ABSTRACT
OBJECTIVE: To establish an animal model of oral squamous cell carcinoma invading the mandible through multi-sample experiments that verified the stability, repeatability, tumorigenicity and mandible destruction rate of the model. METHODS: Oral squamous cell carcinoma cell suspension was injected into the outer side of the mandible through the anterior edge of the masseter muscle of naked mice to observe the tumourforming process. Then, the anatomical, histological and imaging examinations were carried out to determine whether the tumour had invaded the mandible. By comparing the tumour growth of multiple groups of various squamous cell carcinoma cells (CAL27, HN6 and HN30 cells), the changes in body weight and characteristics of tumour formation were compared, and the experience was summarised to further verify the stability, repeatability, tumour formation rate and arch damage rate of the model. RESULTS: The subsequent specimens of tumour-bearing nude mice were validated once the model had been established. In vitro, tumour tissue wrapped around the mandible's tumour-bearing side, and the local texture was tough with no resistance to acupuncture. Haematoxylin and eosin staining revealed that squamous cells were infiltrating the mandible in both the horizontal and sagittal planes. Microcomputed tomography results showed that the mandible on the tumour-bearing side displayed obvious erosion damage. Cell lines with various passage rates clearly had diverse tumour-bearing life cycles. CONCLUSION: This study successfully established an animal model of oral squamous cell carcinoma invasion of the mandible. The model has excellent biological stability, repeatability, tumorigenesis rate and mandible destruction rate.
Subject(s)
Carcinoma, Squamous Cell , Disease Models, Animal , Mandible , Mice, Nude , Mouth Neoplasms , Neoplasm Invasiveness , Animals , Mouth Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Mice , Mandible/pathology , Cell Line, Tumor , X-Ray Microtomography , Mandibular Neoplasms/pathology , Mandibular Neoplasms/diagnostic imaging , Neoplasm Transplantation , Male , Mice, Inbred BALB CABSTRACT
Pyroptosis, as a new programmed death mode, plays an important role in the development and progression of prostate cancer, and the drugs targeting the pyroptosis pathway, as a new therapeutic strategy, may produce a significant influence on the treatment of prostate cancer . However, the precise mechanism of cellular pyroptosis remains unclear, necessitating further investigation. This paper presents a summary of the role of cellular pyroptosis in prostate cancer over recent years. It includes a discussion of the mechanism of pyroptosis, its role in prostate cancer development, and its clinical applications. This will provide clinicians with a new strategy for treatment and drug development.
Subject(s)
Disease Progression , Prostatic Neoplasms , Pyroptosis , Humans , Prostatic Neoplasms/pathology , MaleABSTRACT
The complete characterization of the almost-entropic region yields rate regions for network coding problems. However, this characterization is difficult and open. In this paper, we propose a novel algorithm to determine whether an arbitrary vector in the entropy space is entropic or not, by parameterizing and generating probability mass functions by neural networks. Given a target vector, the algorithm minimizes the normalized distance between the target vector and the generated entropic vector by training the neural network. The algorithm reveals the entropic nature of the target vector, and obtains the underlying distribution, accordingly. The proposed algorithm was further implemented with convolutional neural networks, which naturally fit the structure of joint probability mass functions, and accelerate the algorithm with GPUs. Empirical results demonstrate improved normalized distances and convergence performances compared with prior works. We also conducted optimizations of the Ingleton score and Ingleton violation index, where a new lower bound of the Ingleton violation index was obtained. An inner bound of the almost-entropic region with four random variables was constructed with the proposed method, presenting the current best inner bound measured by the volume ratio. The potential of a computer-aided approach to construct achievable schemes for network coding problems using the proposed method is discussed.
ABSTRACT
This study demonstrates the effectiveness of synthetic nicotinamide cofactors as cost-effective alternatives to NADPH in imine reductase (IRED) catalysis. The synthetic cofactors maintained catalytic activity and stereoselectivity, achieving high conversion rates. Molecular docking studies revealed key structural interactions influencing performance. Combining a glucose dehydrogenase (GDH) recycling system further enhanced the stability and efficiency. These findings highlight the potential of synthetic cofactors to reduce costs and improve the feasibility of IRED-catalyzed processes for industrial applications.
ABSTRACT
Urtica cannabina L. (UL) has been used clinically for centuries because of its anti-inflammatory properties. This study aimed to investigate the underlying mechanisms and anti-inflammatory effects of different UL concentrations in zebrafish. To elucidate UL's anti-inflammatory properties, two inflammation zebrafish models were designed 1) by severing the zebrafish's caudal fin to assess the repairing effect of UL on the tail inflammation, and 2) by inducing lipopolysaccharides (LPS)-mediated intestinal inflammation to assess the protective and reparative effects of UL on intestinal inflammation at the histological and genetic levels. Furthermore, the effect of UL on the LPS-induced intestinal flora changes was also assessed. After caudal fin resection, a scar formed on the tail of the zebrafish, and the area of the caudal fin increased by 1.30 times as much as that of the control group (P < 0.01). Moreover, this tail scar was alleviated after 10 mg/g UL supplementation but not after 30 mg/g UL dose. LPS decreased the feed intake and body weight of the zebrafish; however, these effects were reversed after 10 and 30 mg/g doses of UL. In addition, the LPS treatment also reduced the intestinal goblet cells by 49% in the zebrafish when compared with the control, which was significantly restored after 10 and 30 mg/g UL treatments. At the genetics level, the expression of the pro-inflammatory cytokine genes (TNF-α, IL6, and IL8) showed that 10 and 30 mg/g UL doses could rescue LPS-induced expression. The gut microbiota analysis revealed changes in the abundance of four major bacterial phyla in the 10 and 30 mg/g UL-treated groups, with an increased probiotic Bacteroidota and decreased pathogenic bacteria. These results indicate that UL strongly inhibits inflammation caused by caudal fin removal and LPS-induced inflammatory changes in the zebrafish intensity, suggesting that UL is a feed additive that could be developed to improve resistance to inflammation in livestock.
Subject(s)
Anti-Inflammatory Agents , Lipopolysaccharides , Zebrafish , Animals , Anti-Inflammatory Agents/pharmacology , Inflammation/drug therapy , Inflammation/pathology , Gastrointestinal Microbiome/drug effects , Food Additives/pharmacology , Animal Feed , Plant Extracts/pharmacologyABSTRACT
Self-assembled protein cages are attractive scaffolds for organizing various proteins of interest (POIs) toward applications in synthetic biology and medical science. However, specifically attaching multiple POIs to a single protein cage remains challenging, resulting in diversity among the functionalized particles. Here, we present the engineering of a self-assembled protein cage, DTMi3ST, capable of independently recruiting two different POIs using SpyCatcher (SC)/SpyTag (ST) and DogCatcher (DC)/DogTag (DT) chemistries, thereby reducing variability between assemblies. Using fluorescent proteins as models, we demonstrate controlled targeting of two different POIs onto DTMi3ST protein cages both in vitro and inside living cells. Furthermore, dual functionalization of the DTMi3ST protein cage with a membrane-targeting peptide and ß-galactosidase resulted in the construction of membrane-bound enzyme assemblies in Escherichia coli, leading to a 69.6% enhancement in substrate utilization across the membrane. This versatile protein cage platform provides dual functional nanotools for biological and biomedical applications.
Subject(s)
Escherichia coli , Protein Engineering , Escherichia coli/genetics , Peptides/chemistry , beta-Galactosidase/chemistry , beta-Galactosidase/metabolism , HumansABSTRACT
An electrochemical gem-difluorination of indeno[1,2-c]furans using commercially available and easy-to-use triethylamine trihydrofluoride as both the electrolyte and fluorinating agent was developed. Remarkably, different reaction pathways of indeno[1,2-c]furans, i.e., paired electrolysis and net oxidation, are operative in a batch reactor and a continuous-flow microreactor to afford the corresponding gem-difluorinated indanones and indenones, respectively.
ABSTRACT
The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer (GC). As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. Here, we identified a vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired GC spheroid formation and reduced stemness marker expression, while FOXP4 upregulation potentiated cancer cell stemness. RNA-seq analysis revealed SOX12 as downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small molecule screen identified 42-(2-Tetrazolyl)rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed GC tumor growth and enhanced the efficacy of 5-FU chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in GC regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for GC.
ABSTRACT
Microplastic (MP) accumulation has recently become a pressing global environmental challenge. As a major producer and consumer of plastic products, China's MP pollution has garnered significant attention from researchers. However, accurate and comprehensive investigations of national-level MP pollution are still lacking. In this study, we systematically collated a national MP pollution dataset consisting of 7766 water, soil, and sediment sampling sites from 544 publicly published studies, revealing the spatiotemporal distribution and potential risks of MP pollution in China. The results indicate that MP distribution is influenced by various regional factors, including economic development level, population distribution, and geographical environment, exhibiting considerable range and complexity. MP concentrations are generally higher in economically prosperous areas, but the degree of pollution varies significantly across different environmental media. Given the uncertainty and lack of standardized data in traditional microplastic risk assessment methods, this article highlights the urgency of developing a comprehensive big data and artificial intelligence (AI)-based regulatory framework. This work provides a substantial amount of accurate MP pollution data and offers a fresh perspective on leveraging AI for microplastic pollution regulation.
ABSTRACT
Background: Direct oral anticoagulants (DOACs) have demonstrated clinical benefits and better patient adherence over low-molecular-weight heparin (LMWH) in treating patients with cancer-associated venous thrombosis (CAT). We aimed to compare the cost-effectiveness of DOACs against LMWH in patients with CAT from the perspective of the Hong Kong healthcare system. Methods: A Markov state-transition model was performed to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) for DOACs and LMWH in a hypothetical cohort of 10,000 patients with CAT over a 5-year lifetime horizon. The model was primarily based on the health states of no event, recurrent venous thromboembolism, bleeding, and death. Transition probabilities, relative risks, and utilities were derived from the literature. Resource cost data were obtained from the Hong Kong Hospital Authority. Deterministic and probabilistic sensitivity analyses tested the robustness of the results. Results: Relative to LMWH, DOACs were associated with increased QALYs (1.52 versus 1.50) at a lower medical cost of USD 2,232 versus 8,224 in five years. The cost of LMWH was the main contributor to the outcome. Out of 10,000 simulated cases, DOACs were dominant in 15.8% and cost-effective in 42.1%, at the willingness-to-pay threshold of USD 148,392 per additional QALY. Conclusions: DOACs were associated with greater QALY improvements and lower overall costs compared to LMWH. Accounting for uncertainty, DOACs were between cost-effective and dominant in 57.9% of cases. DOACs are a cost-effective alternative to LMWH in the management of CAT in Hong Kong.
ABSTRACT
OBJECTIVES: To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China. METHODS: We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline. RESULTS: The MICs of eravacycline against all the strains were in the range of 0.004-16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder. CONCLUSIONS: The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.
Subject(s)
Acinetobacter baumannii , Anti-Bacterial Agents , Enterobacter cloacae , Escherichia coli , Klebsiella pneumoniae , Microbial Sensitivity Tests , Staphylococcus aureus , Tetracyclines , Humans , Anti-Bacterial Agents/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/isolation & purification , Tetracyclines/pharmacology , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/isolation & purification , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/isolation & purification , Enterobacter cloacae/drug effects , Enterobacter cloacae/isolation & purification , Escherichia coli/drug effects , Escherichia coli/isolation & purification , China/epidemiologyABSTRACT
Backgrounds and Aims: Patients with cirrhosis are susceptible to sepsis and septic shock. Cirrhotic patients also have increased capillary permeability and are prone to developing volume overload. Patients with septic shock may have an enhanced pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), both of which are associated with an unfavorable prognosis. It is plausible that pre-existing hyperpermeability may deteriorate when cirrhotic patients develop septic shock. However, it remains unknown whether PVPI and EVLWI can predict the prognosis of cirrhotic patients with septic shock. Pulse Indicator Continuous Cardiac Output (PiCCO) is an established tool to measure PVPI and EVLWI. Therefore, we conducted this retrospective study to investigate the prognostic significance of PVPI and EVLWI in cirrhotic patients with septic shock using PiCCO monitoring. Methods: We included 83 patients with liver cirrhosis and septic shock. EVLW indexed to actual body weight (aEVLWI), EVLW indexed to predicted body weight (pEVLWI), PVPI, disease severity scores, and other biomarkers were analyzed. We collected the PiCCO data on the first 2 days. Results: The overall 28-day mortality was 43.4%. The values of PVPI, aEVLWI, and pEVLWI on day 2 (PVPID2, aEVLWID2, EVLWID2) were significantly higher in non-survivors. The discriminating power of PVPID2 and EVLWID2 to predict 28-day mortality was tested using the area under a ROC curve. The areas under ROC curves (mean ± SEM) were 0.713 ± 0.061 and 0.650 ± 0.063 for PVPID2 and pEVLWID2. In the multivariate analysis, PVPID2, bilirubin, and lactate were independent factors which predicted 28-day mortality. Conclusions: Higher levels of PVPID2 and pEVLWID2 are associated with higher 28-day mortality rates in cirrhotic patients with septic shock. PVPI and pEVLWI may be useful to guide fluid management in this clinical setting.
ABSTRACT
Given the existing uncertainty regarding the effectiveness and safety of switching from low-molecular-weight heparin (LMWH) to direct oral anticoagulants (DOACs) in patients with cancer-associated venous thrombosis (CAT), we conducted a comprehensive population-based cohort study utilizing electronic health database in Hong Kong. A total of 4356 patients with CAT between 2010 and 2022 were included, with 1700 (39.0%) patients switching to DOAC treatment. Compared to continuous LMWH treatment, switching to DOACs was associated with a significantly lower risk of hospitalization due to venous thromboembolism (HR: 0.49 [95% CI = 0.35-0.68]) and all-cause mortality (HR: 0.67 [95% CI = 0.61-0.74]), with no significant difference in major bleeding (HR: 1.04 [95% CI = 0.83-1.31]) within six months. These findings provide reassurance regarding the effectiveness and safety of switching from LMWH to DOACs among patients with CAT, including vulnerable patient groups.
Subject(s)
Anticoagulants , Hemorrhage , Heparin, Low-Molecular-Weight , Neoplasms , Venous Thrombosis , Humans , Neoplasms/drug therapy , Neoplasms/complications , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/adverse effects , Heparin, Low-Molecular-Weight/therapeutic use , Female , Male , Middle Aged , Aged , Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , Anticoagulants/adverse effects , Venous Thrombosis/drug therapy , Administration, Oral , Hong Kong/epidemiology , Hemorrhage/chemically induced , Treatment Outcome , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Cohort Studies , Hospitalization/statistics & numerical data , Drug Substitution , Aged, 80 and overABSTRACT
Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/ß4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/ß4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.
Subject(s)
Carcinogenesis , Colorectal Neoplasms , Drug Resistance, Neoplasm , Peptostreptococcus , Receptor, ErbB-2 , Animals , Humans , Mice , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/microbiology , Colorectal Neoplasms/pathology , Fructose-Bisphosphate Aldolase/metabolism , Fructose-Bisphosphate Aldolase/genetics , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinases/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , /pharmacologyABSTRACT
Marine natural product (MNP) pretrichodermamide B (Pre B, 9) was identified as a novel STAT3 inhibitor in our previous work, while its metabolic instability hindered its further development. To address this drawback, ligand structure-based drug design was adopted leading to a series of Pre B derivatives. Among them, MNP trichodermamide B (tri B, 24) obtained by skeletal rearrangement exhibited more potent antiproliferative activity with an IC50 value of 0.12 µM against HCT116. Notably, 24 stood out with improved metabolic stability (T1/2 = 31 min) and more favorable oral bioavailability (F = 37.5%). Further studies indicated that 24 blocked JAK/STAT3 signaling in dose- and time-dependent manner. In vivo, 24 suppressed tumor growth (TGI = 65%) at a dose of 20 mg/kg in a HCT116-derived xenograft mouse model. Overall, 24 might be a promising lead compound for colon cancer and is worthy of further investigation.
Subject(s)
Antineoplastic Agents , Biological Products , Colonic Neoplasms , Janus Kinases , STAT3 Transcription Factor , Signal Transduction , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Biological Products/chemistry , Biological Products/pharmacology , Biological Products/chemical synthesis , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Drug Screening Assays, Antitumor , HCT116 Cells , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Signal Transduction/drug effects , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Morganella morganii, encompassing two subspecies, subsp. morganii and subsp. sibonii, is a common opportunistic pathogen, notable for intrinsic resistance to multiple antimicrobial agents. Despite its clinical significance, research into the potential evolutionary dynamics of M. morganii remains limited. This study involved the analysis of genome sequences from 431 M. morganii isolates, comprising 206 isolates that cause host infections, obtained from this study and 225 from the NCBI genome data sets. A diverse array of antimicrobial resistance genes (ARGs) was identified in M. morganii isolates, including mcr-1, tet(X4), tmexCD-toprJ, and various carbapenemase genes. In addition, a novel blaKPC-2-bearing plasmid with demonstrated conjugative capability was discovered in M. morganii. The majority of virulence-related genes (VRGs), except for the hlyCABD gene cluster, were found in almost all M. morganii. Three novel genospecies of M. morganii were identified, designated as M. chanii, M. variant1, and M. variant2. Compared to M. sibonii, M. chanii genospecies possessed a greater number of flagellar-related genes, typically located within mobile genetic elements (MGEs), suggesting potential for better environmental adaptability. Phylogenetic analysis further disclosed that M. morganii was divided into 12 sequence clusters (SCs). Particularly, SC9 harbored an elevated abundance of ARGs and VRGs, mainly toxin-related genes, and was associated with a higher presence of MGEs compared to non-SC9 strains. The collective findings suggest that M. morganii undergoes evolution driven by the influence of MGEs, thereby significantly enhancing its adaptability to selective pressures of environmental changes and clinical antimicrobial agents.IMPORTANCEThe growing clinical significance of Morganella morganii arises from its abundant virulence factors and antimicrobial resistance genes, resulting in elevated infection rates and increased clinical scrutiny. However, research on the molecular epidemiology and evolutionary trends of M. morganii has been scarce. Our study established a list of virulence-related genes (VRGs) for M. morganii and conducted a large-scale epidemiological investigation into these VRGs. Based on genomic classification, three novel genotypes of M. morganii were identified, representing evolutionary adaptations and responses to environmental challenges. Furthermore, we discovered the emergence of a sequence cluster enriched with antimicrobial resistance genes, VRGs, and mobile genetic elements, attributed to the selective pressure of antimicrobial agents. In addition, we identified a novel conjugative plasmid harboring the blaKPC-2 gene. These findings hold significance in monitoring and comprehending the epidemiology of M. morganii.
Subject(s)
Molecular Epidemiology , Morganella morganii , Phylogeny , Morganella morganii/genetics , Morganella morganii/drug effects , Morganella morganii/isolation & purification , Morganella morganii/pathogenicity , Humans , Evolution, Molecular , Genome, Bacterial , Anti-Bacterial Agents/pharmacology , Virulence Factors/genetics , Plasmids/genetics , Microbial Sensitivity Tests , Enterobacteriaceae Infections/epidemiology , Enterobacteriaceae Infections/microbiologyABSTRACT
Intrauterine growth restriction (IUGR), when a fetus does not grow as expected, is associated with a reduction in hepatic functionality and a higher risk for chronic liver disease in adulthood. Utilizing early developmental plasticity to reverse the outcome of poor fetal programming remains an unexplored area. Focusing on the biochemical profiles of neonates and previous transcriptome findings, piglets from the same fetus are selected as models for studying IUGR. The cellular landscape of the liver is created by scRNA-seq to reveal sex-dependent patterns in IUGR-induced hepatic injury. One week after birth, IUGR piglets experience hypoxic stress. IUGR females exhibit fibroblast-driven T cell conversion into an immune-adapted phenotype, which effectively alleviates inflammation and fosters hepatic regeneration. In contrast, males experience even more severe hepatic injury. Prolonged inflammation due to disrupted lipid metabolism hinders intercellular communication among non-immune cells, which ultimately impairs liver regeneration even into adulthood. Additionally, Apolipoprotein A4 (APOA4) is explored as a novel biomarker by reducing hepatic triglyceride deposition as a protective response against hypoxia in IUGR males. PPARα activation can mitigate hepatic damage and meanwhile restore over-expressed APOA4 to normal in IUGR males. The pioneering study offers valuable insights into the sexually dimorphic responses to hepatic injury during IUGR.
Subject(s)
Animals, Newborn , Disease Models, Animal , Fetal Growth Retardation , Fetal Growth Retardation/metabolism , Fetal Growth Retardation/genetics , Animals , Female , Male , Swine , Liver/metabolism , Sex Characteristics , Pregnancy , Liver Diseases/metabolism , Liver Diseases/genetics , HumansABSTRACT
OBJECTIVE: The study investigated maternal exposure to heavy metals from industrial sources during pregnancy as potential risk factors for childhood cancer. METHODS: Cases ages 0-19 were identified from California Cancer Registry. Controls (20:1 ratio) were randomly selected from California Birth Registry, frequency-matched by birth year (1998-2016). We estimated maternal exposure to lead, nickel, and cobalt in ambient air from the Toxics Release Inventory. We examined "ever/never" and "high/low" exposures categorized by median exposure. Models were adjusted for maternal age, race/ethnicity, method of payment for prenatal care, neighborhood socioeconomic status, and urban/rural residence. RESULTS: Among highly exposed persons, lead was associated with an increased teratoma risk (adjusted odds ratio [aOR]: 1.52; 95% confidence interval [CI]: 0.97, 2.37), whereas nickel was associated with an increased rhabdomyosarcoma risk (aOR: 1.45; 95% CI: 1.03, 2.04). Cobalt was associated with an increased glioma risk (aOR: 2.25; 95% CI: 1.39, 3.65) among ever-exposed persons. Inverse associations were found between Wilms tumor and nickel among the ever exposed and highly exposed (ever: aOR: 0.75; 95% CI: 0.59, 0.96; high: aOR: 0.64; 95% CI: 0.45, 0.93). CONCLUSIONS: Findings suggest that air pollution from heavy metals released by industrial sources may elevate childhood cancer risk.
Subject(s)
Maternal Exposure , Metals, Heavy , Neoplasms , Prenatal Exposure Delayed Effects , Humans , California/epidemiology , Pregnancy , Female , Maternal Exposure/adverse effects , Maternal Exposure/statistics & numerical data , Child, Preschool , Infant , Prenatal Exposure Delayed Effects/epidemiology , Infant, Newborn , Adolescent , Adult , Young Adult , Risk Factors , Child , Male , Neoplasms/epidemiology , Neoplasms/chemically induced , Neoplasms/etiology , Nickel , Cobalt/adverse effects , Registries , Case-Control Studies , Industry , Lead/analysisABSTRACT
The N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is frequently overexpressed in colorectal cancer and drives chemotherapeutic resistance. To systematically identify druggable targets in colorectal cancer with high expression of YTHDF1, this study used a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets. RUVBL1/2 were overexpressed in primary colorectal cancer samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth of YTHDF1-high colorectal cancer cells, patient-derived primary colorectal cancer organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feedforward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Coimmunoprecipitation and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribosome sequencing revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS, and PI3K-AKT signaling induced by YTHDF1. Finally, the blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing colorectal cancer in vitro and in vivo. Our findings show that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high colorectal cancer. Significance: RUVBL1/2 inhibition is a therapeutic strategy to abrogate YTHDF1-driven oncogenic translation and overcome m6A dysregulation in colorectal cancer.
Subject(s)
ATPases Associated with Diverse Cellular Activities , Adenosine , Colorectal Neoplasms , DNA Helicases , RNA-Binding Proteins , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/drug therapy , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Animals , Mice , DNA Helicases/genetics , DNA Helicases/metabolism , ATPases Associated with Diverse Cellular Activities/metabolism , ATPases Associated with Diverse Cellular Activities/genetics , ATPases Associated with Diverse Cellular Activities/antagonists & inhibitors , Adenosine/analogs & derivatives , Adenosine/metabolism , Carcinogenesis/genetics , Carrier Proteins/metabolism , Carrier Proteins/genetics , Protein Biosynthesis , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Cell Proliferation , Mice, Nude , Xenograft Model Antitumor Assays , PrognosisABSTRACT
In this study, AlGaN-based deep-ultraviolet light-emitting diodes (DUV-LEDs) processed via standard laser dicing (SLD) and multifocal laser stealth dicing (MFLSD) were investigated. Adopting the MFLSD technology would generate a roughing surface rather than the V-shaped grooves on the sidewall of 508 × 508 µm2 DUV-LEDs, which would reduce the forward operating voltage and increase the wall-plug efficiency, light output power, and far-field radiation patterns of these devices. In addition, the wavelength shift, far-field patterns, and light-tracing simulation results of the DUV-LEDs processed with SLD and MFLSD were clearly demonstrated and analyzed. Accordingly, it was observed that the MFLSD process provided more possibilities for photon escape to increase the light extraction efficiency (LEE) of DUV-LEDs, thus decreased the wavelength-redshift and junction temperature in DUV-LEDs. These results provide a reference for advanced nano-processing practices implemented during the fabrication of semiconductor devices.