ABSTRACT
According to the theory of five movements and six climates, the innate constitution plays a crucial role in determining the underlyingpa thological mechanisms of diseases later in life. Previous studies have demonstrated a close association between the constitution, as defined by the theory of five movements and six climates, and the development of various types of tumors. Furt hermore,the tumorsubtype determined by the constitution has prognostic implications. This highlights the potential of utilizing the fivemovements and six climates theory to guide the implementation of precision medicine strategies in thefield of oncology. However, no resear ch has yet been conducted to investigate the use of this theory in guiding the development of tumor molecular classification and precisi onmedicine strategies. The objective of this research is to uncover the biological characteristics of each constitution within a pancanc ercohort and identify potential anti-tumor drugs that are applicable to patients with different constitutional types. By doing so, we aimto c ontribute to the establishment of a precision medicine strategy for tumors derived from the original concepts of traditional Chi nesemedicine(TCM). In this study, we obtainedpan-cancer Bulk RNA-Seq data from UCSC Xena, GWAS cohort data from the UKBiobank, and cis-eQTLs data from eQ TLGen and GTEx V8. We employed machine learning methods to screen for hub genes associated with each constitution. Subsequently, we utilized informatics tools to explore the biological characteristics of each constitut iondefined by the theory of five movements and six bioclimates. Further, potential anti-tumor drugs suitable for patients with differen tconstitutional types were identified through mendelian randomization, molecular docking, and drug-like prediction techniques. Withinthe pan-cancer cohort, significant differences were observed among different constitutions in terms of progression-free interval, biological f unctions, immune cell abundance, tumor drug sensitivity, and immunotherapy response. These findings suggest that the five movements and six climates theory can guide tumor molecular classification and the development of precision medicine strategies. Moreover,the biological characteristics inherent to each constitution partially shed light on the scientific implications of Chinese medicinetheories, offering a fresh perspective towards clinical cancer treatment. Through molecular docking and drug-like prediction, several po tential anti-tumor drugs such as 17-beta-estradiol, serotonin, trans-resveratrol, and linoleic acid were identified. Overall, the util izationof multi-omics approaches pro vides a powerful tool to unravel the scientific foundations of TCM theories. The elucidation of themu lti-omics features associated witheach constitution in tumors serves as the basis for applying the five movements and six climates theoryto tumor molecular classification and the development of precision medicine strategies.
Subject(s)
Neoplasms , Humans , Neoplasms/genetics , Neoplasms/drug therapy , Precision Medicine , RNA-Seq , Medicine, Chinese Traditional , Body Constitution/geneticsABSTRACT
TRIM family proteins are widely found in multicellular organisms and are involved in a wide range of life activities, and also act as crucial regulators in the antiviral natural immune response. This study aimed to reveal the molecular mechanism of rainbow trout TRIM protein in the anti-IHNV process. The results demonstrated that 99.1 % homology between the rainbow trout and the chinook salmon (Oncorhynchus tshawytscha) TRIM32. When rainbow trout were infected with IHNV, the TRIM32 was highly expressed in the gill, spleen, kidney and blood. Meanwhile, rainbow trout TRIM32 has E3 ubiquitin ligase activity and undergoes K29-linked polyubiquitination modifications dependent on the RING structural domain was determined by immunoprecipitation. TRIM32 could interact with the NV protein of IHNV and degrade NV protein through the ubiquitin-proteasome pathway, and was also able to activate NF-κB transcription, thereby inhibiting the replication of IHNV. Moreover, the results of the animal studies showed that the survival rate of rainbow trout overexpressing TRIM32 was 70.2 % which was significantly higher than that of the control group, and stimulating the body to produce high levels of IgM when the host was infected with the virus. In addition, TRIM32 can activate the NF-κB signalling pathway and participate in the antiviral natural immune response. The results of this study will help us to understand the molecular mechanism of TRIM protein resistance in rainbow trout, and provide new ideas for disease resistance breeding, vaccine development and immune formulation development in rainbow trout.
ABSTRACT
Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.
Subject(s)
Autophagy-Related Proteins , Autophagy , Neural Stem Cells , Animals , Neural Stem Cells/physiology , Neural Stem Cells/metabolism , Mice , Autophagy/physiology , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice, Knockout , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/genetics , Gene Expression Regulation , Neoplasm ProteinsABSTRACT
Duck circovirus (DuCV) is one of the most prevalent infectious viruses in the duck industry in China. Although the clinical signs vary, it often causes immunosuppression in the host and leads to secondary infection with other pathogens. Novel goose parvovirus (NGPV) mainly infects ducks and causes short beak and dwarfism syndrome in ducks. However, the incidence of infection in ducks has increased in recent years, and the phenomenon of mixed infection with DuCV is common, resulting in more severe clinical morbidity. However, there are no systematic studies evaluating the presence of mixed infections. In order to investigate the synergistic pathogenicity of DuCV and NGPV co-infection in SPF ducks, a comparative experiment using DuCV and NGPV co-infection and mono-infection bird models was established. The results showed that the clinical signs of short beak, dwarfism and immunosuppression were more obvious in DuCV and NGPV co-infected ducks; the tissue damage of target organs was more serious, and the viral titre in organs and cloacal swabs were more significant compared with those of SPF ducks infected with only one virus. The results indicated that co-infection with DuCV and NGPV could promote viral replication and cause more severe tissue damage and immunosuppression than single virus infection. The present study reveals that the co-infection of NGPV and DuCV has a synergistic pathogenic effect from the aspect of pathogenicity, and the conclusions drawn not only clarify the direction of the subsequent research on the mechanism of co-infection of NGPV and DuCV, but also provide a scientific basis for the research on the co-infection of immunosuppressive pathogens and other pathogens.
ABSTRACT
The velocity field and temperature field are crucial for metal foams to be used as a heat exchanger, but they are difficult to obtain through physical experiments. In this work, the fluid flow behavior and heat transfer performance in open-cell metal foam were numerically studied. Porous 3D models with different porosities (55-75%) and pore sizes (250 µm, 550 µm, and 1000 µm) were created based on the porous structure manufactured by the Lost Carbonate Sintering method. A wide flow velocity range from 0.0001 m/s to 0.3 m/s, covering both laminar and turbulent flow regimes, is fully studied for the first time. Pressure drop, heat transfer coefficient, permeability, form drag coefficient, temperature and velocity distributions were calculated. The calculated results agree well with our previous experimental results, indicating that the model works well. The results showed that pressure drop increased with decreasing porosity and increasing pore size. Permeability increased and the form drag coefficient decreased with increasing porosity, and both increased with increasing pore size. The heat transfer coefficient increased with increasing velocity and porosity, whereas it slightly decreased with increasing pore size. The results also showed that at high velocity, only the metal foam close to the heat source contributes to heat dissipation.
ABSTRACT
Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.
ABSTRACT
Totally implanted venous access ports (TIVAPs), which are typically used in oncological chemotherapy and parenteral nutritional support, are convenient and safe, and thus offer patients a higher quality of life. However, insertion or removal of the device requires a minor surgical operation. Long-term complications (>30 days post insertion), such as catheter migration, catheter-related thrombosis and infection, are major reasons for TIVAP removal and are associated with a number of factors such as body mass index and hemoglobin count. Since management of complications is typically time-consuming and costly, a predictive model of such events may be of great value. Therefore, in the present study, a predictive model for long-term complications following TIVAP implantation in patients with lung cancer was developed. After excluding patients with a large amount of missing data, 902 patients admitted to The First Affiliated Hospital with Nanjing Medical University (Nanjing, China) were ultimately included in the present study. Of the included patients, 28 had complications, indicating an incidence rate of 3.1%. Patients were randomly divided into training and test cohorts (7:3), and three machine learning-based anomaly detection algorithms, namely, the Isolation Forest, one-class Support Vector Machines (one-class SVM) and Local Outlier Factor, were used to construct a model. The performance of the model was initially evaluated by the Matthew's correlation coefficient (MCC), area under curve (AUC) and accuracy. The one-class SVM model demonstrated the highest performance in classifying the risk of complications associated with the use of the intracavitary electrocardiogram method for TIVAP implantation in patients with lung cancer (MCC, 0.078; AUC, 0.62; accuracy, 66.0%). In conclusion, the predictive model developed in the present study may be used to improve the early detection of TIVAP-related complications in patients with lung cancer, which could lead to the conservation of medical resources and the promotion of medical advances.
ABSTRACT
Objective: Network pharmacology is an emerging discipline that applies computational methods to understand drug actions and interactions with multiple molecular targets. Xiao'ai Jiedu is a valued traditional Chinese medicine preparation for which the mechanism of action is not yet established. This study aims to explore the mechanism of Xiao'ai Jiedu in treating lung cancer through network pharmacology. Methods: First, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) data platform was used to analyze the target treatment results of different medicinal materials in Mr. Zhou's cancer prescriptions. Then, functional enrichment analysis was performed to conduct a secondary analysis of the dissemination of cancer biological and pharmacological information in the human body. The Cancer Genome Atlas (TCGA) was used to obtain several cancer-aggressive target groups, and their transcription RNA was extracted for collection. The CIBERSORT evaluation method was used to conduct a Spearman correlation analysis on the data processing results. Then the matching degree between the experimental cells and the principle of drug treatment was analyzed to improve the statistical analysis. Results: Pharmacology research results showed that the network can accurately eliminate cancer detoxification targeted target correlation set, and through the data interpretation found that four different gene transcription have significant influence on lung cancer. The findings also confirmed that the degree of immune cell infiltration has a key role in lung cancer The study summarizes the active ingredients and their targets and mechanisms of action of the elimination of Xiao'ai Jiedu formula for the treatment of lung cancer. Conclusion: Network pharmacology can carry on the processing of the data, find the key to conform to the goal of research data, and the corresponding results are obtained, and the development of network pharmacology is not limited to, the study of lung cancer.
ABSTRACT
Catalysts play a pivotal role in advanced oxidation processes for the remediation of organic wastewater. In this study, a 3D carbon fiber@Fe3O4-CuO catalyst was fabricated, and its efficacy for persulfate activation to remove sulfamethoxazole (SMX) was investigated at extremely low current density. The results of characterization revealed that the catalyst was uniformly distributed on the carbon fiber, and the loaded catalyst was Fe3O4-CuO nanoparticles with a diameter range of 20-50 nm. The SMX removal rate was significantly enhanced at extremely low current density by the metallic oxide catalyst loaded on carbon fiber. Approximately 90 % of SMX was degraded within 90 min when the electric current density was set at 0.1 mA cm-2. This modification process not only improved the persulfate activation efficiency but also enhanced the generation of hydrogen peroxide. Both radical and non-radical pathways were involved in the degradation of SMX. The degradation pathway mainly included hydroxylation, carboxylation, aniline cleavage, and desulfonation reactions. The quantitative structure-activity relationship model indicated that the potential risk of intermediate products to fish, daphnia, and green algae significantly decreased during the electrocatalytic oxidation process. This study provides a novel strategy for persulfate activation, which can significantly enhance the degradation efficiency, toxicity abatement, and energy usage effectiveness of electrocatalytic technology.
ABSTRACT
Cytochrome P450 3A4 (CYP3A4) is the most important and abundant drug-metabolizing enzyme in the human liver. Inter-individual differences in the expression and activity of CYP3A4 affect clinical and precision medicine. Increasing evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in the regulation of CYP3A4 expression. Here, we showed that lncRNA hepatocyte nuclear factor 1 alpha-antisense 1 (HNF1A-AS1) exerted dual functions in regulating CYP3A4 expression in Huh7 and HepG2 cells. Mechanistically, HNF1A-AS1 served as an RNA scaffold to interact with both protein arginine methyltransferase 1 and pregnane X receptor (PXR), thereby facilitating their protein interactions and resulting in the transactivation of PXR and transcriptional alteration of CYP3A4 via histone modifications. Furthermore, HNF1A-AS1 bound to the HNF1A protein, a liver-specific transcription factor, thereby blocking its interaction with the E3 ubiquitin ligase tripartite motif containing 25, ultimately preventing HNF1A ubiquitination and protein degradation, further regulating the expression of CYP3A4. In summary, these results reveal the novel functions of HNF1A-AS1 as the transcriptional and post-translational regulator of CYP3A4; thus, HNF1A-AS1 may serve as a new indicator for establishing or predicting individual differences in CYP3A4 expression.
Subject(s)
RNA, Long Noncoding , Humans , Cytochrome P-450 CYP3A/genetics , Gene Expression Regulation , Hepatocyte Nuclear Factor 1-alpha/genetics , Liver , RNA, Long Noncoding/geneticsABSTRACT
BACKGROUND: Oral inosine loading is a new method to evaluate the effects of purine on urate metabolism. However, individuals respond differently to acute purine intake, and the effects on the metabolism of other purines remain to be explored. METHODS: 35 male participants are recruited. Participants received 500 mg of inosine orally after an overnight fast, and blood and urine samples are collected before and at various time points over 180 min after inosine administration. RESULTS: The serum urate concentration is significantly different between the hyperuricemia (n = 14) and non-hyperuricemia (n = 16) groups before inosine intake, but there is no in urate change after inosine intake. When grouped according to the baseline estimated glomerular filtration rate (eGFR), the increase in urate level in the high-eGFR group is significantly higher than that in the low-eGFR group (pâ = â 0.047). The high-eGFR group showed higher levels of serum xanthine and xanthine oxidase (XOD), the key enzyme in urate synthesis, after inosine loading (pâ <â 0.01). CONCLUSIONS: The increase in urate level is positively related to eGFR after oral acute inosine administration, which may have been due to a higher level of XOD.
Subject(s)
Hyperuricemia , Uric Acid , Humans , Male , Purines/metabolism , Hyperuricemia/drug therapy , Inosine/metabolism , Metabolic Networks and Pathways , ChinaABSTRACT
Ducks infected with duck circovirus (DuCV) show symptoms such as feather loss, growth retardation and low body weight in the flock. The virus induces immunosuppression and increases the prevalence of infection with other pathogens. However, most studies on duck circovirus were focused on coinfection, and fewer studies had been conducted on the pathogenicity of duck circovirus alone. The aim of the present study was to investigate the pathogenesis of DuCV-1 in experimentally infected specific pathogen-free ducks. In this study, we sequenced the whole genome of a strain of duck circovirus and identified the virus genotype as DuCV-1b. This strain of duck circovirus was named SDLH(OR567883). Animal pathogenicity experiments were then conducted, wherein specific pathogen-free ducks were infected by mucosal injection and abdominal injection. Infected ducks were sampled for 4 consecutive weeks after infection and showed symptoms of dwarfism. We further examined the replication of DuCV-1 in the ducks. The highest virus titers in the 2 infection groups were found in the liver and spleen, with different results for the different routes of infection. Pathological sections of duck organs were made and it was found that organs such as the liver and spleen were damaged by DuCV-1. In conclusion, our experimental results indicate that DuCV-1 can infect ducks individually and cause widespread organ damage in infected ducks.
Subject(s)
Circoviridae Infections , Circovirus , Poultry Diseases , Animals , Virulence , Chickens/genetics , Base Sequence , Circovirus/genetics , Circoviridae Infections/veterinaryABSTRACT
The kidneys have a high level of Netrin-1 expression, which protects against some acute and chronic kidney disorders. However, it is yet unknown how Netrin-1 affects renal proximal tubule cells in diabetic nephropathy (DN) under pathological circumstances. Research has shown that autophagy protects the kidneys in animal models of renal disease. In this study, we looked at the probable autophagy regulation mechanism of Netrin-1 and its function in the pathogenesis of DN. We proved that in HK-2 cell, high blood sugar levels caused Netrin-1 to be downregulated, which then triggered the Akt/mTOR signaling pathway and enhanced cell death and actin cytoskeleton disruption. By adding Netrin-1 or an autophagy activator in vitro, these pathogenic alterations were reverted. Our results indicate that Netrin-1 stimulates autophagy by blocking the Akt/mTOR signaling pathway, which underlies high-glucose-induced malfunction of the renal proximal tubules. After HK-2 cells were incubated with Netrin-1 recombination protein and rapamycin under HG conditions for 24 h, the apoptosis was significantly reduced, as shown by the higher levels of Bcl-2, as well as lower levels of Bax and cleaved caspase-3 (P = 0.012, Cohen's d = 0.489, Glass's delta = 0.23, Hedges' g = 0.641). This study reveals that targeting Netrin-1-related signaling has therapeutic potential for DN and advances our knowledge of the processes operating in renal proximal tubules in DN.
Subject(s)
Diabetic Nephropathies , Proto-Oncogene Proteins c-akt , Apoptosis , Autophagy , Diabetic Nephropathies/metabolism , Glucose/adverse effects , Kidney Tubules, Proximal/metabolism , Netrin-1/metabolism , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , HumansABSTRACT
Catalytically inactive Zn2+ is incorporated into cobalt hydroxide to synthesize hierarchical ZnCo-layered double hydroxide nanosheet networks supported on carbon fiber (ZnCo-LDH/CF). The incorporation of Zn2+ is revealed to endow ZnCo-LDH/CF with significantly superior performance in the aspects of the activity and selectivity for methanol electrooxidation to formic acid and the boosting effect for cathodic hydrogen production compared with the counterpart without Zn2+. Density functional theory (DFT) calculation reveals that the incorporation of nonactive Zn2+ can increase the density of states near the Fermi level of LDH (i.e., elevate electrical conductivity to form favorable charge transportation during electrocatalysis) and promote the adsorption and subsequent cleavage of methanol, thus leading to the enhanced methanol electrooxidation performance.
ABSTRACT
Azadirachtin has been used to control agricultural pests for a long time; however, the molecular mechanism of azadirachtin on lepidopterans is still not clear. In this study, the fourth instar larvae of fall armyworm were fed with azadirachtin, and then the ecdysis was blocked in the fourth instar larval stage (L4). The prothoracic glands (PGs) of the treated larvae were dissected for RNA sequencing to determine the effect of azadirachtin on ecdysis inhibition. Interestingly, one of the PG-enriched genes, the nuclear hormone receptor 3 (HR3), was decreased after azadirachtin treatment, which plays a critical role in the 20-hydroxyecdysone action during ecdysis. To deepen the understanding of azadirachtin on ecdysis, the HR3 was knocked out by using the CRISPR/Cas9 system, while the HR3 mutants displayed embryonic lethal phenotype; thus, the stage-specific function of HR3 during larval molting was not enabled to unfold. Hence, the siRNA was injected into the 24 h L4 larvae to knock down HR3. After 96 h, the injected larvae were blocked in the old cuticle during ecdysis which is consistent with the azadirachtin-treated larvae. Taken together, we envisioned that the inhibition of ecdysis in the fall armyworm after the azadirachtin treatment is due to an interference with the expression of HR3 in PG, resulting in larval mortality. The results in this study specified the understanding of azadirachtin on insect ecdysis and the function of HR3 in lepidopteran in vivo.
Subject(s)
Molting , Receptors, Cytoplasmic and Nuclear , Animals , Molting/genetics , Larva/metabolism , Spodoptera/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolismABSTRACT
Fungal cell walls undergo continual remodeling that generates ß-1,3-glucan fragments as products of endo-glycosyl hydrolases (GHs), which can be recognized as pathogen-associated molecular patterns (PAMPs) and trigger plant immune responses. How fungal pathogens suppress those responses is often poorly understood. Here, we study mechanisms underlying the suppression of ß-1,3-glucan-triggered plant immunity by the blast fungus Magnaporthe oryzae. We show that an exo-ß-1,3-glucanase of the GH17 family, named Ebg1, is important for fungal cell wall integrity and virulence of M. oryzae. Ebg1 can hydrolyze ß-1,3-glucan and laminarin into glucose, thus suppressing ß-1,3-glucan-triggered plant immunity. However, in addition, Ebg1 seems to act as a PAMP, independent of its hydrolase activity. This Ebg1-induced immunity appears to be dampened by the secretion of an elongation factor 1 alpha protein (EF1α), which interacts and co-localizes with Ebg1 in the apoplast. Future work is needed to understand the mechanisms behind Ebg1-induced immunity and its suppression by EF1α.
Subject(s)
Ascomycota , Peptide Elongation Factor 1 , Cell Wall , Plant ImmunityABSTRACT
The sensitive analysis of glycoproteins is of great importance for early diagnosis and prognosis of diseases. In this work, a sandwich-type electrochemical aptasensor was developed for the detection of glycoproteins using 4-formylphenylboric acid (FPBA)-modified Cu-based metal-organic frameworks (FPBA-Cu-MOFs) as dual-functional signal probes. The target captured by the aptamer-modified electrode allowed the attachment of FPBA-Cu-MOFs based on the interaction between boronic acid and glycan on glycoproteins. Large numbers of Cu2+ ions in FPBA-Cu-MOFs produced an amplified signal for the direct voltammetric detection of glycoproteins. The electrochemical aptasensor showed a detection limit as low as 6.5 pg mL-1 for prostate specific antigen detection. The method obviates the use of antibody and enzymes for molecular recognition and signal output. The dual-functional MOFs can be extended to the design of other biosensors for the determination of diol-containing biomolecules in clinical diagnosis.
Subject(s)
Boronic Acids , Metal-Organic Frameworks , Male , Humans , Glycoproteins , Antibodies , ElectrodesABSTRACT
In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.
Subject(s)
Colorectal Neoplasms , Diapause , Humans , Animals , Histones/metabolism , Glycolysis , Cell Proliferation , Colorectal Neoplasms/metabolism , Lactates , Adenosine Triphosphatases/metabolism , Chromosomal Proteins, Non-Histone/metabolismABSTRACT
PURPOSE: Segmentation of liver vessels from CT images is indispensable prior to surgical planning and aroused a broad range of interest in the medical image analysis community. Due to the complex structure and low-contrast background, automatic liver vessel segmentation remains particularly challenging. Most of the related researches adopt FCN, U-net, and V-net variants as a backbone. However, these methods mainly focus on capturing multi-scale local features which may produce misclassified voxels due to the convolutional operator's limited locality reception field. METHODS: We propose a robust end-to-end vessel segmentation network called Inductive BIased Multi-Head Attention Vessel Net(IBIMHAV-Net) by expanding swin transformer to 3D and employing an effective combination of convolution and self-attention. In practice, we introduce voxel-wise embedding rather than patch-wise embedding to locate precise liver vessel voxels and adopt multi-scale convolutional operators to gain local spatial information. On the other hand, we propose the inductive biased multi-head self-attention which learns inductively biased relative positional embedding from initialized absolute position embedding. Based on this, we can gain more reliable queries and key matrices. RESULTS: We conducted experiments on the 3DIRCADb dataset. The average dice and sensitivity of the four tested cases were 74.8[Formula: see text] and 77.5[Formula: see text], which exceed the results of existing deep learning methods and improved graph cuts method. The Branches Detected(BD)/Tree-length Detected(TD) indexes also proved the global/local feature capture ability better than other methods. CONCLUSION: The proposed model IBIMHAV-Net provides an automatic, accurate 3D liver vessel segmentation with an interleaved architecture that better utilizes both global and local spatial features in CT volumes. It can be further extended for other clinical data.