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Neoplasia (New York, N.Y.) Jun 2024Cancer of unknown primary (CUP) is a rare type of metastatic cancer in which the origin of the tumor is unknown. Since the treatment strategy for patients with...
Cancer of unknown primary (CUP) is a rare type of metastatic cancer in which the origin of the tumor is unknown. Since the treatment strategy for patients with metastatic tumors depends on knowing the primary site, accurate identification of the origin site is important. Here, we developed an image-based deep-learning model that utilizes a vision transformer algorithm for predicting the origin of CUP. Using DNA methylation dataset of 8,233 primary tumors from The Cancer Genome Atlas (TCGA), we categorized 29 cancer types into 18 organ classes and extracted 2,312 differentially methylated CpG sites (DMCs) from non-squamous cancer group and 420 DMCs from squamous cell cancer group. Using these DMCs, we created organ-specific DNA methylation images and used them for model training and testing. Model performance was evaluated using 394 metastatic cancer samples from TCGA (TCGA-meta) and 995 samples (693 primary and 302 metastatic cancers) obtained from 20 independent external studies. We identified that the DNA methylation image reveals a distinct pattern based on the origin of cancer. Our model achieved an overall accuracy of 96.95 % in the TCGA-meta dataset. In the external validation datasets, our classifier achieved overall accuracies of 96.39 % and 94.37 % in primary and metastatic tumors, respectively. Especially, the overall accuracies for both primary and metastatic samples of non-squamous cell cancer were exceptionally high, with 96.79 % and 96.85 %, respectively.
PubMed: 38943996
DOI: 10.1016/j.neo.2024.101021 -
International Immunopharmacology Jun 2024Lung adenocarcinoma (LUAD) is the most common and aggressive cancer with a high incidence. N1-specific pseudouridine methyltransferase (EMG1), a highly conserved...
BACKGROUND AND AIMS
Lung adenocarcinoma (LUAD) is the most common and aggressive cancer with a high incidence. N1-specific pseudouridine methyltransferase (EMG1), a highly conserved nucleolus protein, plays an important role in the biological development of ribosomes. However, the role of EMG1 in the progression of LUAD is still unclear.
METHODS
The expression of EMG1 in LUAD cells, and LUAD tissues, and adjacent noncancerous tissues was quantified using real-time polymerase chain reaction (PCR) and western blotting. The roles of EMG1 in LUAD cell proliferation, migration, invasion and tumorigenicity were explored in vitro and in vivo. Western blot analysis to underlying molecular mechanism of EMG1 regulating the biological function of LUAD. EMG1 expression and its impact on tumor prognosis were analyzed using a range of databases including GEPIA, UALCAN, cBioPortal, LinkedOmics, and Kaplan-Meier Plotter.
RESULTS
EMG1 expression was elevated in LUAD patients compared to normal tissues, and EMG1 expression was strongly correlated with prognosis in LUAD patients. EMG1 expression correlated with age, gender, N stage, T stage, and pathologic stage. EMG1 expression was strongly positively correlated with MRPL51, PHB2, SNRPG, ATP5MD, and TPI1, and strongly negatively correlated with MACF1, DOCK9, RAPGEF2, SYNJ1, and KIDINS220, the major enrichment pathways for EMG1 and related genes include Cell cycle, DNA Replication and Pathways in cancer signaling pathways. EMG1 expression level was significantly increased in LUAD cell lines and tissues. Knockdown of EMG1 could inhibit LUAD cell proliferation, migration, invasion, and tumorigenicity. Besides, EMG1 overexpression could promote LUAD cell proliferation, migration, and invasion. High expression of EMG1 predicts poor prognosis in LUAD patients, and EMG1 may play an oncogenic role in the tumor microenvironment by participating in the infiltration of LUAD immune cells.
CONCLUSIONS
EMG1 regulated various functions in LUAD by directly mediating Akt/mTOR/p70s6k signaling pathways activation. The results suggest that EMG1 may be a novel biomarker for assessing prognosis and immune cell infiltration in LUAD.
PubMed: 38943975
DOI: 10.1016/j.intimp.2024.112553 -
Biochimica Et Biophysica Acta.... Jun 2024Toll-like receptor 9 (Tlr9) is a pathogen recognition receptor detecting unmethylated DNA derivatives of pathogens and damaged host cells. It is therefore an important...
BACKGROUND & AIMS
Toll-like receptor 9 (Tlr9) is a pathogen recognition receptor detecting unmethylated DNA derivatives of pathogens and damaged host cells. It is therefore an important modulator of innate immunity. Here we investigated the role of Tlr9 in fibrogenesis and progression of hepatocellular carcinoma in chronic liver disease.
MATERIALS AND METHODS
We treated mice with a constitutive deletion of Tlr9 (Tlr9) with DEN/CCl for 24 weeks. As a second model, we used hepatocyte-specific Nemo knockout (Nemo) mice and generated double knockout (NemoTlr9) animals.
RESULTS
We show that Tlr9 is in the liver primarily expressed in Kupffer cells, suggesting a key role of Tlr9 in intercellular communication during hepatic injury. Tlr9 deletion resulted in reduced liver fibrosis as well as tumor burden. We observed down-regulation of hepatic stellate cell activation and consequently decreased collagen production in both models. Tlr9 deletion was associated with decreased apoptosis and compensatory proliferation of hepatocytes, modulating the initiation and progression of hepatocarcinogenesis. These findings were accompanied by a decrease in interferon-β and an increase in chemokines having an anti-tumoral effect.
CONCLUSIONS
Our data define Tlr9 as an important receptor involved in fibrogenesis, but also in the initiation and progression of hepatocellular carcinoma during chronic liver diseases.
PubMed: 38943920
DOI: 10.1016/j.bbadis.2024.167321 -
Journal of Colloid and Interface Science Jun 2024Targeted breast cancer therapies hold the potential to improve the efficiency of drug delivery to the pathology site without impacting the viability and function of...
Targeted breast cancer therapies hold the potential to improve the efficiency of drug delivery to the pathology site without impacting the viability and function of healthy cells. Herein, we developed multifunctional nanocarriers that target simultaneously several downstream signaling processes in triple negative breast cancer cells. The system comprises pH sensitive CaCO nanoparticles (NPs) as carriers of the anticancer drug doxorubicin (DOX). The NPs were coated in a layer-by-layer (LbL) fashion using poly-l-lysine and hyaluronic acid to target receptors overexpressed in breast cancer (e.g. CD44, RHAMM). Spheroids of the triple-negative Hs578T cell line were used as a 3D model to assess the therapeutic potential of this system. Our results showed that the NPs act via a synergistic mechanism that combines Ca overload causing cell calcification and DNA damage by DOX. The LbL coating was crucial for the protection of the healthy cells, i.e. it provides NPs with targeting capacity. The overall data suggests that the LbL-coated NPs loaded with DOX hold great potential for the treatment of breast cancer.
PubMed: 38943911
DOI: 10.1016/j.jcis.2024.06.159 -
Journal of Colloid and Interface Science Jun 2024The biofilm-mediated implant infections pose a huge threat to human health. It is urgent to explore strategies to reverse this situation. Herein, we design...
The biofilm-mediated implant infections pose a huge threat to human health. It is urgent to explore strategies to reverse this situation. Herein, we design 3-amino-1,2,4-triazole-5-thiol (ATT)-modified gold nanoclusters (AGNCs) to realize biofilm-targeting and near-infrared (NIR)-II light-responsive antibiofilm therapy. The AGNCs can interact with the bacterial extracellular DNA through the formation of hydrogen bonds between the amine groups on the ATT and the hydroxyl groups on the DNA. The AGNCs show photothermal properties even at a low power density (0.5 W/cm) for a short-time (5 min) irradiation, making them highly effective in eradicating the biofilm with a dispersion rate up to 90 %. In vivo infected catheter implantation model demonstrates an exceptional high ability of the AGNCs to eradicate approximately 90 % of the bacteria encased within the biofilms. Moreover, the AGNCs show no detectable toxicity or systemic effects in mice. Our study suggests the great potential of the AGNCs for long-term prevention and elimination of the biofilm-mediated infections.
PubMed: 38943910
DOI: 10.1016/j.jcis.2024.06.172 -
European Journal of Cancer (Oxford,... Jun 2024Circulating tumor DNA (ctDNA) has emerged as a promising tool for early cancer detection and minimal residual disease monitoring. However, the biology underlying ctDNA...
BACKGROUND
Circulating tumor DNA (ctDNA) has emerged as a promising tool for early cancer detection and minimal residual disease monitoring. However, the biology underlying ctDNA release and its variation across cancer types and histologies remains poorly understood. This study investigated the biology behind ctDNA shedding in colorectal cancer.
METHODS
The study included a local cohort of 747 stage I-III colorectal cancer patients. All patients had ctDNA measurement prior to treatment and extensive clinical data. Primary tumor RNA sequencing and whole exome sequencing was performed in 95 and 652 patients respectively. Additionally, the study evaluated 89 non-small cell lung cancer patients from the TRACERx cohort, comprising primary tumor RNA sequencing and ctDNA measurement.
RESULTS
We found tumor size and proliferative capacity to be key factors associated with ctDNA shedding in colorectal cancer. Furthermore, we found that the secretory and CMS3 colorectal cancer subtypes exhibited lower ctDNA shedding, while microsatellite instability (MSI) tumors had higher levels of ctDNA. Mutational analysis did not reveal any genes or pathways associated with ctDNA shedding in colorectal cancer. A comparison of transcriptomic profiles across multiple cancer types demonstrated that colorectal cancer and lung squamous cell carcinoma tumors shared a high-proliferative ctDNA shedding phenotype, while lung adenocarcinoma tumors displayed a distinct low-proliferative subgroup. Additionally, proliferation levels correlated with ctDNA detection sensitivity across multiple cancer types.
CONCLUSION
These findings suggest that tumor size and proliferative capacity are drivers of ctDNA release in colorectal cancer and provide insights into the biology of ctDNA shedding on a pan-cancer level.
PubMed: 38943900
DOI: 10.1016/j.ejca.2024.114186 -
Archives of Oral Biology Jun 2024In this in vivo proof-of-concept study, acquired pellicle engineering was implemented to promote alterations in the protein composition of the acquired enamel pellicle...
OBJECTIVE
In this in vivo proof-of-concept study, acquired pellicle engineering was implemented to promote alterations in the protein composition of the acquired enamel pellicle (AEP) and the bacterial composition of the dental biofilm after treatment with Sugarcane cystatin (CaneCPI-5).
DESIGN
After prophylaxis, 10 volunteers rinsed (10 mL, 1 min) with the following solutions: 1) deionized water (HO- negative control or 2) 0.1 mg/mL CaneCPI-5. The AEP and biofilm were formed along 2 or 3 h, respectively. The AEP was collected with electrode filter papers soaked in 3 % citric acid. After protein extraction, samples were analyzed by quantitative shotgun label-free proteomics. The biofilm microbiome was collected with a dental curette. The DNA was extracted, amplified, and analyzed by 16S-rRNA Next Generation Sequencing (NGS).
RESULTS
Treatment with CaneCPI-5 increased several proteins with antimicrobial, acid-resistance, affinity for hydroxyapatite, structural and calcium binding properties, such as Cysteine-rich-3 (6-fold-p = 0.03), Cystatin-B (5.5-fold-p < 0.01), Neutrophil-defensin 1 (4.7-fold-p < 0.01), Mucin (3.9-fold-p < 0.01), Immunoglobulin-heavy-constant (3.8-fold-p < 0.01) and Lactotransferrin (2.8-fold-p < 0.01). Microbiome revealed that several commensal bacteria had their abundance increased after rinsing with CaneCPI-5, such as Corynebacterium and Neisseria, while Streptococcus and Prevotella nigrescens were decreased. The results indicate the efficiency of CaneCPI-5 in promoting beneficial changes in the AEP and biofilm, making this phytocystatin a potential target for incorporation into dental products.
CONCLUSION
Cane demonstrated the capability to alter the protein composition of the acquired enamel pellicle (AEP) and the initial colonizers of the biofilm, enhancing the presence of proteins and bacteria crucial for dental protection.
PubMed: 38943859
DOI: 10.1016/j.archoralbio.2024.106025 -
Biosensors & Bioelectronics Jun 2024Most multiplexed photoelectrochemical (PEC) sensors require additional instrumentation and cumbersome electrode modification and surface partitioning, which limits their...
Most multiplexed photoelectrochemical (PEC) sensors require additional instrumentation and cumbersome electrode modification and surface partitioning, which limits their portability and instrument miniaturization. Herein, a pH-responsive programmable triple DNA nanomachine was developed for constructing a reconfigurable multiplex PEC sensing platform. By programming the base sequence, T-A·T-riched triple DNA was designed to construct integrated nano-controlled release machine (INCRM) for simultaneous recognition of multiple targets. The INCRM enables to recognize two targets in one step, and sequentially separate the signal labels by pH adjustment. The detached signal label catalyzes glucose to produce gluconic acid, causing the C-riched DNA fold into a triple structure on the electrode surface. As a result, one target can be detected relying on the enhanced photocurrent due to accelerated electron transfer between the CdS QD labeled at the end of C-riched DNA and the electrode. The triplex DNA dissociation in pH 7.4 buffer reconfigures the electrode interface, which can be continued to detect another target. The feasibility of the multiplexed sensor is verified by the detection of extensively coexisting antibiotics enrofloxacin (ENR) and ciprofloxacin (CIP). Under the optimal conditions, wide linear range (10 fg/mL ∼ 1 μg/mL) and low detection limit (3.27 fg/mL and 9.60 fg/mL) were obtained. The pH-regulated programmable triplex DNA nanomachine-based sensing platform overcomes the technical difficulties of conventional multiplexed PEC assay, which may open the way for miniaturization of multiplexed PEC sensors.
PubMed: 38943856
DOI: 10.1016/j.bios.2024.116540 -
Journal of Trace Elements in Medicine... Jun 2024Testicular toxicity is a complication of cisplatin therapy and it limits its use. Since cisplatin-induced testicular damage is mediated by inflammation and oxidative...
BACKGROUND
Testicular toxicity is a complication of cisplatin therapy and it limits its use. Since cisplatin-induced testicular damage is mediated by inflammation and oxidative stress, evaluation of the protective role of antioxidant and anti-inflammatory molecules such as micronized purified flavonoid fraction (Daflon®) is pertinent.
AIM
Therefore, this study investigated the mitigating effect of daflon against cisplatin-induced testicular toxicity. Also, the impact of daflon on Nrf2/HO-1 and TLR4/NF-kB pathways, which are key pathways in cisplatin toxicity, was explored.
MATERIALS AND METHODS
After 2 weeks of acclimatization, 20 male albino Wistar rats were allotted at random into 4 equal groups; control, daflon-treated, cisplatin-treated, and cisplatin+daflon-treated.
RESULTS
Daflon significantly restored cisplatin-induced reductions in body weight (112.20±9.01 vs. 129.60±5.68, P= 0.0175), body weight gain (-39.80±9.52 vs. -16.80±16.53, P= 0.0154), and testicular weight (1.69±0.08 vs. 1.95±0.13, P= 0.0980) and alterations in testicular histology. In addition, daflon abrogated cisplatin-induced rise in testicular CK (55.53±2.77 vs. 37.40±3.29, P< 0.0001) and LDH (74.52±3.20 vs. 65.89±2.08, P= 0.0009) activities, and lactate content (180.50±4.19 vs. 166.20±2.78, P< 0.0001). Also, daflon alleviated cisplatin-induced suppression of GnRH (5.09±0.60 vs. 10.17±0.51, P< 0.0001), LH (1.33±0.07 vs. 2.77±0.13, P< 0.0001), FSH (0.51±0.10 vs. 1.82±0.09, P< 0.0001), and testosterone (2.39±0.11 vs. 4.70±0.33, P< 0.001) as well as lowered sperm quality. More so, daflon attenuated cisplatin-induced testicular oxidative stress, inflammation, and apoptosis evidenced by daflon-driven suppression of MDA (14.16±0.66 vs. 9.22±0.52, P< 0.0001), TNF-α (79.42±5.66 vs. 54.13±3.56, P< 0.0001), IL-1β (8.63±0.41 vs. 3.37±0.43, P< 0.0001), IL-6 (6.87±0.48 vs. 3.67±0.32, P< 0.0001), and caspase 3 activity (4.20±0.26 vs. 0.72±0.23, P< 0.0001) and DNA fragmentation (34.60±3.05 vs. 17.20±3.19, P< 0.0001), and upregulation of GSH level (0.07±0.03 vs. 0.36±0.03, P< 0.0001), and GPx (5.96±0.46 vs. 11.88±1.05, P< 0.0001), GST (5.16±0.71 vs. 11.50±0.81, P< 0.0001), SOD (1.29±0.15 vs. 2.81±0.29, P< 0.0001), and catalase activities (6.18±0.69 vs. 10.71±0.74, P< 0.0001). Furthermore, daflon upregulated testicular Nrf2 expression (40.25±2.65 vs. 66.62±4.01, P< 0.0001) and HO-1 (4.18±0.56 vs. 8.79±0.55, P< 0.0001) activity but downregulated TLR4 (11.63±0.89 vs. 7.23±0.43, P< 0.0001) and NF-kB levels (113.20±3.36 vs. 78.22±3.90, P< 0.0001) in cisplatin-treated rats.
CONCLUSION
Collectively, the ameliorative effect of daflon on cisplatin-induced testicular toxicity is associated with inhibition of oxidative stress and TLR4/NF-kB-mediated inflammatory pathways and activation of Nrf2/HO-1 signaling.
PubMed: 38943836
DOI: 10.1016/j.jtemb.2024.127489 -
DNA Repair Jun 2024The Mediator complex is an essential coregulator of RNA polymerase II transcription. More recent developments suggest Mediator functions as a link between transcription...
The Mediator complex is an essential coregulator of RNA polymerase II transcription. More recent developments suggest Mediator functions as a link between transcription regulation, genome organisation and DNA repair mechanisms including nucleotide excision repair, base excision repair, and homologous recombination. Dysfunctions of these processes are frequently associated with human pathologies, and growing evidence shows Mediator involvement in cancers, neurological, metabolic and infectious diseases. The detailed deciphering of molecular mechanisms of Mediator functions, using interdisciplinary approaches in different biological models and considering all functions of this complex, will contribute to our understanding of relevant human diseases.
PubMed: 38943827
DOI: 10.1016/j.dnarep.2024.103714