Trait Loci; Antineoplastic Agents; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 38762700
DOI: 10.1038/s41598-024-62178-w -
Scientific Reports May 2024Matrix metalloproteinases (MMPs) had a variety of subtypes, which may be related to tumor invasion and angiogenesis, and the polymorphisms from MMPs have been also... (Meta-Analysis)
Meta-Analysis
Matrix metalloproteinases (MMPs) had a variety of subtypes, which may be related to tumor invasion and angiogenesis, and the polymorphisms from MMPs have been also associated with the susceptibility to a variety of tumors, including prostate cancer (PCa). However, previous studies have not systematically analyzed the association between MMP and prostate cancer, so we conducted systematic data collection and analyzed to evaluate the relationship among polymorphisms in MMPs and PCa susceptibility. We searched PubMed, Web of Science, Embase and Google Scholar for all papers published up to Apr 3rd, 2023, and systematically analyzed the relationship among MMP1-1607 2G/1G, MMP2-1306 T/C, MMP2-735 T/C, MMP7-181 G/A, MMP9-1562 T/C and PCa susceptibility using multiple comparative models and subgroup analyses. We found that MMP2-1306 T/C polymorphism showed associations with PCa susceptibility, with the Ethnicity subgroup (Asian) being more pronounced. Similarly, MMP9-1562 T/C has also had associations with PCa susceptibility. Our current study found that the polymorphisms of, MMP2-1306 T/C, and MMP9-1562 T/C had strong associations with PCa risk.
Topics: Humans; Male; Prostatic Neoplasms; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Matrix Metalloproteinase 9; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Risk Factors; Matrix Metalloproteinase 7; Matrix Metalloproteinase 1
PubMed: 38762659
DOI: 10.1038/s41598-024-62016-z -
Nature Communications May 2024Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients...
Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC.
Topics: Female; Humans; Ovarian Neoplasms; Deep Learning; Cystadenocarcinoma, Serous; Platinum; Middle Aged; Aged; Biomarkers, Tumor; Treatment Outcome; Neoplasm Grading; Cohort Studies; Adult; Reproducibility of Results
PubMed: 38762636
DOI: 10.1038/s41467-024-48667-6 -
Scientific Reports May 2024Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput...
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput biomarker interrogation in tissues but may not capture histological features of cancer with potential biological relevance. Topographic TMAs (T-TMAs) representing pathophysiological hallmarks of cancer were constructed from representative, retrospective PDAC diagnostic material, including 72 individual core tissue samples. The T-TMA was interrogated with tissue hybridization-based experiments to confirm the accuracy of the topographic sampling, expression of pro-tumourigenic and immune mediators of cancer, totalling more than 750 individual biomarker analyses. A custom designed Next Generation Sequencing (NGS) panel and a spatial distribution-specific transcriptomic evaluation were also employed. The morphological choice of the pathophysiological hallmarks of cancer was confirmed by protein-specific expression. Quantitative analysis identified topography-specific patterns of expression in the IDO/TGF-β axis; with a heterogeneous relationship of inflammation and desmoplasia across hallmark areas and a general but variable protein and gene expression of c-MET. NGS results highlighted underlying genetic heterogeneity within samples, which may have a confounding influence on the expression of a particular biomarker. T-TMAs, integrated with quantitative biomarker digital scoring, are useful tools to identify hallmark specific expression of biomarkers in pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Biomarkers, Tumor; Tissue Array Analysis; High-Throughput Nucleotide Sequencing; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Retrospective Studies; Transcriptome; Male; Female; Middle Aged; Aged
PubMed: 38762572
DOI: 10.1038/s41598-024-62031-0 -
Cell Death Discovery May 2024Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5...
Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC. A schematic diagram demonstrating the regulatory effect of GAS5 on immune cell infiltration by activating type I interferon signaling via MYBBP1A-p53/IRF1 axis in non-small cell lung cancer. IFN, interferon.
PubMed: 38762546
DOI: 10.1038/s41420-024-01997-2 -
Scientific Reports May 2024Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in...
Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in IDH-wildtype GB is O6-methylguanine-DNA methyltransferase (MGMT) methylation (mMGMT), which is associated with improved treatment response and survival. However, current efforts to monitor GB patients through mMGMT detection have proven unsuccessful. Small extracellular vesicles (sEVs) hold potential as a key element that could revolutionize clinical practice by offering new possibilities for liquid biopsy. This study aimed to determine the utility of sEV-based liquid biopsy as a predictive biomarker and disease monitoring tool in patients with IDH-wildtype GB. Our findings show consistent results with tissue-based analysis, achieving a remarkable sensitivity of 85.7% for detecting mMGMT in liquid biopsy, the highest reported to date. Moreover, we suggested that liquid biopsy assessment of sEV-DNA could be a powerful tool for monitoring disease progression in IDH-wildtype GB patients. This study highlights the critical significance of overcoming molecular underdetection, which can lead to missed treatment opportunities and misdiagnoses, possibly resulting in ineffective therapies. The outcomes of our research significantly contribute to the field of sEV-DNA-based liquid biopsy, providing valuable insights into tumor tissue heterogeneity and establishing it as a promising tool for detecting GB biomarkers. These results have substantial implications for advancing predictive and therapeutic approaches in the context of GB and warrant further exploration and validation in clinical settings.
Topics: Humans; Glioblastoma; Extracellular Vesicles; Liquid Biopsy; DNA Modification Methylases; DNA Repair Enzymes; DNA Methylation; Male; Female; Biomarkers, Tumor; Middle Aged; Tumor Suppressor Proteins; Brain Neoplasms; Aged; Adult; Prognosis
PubMed: 38762534
DOI: 10.1038/s41598-024-62061-8 -
Scientific Reports May 2024Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological...
Neuroprotective and cognitive enhancing effects of herbecetin against thioacetamide induced hepatic encephalopathy in rats via upregulation of AMPK and SIRT1 signaling pathways.
Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological characteristics. The purpose of this study was to assess the ability of herbacetin to protect against the cognitive deficits associated with thioacetamide (TAA) rat model and delineate the underlying behavioral and pharmacological mechanisms. Rats were pretreated with herbacetin (20 and 40 mg/kg) for 30days. On 30th day, the rats were injected with TAA (i.p. 350 mg/kg) in a single dose. In addition to a histpathological studies, ultra-structural architecture of the brain, liver functions, oxidative stress biomarkers, and behavioral tests were evaluated. Compared to the TAA-intoxicated group, herbacetin improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels. Herbacetin reduced brain levels of malodialdeyde, glutamine synthetase (GS), tumor necrosis factor- alpha (TNF-α), interleukin 1 B (IL-1β), annexin v, and increased brain GSH, Sirtuin 1 (SIRT1), and AMP-activated kinase (AMPK) expression levels. Also, herbacetin improve the histopathological changes and ultra- structure of brain tissue via attenuating the number of inflammatory and apoptotic cells. Herbacetin treatment significantly reduced the toxicity caused by TAA. These findings suggest that herbacetin might be taken into account as a possible neuroprotective and cognitive enhancing agent due to its ability to reduce oxidative stress, inflammation and apoptosis associated with TAA.
Topics: Animals; Thioacetamide; Sirtuin 1; Hepatic Encephalopathy; Rats; Neuroprotective Agents; Signal Transduction; AMP-Activated Protein Kinases; Male; Oxidative Stress; Up-Regulation; Cognition; Brain; Rats, Wistar; Liver; Disease Models, Animal
PubMed: 38762495
DOI: 10.1038/s41598-024-61639-6 -
BMC Urology May 2024Index tumors are the most aggressive tumors of the prostate. However, their clinical significance remains unclear. This study aimed to assess the incidence of index...
BACKGROUND
Index tumors are the most aggressive tumors of the prostate. However, their clinical significance remains unclear. This study aimed to assess the incidence of index tumor location according to the zonal origin and whether these locations affect the prognosis after radical prostatectomy in patients with negative surgical margins.
METHODS
This single-centered, retrospective study evaluated 1,109 consecutive patients who underwent radical prostatectomies. An index tumor was defined as the largest tumor in the prostate gland. We detected these locations based on McNeal's zonal origin using whole-mount sections. Biochemical recurrence (BCR) free survival curves were generated using the Kaplan-Meier method. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine the predictive factors for early BCR (within 1-year).
RESULTS
A total of 621 patients with negative surgical margins who did not receive adjuvant therapy were included in this study. The index tumor were located in the transitional zone in 191 patients (30.8%), the peripheral zone in 399 patients (64.3%), and the central zone in 31 patients (5.0%). In total, 22 of 621 patients (3.5%) experienced early BCR and 70 patients (11.2%) experienced overall BCR at a median follow-up of 61.7 months. According to the index tumor location, the early BCR-free rates were 99.5%, 95.7 %, and 83.3% in the transitional, peripheral, and central zones, respectively. On multivariate analysis, the index tumor in the central zone was an independent predictor of early BCR with negative surgical margins following radical prostatectomy, followed by prostatectomy pathological grade, index tumor in the peripheral zone, and high prostate-specific antigen level.
CONCLUSIONS
We assessed the significance of index tumor location in patients with negative surgical margins following radical prostatectomy. Index tumors located in the central zone, although infrequent, were the strongest predictive factors for early BCR. Our results may allow urologists and patients to reconsider the therapeutic strategies for prostate cancer.
Topics: Humans; Male; Prostatectomy; Retrospective Studies; Margins of Excision; Prostatic Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Aged; Prostate-Specific Antigen; Prognosis
PubMed: 38762458
DOI: 10.1186/s12894-024-01499-4