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Colorectal cancer is a heterogeneous disease which can be divided into proximal colon cancer, distal colon cancer and rectal cancer according to the anatomical location of the tumor. Each anatomical location of colorectal cancer exhibits distinct characteristics in terms of incidence, clinical manifestations, molecular phenotypes, treatment, and prognosis. Notably, proximal colon cancer differs significantly from cancers of other anatomical subsites. An increasing number of studies have highlighted the presence of unique tumor biological characteristics in proximal colon cancer. Gaining a deeper understanding of these characteristics will facilitate accurate diagnosis and treatment approaches.
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Colonic Neoplasms , Humans , Colonic Neoplasms/pathology , Colonic Neoplasms/diagnosis , Prognosis , Colon/pathologyABSTRACT
BACKGROUND: This study investigated the perioperative outcomes of patients undergoing conversion total hip arthroplasty (THA) after failed peri-hip bone flap grafting (PBFG) and compared them with those patients undergoing primary THA for osteonecrosis of the femoral head (ONFH). METHODS: From January 2010 to December 2021, 163 Chinese patients (163 hips) were treated by conversion THA after failed PBFG (containing 94 patients who had pedicled vascularized iliac bone flap grafting and 69 patients who had pedicled vascularized greater trochanter bone flap grafting), and 178 Chinese patients were treated by primary THA. The preoperative baseline data and perioperative indicators in both groups were compared. RESULTS: In the conversion group, patients had significantly greater blood loss, a longer length of stay, and greater changes in serum hemoglobin than those in the primary THA group (P < 0.05). The operative room time, transfusion volume, calculated blood loss, changes in serum hematocrit, and increased superficial infection (P > 0.05) in the conversion group were greater compared with the primary cohort; however, the difference was not statistically significant. The mean postoperative Harris Hip Scoring System (HHS) of the PBFG group at the one-month follow-up was 81, and the control group had an 82 score. Importantly, subgroup analysis of the PBFG group indicated that there was no significant difference between patients who had prior pedicled vascularized iliac bone flap grafting and pedicled vascularized greater trochanter bone flap grafting (P > 0.05), except for the operative room time (P = 0.032). CONCLUSION: Hip-sparing surgery of ONFH did not make THA more difficult or lead to more peri-operative complications, but increased blood loss and extended hospital stay from a prior PBFG are still notable problems in clinical practice. Thus, it is necessary for surgeons to focus attention on the improvement of the preoperative condition and prepare for any specific intraoperative challenges.
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Rationale: Sepsis is a life-threatening organ dysfunction and lack of effective measures in the current. Exosomes from mesenchymal stem cells (MSCs) reported to alleviate inflammation during sepsis, and the preconditioning of MSCs could enhance their paracrine potential. Therefore, this study investigated whether exosomes secreted by lipopolysaccharide (LPS)-pretreated MSCs exert superior antiseptic effects, and explored the underlying molecular mechanisms. Methods: Exosomes were isolated and characterized from the supernatants of MSCs. The therapeutic efficacy of normal exosomes (Exo) and LPS-pretreated exosomes (LPS-Exo) were evaluated in terms of survival rates, inflammatory response, and organ damage in an LPS-induced sepsis model. Macrophages were stimulated with LPS and treated with Exo or LPS-Exo to confirm the results of the in vivo studies, and to explain the potential mechanisms. Results: LPS-Exo were shown to inhibit aberrant pro-inflammatory cytokines, prevent organ damages, and improve survival rates of the septic mice to a greater extent than Exo. In vitro, LPS-Exo significantly promoted the M2 polarization of macrophages exposed to inflammation. miRNA sequencing and qRT-PCR analysis identified the remarkable expression of miR-150-5p in LPS-Exo compared to that in Exo, and exosomal miR-150-5p was transferred into recipient macrophages and mediated macrophage polarization. Further investigation demonstrated that miR-150-5p targets Irs1 in recipient macrophages and subsequently modulates macrophage plasticity by down-regulating the PI3K/Akt/mTOR pathway. Conclusion: The current findings highly suggest that exosomes derived from LPS pre-conditioned MSCs represent a promising cell-free therapeutic method and highlight miR-150-5p as a novel molecular target for regulating immune hyperactivation during sepsis.
Subject(s)
Exosomes , Insulin Receptor Substrate Proteins , Lipopolysaccharides , Macrophages , Mesenchymal Stem Cells , MicroRNAs , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Sepsis , Signal Transduction , TOR Serine-Threonine Kinases , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Exosomes/metabolism , Mesenchymal Stem Cells/metabolism , Sepsis/metabolism , Sepsis/immunology , TOR Serine-Threonine Kinases/metabolism , Mice , Proto-Oncogene Proteins c-akt/metabolism , Macrophages/metabolism , Macrophages/immunology , Insulin Receptor Substrate Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Male , Mice, Inbred C57BL , Macrophage Activation/drug effects , Disease Models, AnimalABSTRACT
Apoptosis-inducing factor mitochondrion-associated 2 (AIFM2) has been identified as a gene with anti-ferroptosis properties. To explore whether AIFM2 exerts anti-ferroptosis role in yaks (Bos grunniens), we cloned yak AIFM2 gene and analyzed its biological characteristics. The coding region of AIFM2 had 1122 bp and encoded 373 amino acids, which was conserved in mammals. Next, RT-qPCR results showed an extensive expression of AIMF2 in yak tissues. Furthermore, we isolated yak skin fibroblasts (YSFs) and established a bisphenol A (BPA)-induced ferroptosis model to further investigate the role of AIFM2. BPA elevated oxidative stress (reactive oxygen species, ROS) and lipid peroxidation (malondialdehyde, MDA and BODIPY), and reduced cell viability and antioxidant capacity (glutathione, GSH), with the severity depending on the dosage. Of note, a supplement of Ferrostatin-1 (Fer), an inhibitor of ferroptosis, restored the previously mentioned indicators. Subsequently, we constructed an AIFM2 overexpression vector and designed AIFM2 specific interfering siRNAs, which were transfected into YSFs. The results showed that overexpressing AIFM2 alleviated ferroptosis, characterizing by significant changes of cell viability, ROS, BODIPY, MDA and GSH. Meanwhile, interfering AIFM2 aggravated ferroptosis, demonstrating the critical anti-ferroptosis role of the yak AIFM2 gene. This study shed light on further exploring the molecular mechanism of AIFM2 in plateau adaptability.
Subject(s)
Benzhydryl Compounds , Ferroptosis , Fibroblasts , Phenols , Animals , Cattle , Phenols/pharmacology , Phenols/toxicity , Fibroblasts/drug effects , Fibroblasts/physiology , Ferroptosis/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Cell Survival/drug effectsABSTRACT
The inherent benefits of aqueous Zn-ion batteries (ZIBs), such as environmental friendliness, affordability, and high theoretical capacity, render them promising candidates for energy storage systems. Nevertheless, the Zn anodes of ZIBs encounter severe challenges, including dendrite formation, hydrogen evolution reaction, corrosion, and surface passivation. These would result in the infeasibility of ZIBs in practical situations. To this end, artificial interfaces with functionalized materials are crafted to protect the Zn anode. They have the capability to modulate the zinc ion flux in proximity to the electrode surface and shield it from aqueous electrolytes by leveraging either size effects or charge effects. Considering metal-organic frameworks (MOFs) with tunable pore size, chemical composition, and stable framework structures, they have emerged as effective materials for building artificial interfaces, prolonging the lifespan, and improving the unitization of Zn anode. In this review, the contributions of MOFs for protecting Zn anode, which mainly involves facilitating homogeneous nucleation, manipulating selective deposition, regulating ion and charge flux, accelerating Zn desolvation, and shielding against free water and anions are comprehensively summarized. Importantly, the future research trajectories of MOFs for the protection of the Zn anode are underscored, which may propose new perspectives on the practical Zn anode and endow the MOFs with high-value applications.
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Background: Varicocele is a major correctable cause of male infertility. Shear wave elastography (SWE) represents a valuable approach for assessing spermatogenesis in infertile men; however, its application in infertile men with varicocele remains unreported in the literature to date. The objective of this study was to investigate the correlation between testicular stiffness and spermatogenesis in individuals with varicocele. Methods: A total of 568 participants with left-side varicocele and 475 age-matched healthy controls were enrolled. The mean, left, and right testicular volumes (Volume-mean, Volume-L, and Volume-R), the mean elastic modulus of bilateral, left, and right testes (Emean, Emean-L, and Emean-R); the maximum elastic modulus of bilateral, left, and right testes (Emax, Emax-L, and Emax-R); the minimum elastic modulus of bilateral, left, and right testes (Emin, Emin-L, and Emin-R) were calculated. Results: Receiver operating characteristic (ROC) curves for Volume-R and Emax were constructed to identify participants with sperm concentrations below 5 million/mL. The areas under the ROC curves (AUCs) were 0.801 and 0.775, respectively. Combining these 2 markers improved their diagnostic value with an AUC of 0.820 and sensitivity and specificity of 94.6% and 59.8% [95% confidence interval (CI): 0.772-0.867, P<0.01], respectively. A total of 69 participants underwent microsurgical varicocelectomy (including 42 cases with improved semen results and 27 without). The ROC curves of Emax-L and Volume-L were constructed for the differential diagnosis between the improved and unimproved groups; the AUCs were 0.723 and 0.855, respectively. Combining these 2 markers improved their diagnostic value with an AUC of 0.867 (95% CI: 0.772-0.961, P<0.01) and sensitivity and specificity of 81.5% and 81.0%, respectively. Conclusions: Our findings suggest that SWE can be used for varicocele to assess testicular parenchyma damage and Volume-L combined with Emax-L offers a more accurate method for predicting semen parameter improvement after microscopic subinguinal varicocelectomy in men with varicocele.
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Background: The relationship between microcirculatory disorders and testicular spermatogenesis is an area of ongoing interest among urologists. The objective of this prospective observational study was to investigate the correlation between testicular microcirculation and spermatogenesis, as well as the predictive value of ultrasonic microvascular density (UMVD) and ultrasonographic volume estimation (UVE) in successful sperm retrieval among men with non-obstructive azoospermia (NOA). Methods: Testicular UMVD derived from Angio PLUSTM Planwave Ultrasensitive Imaging (AP), UVE were obtained. Participants were divided into 4 groups (normozoospermia; asthenozoospermia, teratozoospermia, or asthenoteratozoospermia; oligozoospermia; NOA). Results: The study included a total of 875 participants. No significant difference was found in UMVD-mean between different semen groups (P>0.05). A total of 108 participants with NOA underwent microdissection testicular sperm extraction (micro-TESE). Participants with successful sperm retrieval (40 cases) showed significant differences in testicular UMVD and UVE compared to those with negative retrieval (68 cases) (P<0.01). We generated receiver operating characteristic (ROC) curves for UMVD and testicular UVE to differentiate participants with successful sperm retrieval from those without. The area under the curve (AUC) was 0.760 [95% confidence interval (CI): 0.658-0.849, P<0.01] for UMVD and 0.716 (95% CI: 0.609-0.822, P<0.01) for testicular UVE, respectively. The optimal cutoff value was determined based on the maximum Youden index. When UMVD was set at 28.50/cm2, its sensitivity and specificity were calculated as 57.5% and 85.3%, respectively. For testicular UVE, a cutoff value of 8.94 mL resulted in a sensitivity of 60.0% and specificity of 82.4%. Combining UMVD with testicular UVE improved diagnostic performance (AUC: 0.856, 95% CI: 0.772-0.929, P<0.01) with a sensitivity of 79.4% and specificity of 77.5%. Conclusions: The present study demonstrates the utility of AP as a predictive tool for successful sperm retrieval prior to micro-TESE. Furthermore, the combination of testicular UMVD and UVE provides a highly valuable diagnostic approach for predicting micro-TESE success and can be routinely implemented before the procedure. A testicular UMVD exceeding 28.50/cm2 and a testicular UVE larger than 8.94 mL strongly indicate favorable outcomes in terms of sperm retrieval.
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Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child-Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.
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The high-speed impact-resistanct materials are of great significance while their development is hindered by the intrinsic tradeoff between mechanical strength and energy dissipation capability. Herein, the new chemical system of molecular granular material (MGM) is developed for the design of impact-resistant materials from the supramolecular complexation of sub-nm molecular clusters (MCs) and hyper-branched polyelectrolytes. Their hierarchical aggregation provides the origin of the decoupling of mechanical strengths and structural relaxation dynamics. The MCs' intrinsic fast dynamics afford excellent high-speed impact-resistance, up to 5600 s-1 impact in a typical split-Hopkinson pressure bar test while only tiny boundary cracks can be observed even under 7200 s-1 impact. The high loadings of MCs and their hierarchical aggregates provide high-density sacrificial bonding for the effective dissipation of the impact energy, enabling the protection of fragile devices from the direct impact of over 200 m s-1 bullet. Moreover, the MGMs can be conveniently processed into protective coatings or films with promising recyclability due to the supramolecular interaction feature. The research not only reveals the unique relaxation dynamics and mechanical properties of MGMs in comparison with polymers and colloids, but also develops new chemical systems for the fabrication of high-speed impact-resistant materials.
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Three surveys were carried out to study the phytoplankton role in influencing the Hg distribution in a poorly eutrophic estuary by measuring the total Hg (THg) and methylHg (MeHg) concentrations in waters and four-size fractions of phytoplankton. The THg and MeHg concentrations in waters and phytoplankton varied markedly temporal during the three surveys. The total concentrations of THg and MeHg in the four-size fractions of phytoplankton ranged between 0.62 and 28.15 mg/kg and 0.022-4.411 mg/kg, respectively. The dominance of THg and MeHg phytoplankton concentrations differed from different size fractions and varied with the various surveys. The huge uptake of Hg by abundant phytoplankton decreased both Hg concentrations in waters and phytoplankton, which was attributed to the biomass dilution effect during the July survey. The Hg partition between water and phytoplankton provided substantial evidence to illustrate the huge uptake of Hg by the abundant phytoplankton.
Subject(s)
Environmental Monitoring , Estuaries , Eutrophication , Mercury , Methylmercury Compounds , Phytoplankton , Water Pollutants, Chemical , Water Pollutants, Chemical/analysis , Methylmercury Compounds/analysis , Mercury/analysis , TaiwanABSTRACT
All-inorganic cesium lead halide (CsPbX3, X = Cl, Br, I) perovskite nanocrystals have drawn great interest because of their excellent photophysical properties and potential applications. However, their poor stability in water greatly limited their use in applications that require stable structures. In this work, a facile approach to stabilize CsPbBr3 nanowires is developed by using SU-8 as a protection medium; thereby creating stable CsPbBr3/SU-8 microstructures. Through photolithography and layer-by-layer deposition, CsPbBr3/SU-8 is used to fabricate bilayer achiral microswimmers (BAMs), which consist of a top CsPbBr3/SU-8 layer and a bottom Fe3O4 magnetic layer. Compared to pure CsPbBr3 nanowires, the CsPbBr3/SU-8 shows long-term structural and fluorescence stability in water against ultrasonication treatment. Due to the magnetic layer, the motion of the microswimmers can be controlled precisely under a rotating magnetic field, allowing them to swim at low Reynolds number and tumble or roll on surfaces. Furthermore, CsPbBr3/SU-8 can be used to fabricate various types of planar microstructures with high throughput, high consistency, and fluorescence properties. This work provides a method for the stabilization of CsPbBr3 and demonstrates the potential to mass fabricate planar microstructures with various shapes, which can be used in different applications such as microrobotics.
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Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R. torques). Mechanistically, R. torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R. torques. Finally, we show that either the colonization of R. torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Ceramides , Mice, Inbred C57BL , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Mice , Ceramides/metabolism , Male , Fatty Liver/metabolism , Signal Transduction/drug effects , Humans , Gastrointestinal Microbiome/drug effects , Metabolic Diseases/metabolismABSTRACT
The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N'-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.
Subject(s)
Benzenesulfonamides , Receptors, Opioid, kappa , Sulfonamides , Animals , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/chemical synthesis , Ligands , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, kappa/antagonists & inhibitors , Mice , Male , Molecular Structure , Humans , Drug Discovery , Dose-Response Relationship, Drug , Analgesics/pharmacology , Analgesics/chemistry , Analgesics/chemical synthesis , RatsABSTRACT
Autophagy is a highly conserved cellular homeostasis maintenance mechanism in eukaryotes. Microtubule-associated protein light chain 3 (LC3) plays a crucial role in autophagy. It has multiple pairs of protein-protein interactions (PPIs) with other proteins, and these PPIs have an effect on the regulation of autophagosome formation and the recruitment of autophagic substrates. In our previous work, a small molecule covalent inhibitor DC-LC3in-D5 which could inhibit LC3A/B PPIs was identified, but a detailed study of structure-activity relationships (SARs) was lacking. Herein, a new molecule LC3in-C42 was discovered utilizing the hybridization of advantageous fragments, whose potency (IC50 = 7.6 nM) had been greatly improved compared with that of DC-LC3in-D5. LC3in-C42 inhibits autophagy at the cellular level and its efficacy far exceeds that of DC-LC3in-D5. Thus far, LC3in-C42 stands as the most potent LC3A/B small molecule inhibitor. LC3in-C42 could serve as a powerful tool for LC3A/B protein and autophagy research.
Subject(s)
Autophagy , Microtubule-Associated Proteins , Microtubule-Associated Proteins/metabolism , Microtubule-Associated Proteins/antagonists & inhibitors , Humans , Structure-Activity Relationship , Autophagy/drug effects , Drug Design , Molecular Structure , Drug DiscoveryABSTRACT
Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.
Subject(s)
Ferroptosis , Macrophages , Mice, Inbred C57BL , NF-E2-Related Factor 2 , Phospholipid Hydroperoxide Glutathione Peroxidase , Signal Transduction , Spleen , Animals , Humans , Male , Mice , Ferroptosis/drug effects , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Lipid Peroxidation/drug effects , Macrophages/drug effects , Macrophages/metabolism , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/genetics , Signal Transduction/drug effects , Spleen/drug effects , Spleen/cytology , Spleen/metabolismABSTRACT
The Microbiome Protocols eBook (MPB) serves as a crucial bridge, filling gaps in microbiome protocols for both wet experiments and data analysis. The first edition, launched in 2020, featured 152 meticulously curated protocols, garnering widespread acclaim. We now extend a sincere invitation to researchers to participate in the upcoming 2nd version of MPB, contributing their valuable protocols to advance microbiome research.
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Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.
Subject(s)
Aquaporin 1 , Intestinal Mucosa , Animals , Aquaporin 1/genetics , Aquaporin 1/metabolism , Mice , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Mice, Inbred C57BL , Inflammation/metabolism , Inflammation/genetics , Inflammation/chemically induced , Male , Epithelial Cells/drug effects , Epithelial Cells/metabolism , NF-kappa B/metabolism , NF-kappa B/genetics , Diethylhexyl Phthalate/toxicity , Phthalic Acids , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. METHODS: Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. RESULTS: A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10-7) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10-6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field. CONCLUSION: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.
Subject(s)
Enhancer Elements, Genetic , Neoplasms , Quantitative Trait Loci , Humans , Enhancer Elements, Genetic/genetics , Neoplasms/genetics , Genetic Variation/genetics , Genome-Wide Association Study/methods , Colorectal Neoplasms/genetics , Case-Control Studies , RNA/genetics , China , Enhancer RNAsABSTRACT
OBJECTIVE: The aim of this study was to evaluate the occurrence and factors predisposing to delirium following brain tumor resection. METHODS: Data from patients who underwent brain tumor resection surgery from 2016 to 2019 were extracted from the National Inpatient Sample database and retrospectively analyzed. The difference between the 2 groups was compared by Wilcoxon rank test or χ2 test was used. Univariate and multivariate logistic regression analyses were used to identify the risk factors of delirium after brain tumor resection. RESULTS: From 2016 to 2019, 28,340 patients who underwent brain tumor resection were identified in the National Inpatient Sample database, with the incidence of delirium being 4.79% (1357/28,340). It was found that increased incidence of delirium was significantly associated with age over 75 years and males (all P < 0.001). Besides, patients with delirium were more likely to have multiple comorbidities and to receive elective surgery (all P < 0.001). The results of logistic regression analysis showed that self-pay (odds ratio [OR] = 0.51; confidence interval [CI] = 0.31-0.83; P = 0.007), elective admission (OR = 0.53; CI = 0.47-0.60; P < 0.001), obesity (OR = 0.77; CI = 0.66-0.92; P = 0.003), females (OR = 0.79; CI = 0.71-0.88; P < 0.001), and private insurance (OR = 0.80; CI = 0.67-0.95; P = 0.012) were associated with lower occurrence of delirium. Besides, delirium was related to extra total hospital charges (P < 0.001), increased length of stay (P < 0.001), higher inpatient mortality (P = 0.001), and perioperative complications (including heart failure, acute renal failure, urinary tract infection, urinary retention, septicemia, pneumonia, blood transfusion, and cerebral edema) (P < 0.001). CONCLUSIONS: Many factors were associated with the occurrence of delirium after brain tumor resection. Therefore, clinicians should identify high-risk patients prone to delirium in a timely manner and take effective management measures to reduce adverse outcomes.