Metadherin promotes stem cell phenotypes and correlated with immune infiltration in hepatocellular carcinoma

BACKGROUND Metadherin(MTDH)is a key oncogene in most cancer types,including hepato-cellular carcinoma(HCC).Notably,MTDH does not affect the stemness pheno-type or immune infiltration of HCC.AIM To explore the role of MTDH on stemness and immune infiltration in HCC.METHODS MTDH expression in HCC tissues was detected using TCGA and GEO databases.Immunohistochemistry was used to analyze the tissue samples.MTDH was stably knocked down or overexpressed by lentiviral transfection in the two HCC cell lines.The invasion and migration abilities of HCC cells were evaluated using Matrigel invasion and wound healing assays.Next,we obtained liver cancer stem cells from the spheroids by culturing them in a serum-free medium.Gene expression was determined by western blotting and quantitative reverse transcri-ption PCR.Flow cytometry,immunofluorescence,and tumor sphere formation assays were used to characterize stem-like cells.The effects of MTDH inhibition on tumor growth were evaluated in vivo.The correlation of MTDH with immune cells,immunomodulators,and chemokines was analyzed using ssGSEA and TISIDB databases.RESULTS HCC tissues expressed higher levels of MTDH than normal liver tissues.High MTDH expression was associated with a poor prognosis.HCC cells overex-pressing MTDH exhibited stronger invasion and migration abilities,exhibited a stem cell-like phenotype,and formed spheres;however,MTDH inhibition attenuated these effects.MTDH inhibition suppressed HCC progression and CD133 expression in vivo.MTDH was positively correlated with immature dendritic,T helper 2 cells,central memory CD8^(+)T,memory B,activated dendritic,natural killer(NK)T,NK,activated CD4^(+)T,and central memory CD4^(+)T cells.MTDH was negatively correlated with activated CD8^(+)T cells,eosinophils,activated B cells,monocytes,macrophages,and mast cells.A positive correlation was observed between the MTDH level and CXCL2 expression,whereas a negative correlation was observed between the MTDH level and CX3CL1 and CXCL12 expression.CONCLUSION High levels of MTDH expression in patients with HCC are associated with poor prognosis,promoting tumor stemness,immune infiltration,and HCC progression.

Surrogate modeling for unsaturated infiltration via the physics and equality-constrained artificial neural networks

Machine learning(ML)provides a new surrogate method for investigating groundwater flow dynamics in unsaturated soils.Traditional pure data-driven methods(e.g.deep neural network,DNN)can provide rapid predictions,but they do require sufficient on-site data for accurate training,and lack interpretability to the physical processes within the data.In this paper,we provide a physics and equalityconstrained artificial neural network(PECANN),to derive unsaturated infiltration solutions with a small amount of initial and boundary data.PECANN takes the physics-informed neural network(PINN)as a foundation,encodes the unsaturated infiltration physical laws(i.e.Richards equation,RE)into the loss function,and uses the augmented Lagrangian method to constrain the learning process of the solutions of RE by adding stronger penalty for the initial and boundary conditions.Four unsaturated infiltration cases are designed to test the training performance of PECANN,i.e.one-dimensional(1D)steady-state unsaturated infiltration,1D transient-state infiltration,two-dimensional(2D)transient-state infiltration,and 1D coupled unsaturated infiltration and deformation.The predicted results of PECANN are compared with the finite difference solutions or analytical solutions.The results indicate that PECANN can accurately capture the variations of pressure head during the unsaturated infiltration,and present higher precision and robustness than DNN and PINN.It is also revealed that PECANN can achieve the same accuracy as the finite difference method with fewer initial and boundary training data.Additionally,we investigate the effect of the hyperparameters of PECANN on solving RE problem.PECANN provides an effective tool for simulating unsaturated infiltration.

Evaluation of frictional pressure drop correlations for air-water and air-oil two-phase flow in pipeline-riser system

Accurate prediction of the frictional pressure drop is important for the design and operation of subsea oil and gas transporting system considering the length of the pipeline. The applicability of the correlations to pipeline-riser flow needs evaluation since the flow condition in pipeline-riser is quite different from the original data where they were derived from. In the present study, a comprehensive evaluation of 24prevailing correlation in predicting frictional pressure drop is carried out based on experimentally measured data of air-water and air-oil two-phase flows in pipeline-riser. Experiments are performed in a system having different configuration of pipeline-riser with the inclination of the downcomer varied from-2°to-5°to investigated the effect of the elbow on the frictional pressure drop in the riser. The inlet gas velocity ranges from 0.03 to 6.2 m/s, and liquid velocity varies from 0.02 to 1.3 m/s. A total of885 experimental data points including 782 on air-water flows and 103 on air-oil flows are obtained and used to access the prediction ability of the correlations. Comparison of the predicted results with the measured data indicate that a majority of the investigated correlations under-predict the pressure drop on severe slugging. The result of this study highlights the requirement of new method considering the effect of pipe layout on the frictional pressure drop.

SOX11 as a potential prognostic biomarker in hepatocellular carcinoma linked to immune infiltration and ferroptosis

Objective:SOX11 is expressed in numerous malignancies,including hepatocellular carcinomas(HCC),but its oncogenic function has not been elucidated.Here,we performed a comprehensive bioinformatics analysis of the Liver Hepatocellular Carcinoma(LIHC)dataset to investigate the function of SOX11 in tumorgenesis.Methods:SOX11 expression data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)were validated by immunohistochemistry(IHC).Co-expression,differential expression,and functional analyses utilized TCGA-LIHC,Timer 2.0,Metascape,GTEx,and LinkedOmics databases.Associations with immune infiltration,ferroptosis,and immune checkpoint genes were assessed.Genetic changes were explored via CBioPortal.Logistic regression,receiver operating characteristic curve(ROC),Kaplan-Meier analysis,and nomogram modeling evaluated associations with HCC clinicopathological features.SOX11’s impact on proliferation and migration was studied in HepG2 and HuH7 cell lines.Results:SOX11 was significantly elevated in HCC tumors compared to controls.SOX11-associated genes exhibited differential expression in pathways involving extracellular membrane ion channels.Significant associations were found between SOX11 levels,immune infiltration,ferroptosis,and immune checkpoint genes in HCC tissue.SOX11 levels correlated with HCC stage,histologic grade,and tumor status,and independently predicted overall and disease-specific survival.SOX11 expression effectively distinguished between tumor and normal liver tissue.Spearman correlations highlighted a significant relationship between SOX11 and ferroptosis-associated genes.Decreased SOX11 levels in HepG2 and HuH7 cells resulted in reduced proliferation and migration.Conclusions:SOX11 was found to represent a promising biomarker within HCC diagnosis and prognosis together with being a possible drug-target.

CRABP2 regulates infiltration of cancer-associated fibroblasts and immune response in melanoma

Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.

A Prognostic Biomarker for Bladder Cancer Correlated with Immune Infiltration Is PAEP

Background: A major cause of cancer death worldwide is bladder cancer, which is the most common malignant tumor of the urinary tract. PAEP is a member of the kernel lipocalin superfamily whose members share relatively low sequence similarity but have highly conserved exon/intron structure and three-dimensional protein folding. Most lipocalins are clustered on the long arm of chromosome 9. The purpose of this study was to clarify the correlation between PAEP expression level and bladder cancer. Methods: In the TCGA database, we obtained clinical and RNA sequencing data of 431 BLCA patients, including 412 BLCA tissues and 19 normal bladder tissues in the study. Analyses of bioinformatics were conducted in this study to determine the role of PAEP in bladder cancer. A quantitative real-time PCR method was used to quantitate the gene expression profile. Additionally, the effect of PAEP on tumor immune infiltration and prognosis was analyzed. Results: PAEP was a poor prognostic biomarker of bladder cancer because it was significantly upregulated. bladder cancer patients with higher PAEP expression had poor outcomes. An AUC of 0.780 was calculated from the area under the ROC curve. PAEP was associated with T stage, pathologic stage, Histologic grade and Subtype of bladder cancer patients, and served as an independent predictor of overall survival in bladder cancer patients. Functional enrichment analysis revealed PAEP was obviously enriched in pathways connected with carcinogenesis and immunosuppression. The expression of PAEP was significantly associated with tumor immune cells and immune checkpoints according to ssGSEA and Spearman correlation analysis. Conclusions: In this study, we screened and detected a mRNA, PAEP is a prognostic and immune-related biomarker in BLCA, which may contribute to the early diagnosis and treatment of BLCA.

Pressure transient characteristics of non-uniform conductivity fractured wells in viscoelasticity polymer flooding based on oil-water two-phase flow

Polymer flooding in fractured wells has been extensively applied in oilfields to enhance oil recovery.In contrast to water,polymer solution exhibits non-Newtonian and nonlinear behavior such as effects of shear thinning and shear thickening,polymer convection,diffusion,adsorption retention,inaccessible pore volume and reduced effective permeability.Meanwhile,the flux density and fracture conductivity along the hydraulic fracture are generally non-uniform due to the effects of pressure distribution,formation damage,and proppant breakage.In this paper,we present an oil-water two-phase flow model that captures these complex non-Newtonian and nonlinear behavior,and non-uniform fracture characteristics in fractured polymer flooding.The hydraulic fracture is firstly divided into two parts:high-conductivity fracture near the wellbore and low-conductivity fracture in the far-wellbore section.A hybrid grid system,including perpendicular bisection(PEBI)and Cartesian grid,is applied to discrete the partial differential flow equations,and the local grid refinement method is applied in the near-wellbore region to accurately calculate the pressure distribution and shear rate of polymer solution.The combination of polymer behavior characterizations and numerical flow simulations are applied,resulting in the calculation for the distribution of water saturation,polymer concentration and reservoir pressure.Compared with the polymer flooding well with uniform fracture conductivity,this non-uniform fracture conductivity model exhibits the larger pressure difference,and the shorter bilinear flow period due to the decrease of fracture flow ability in the far-wellbore section.The field case of the fall-off test demonstrates that the proposed method characterizes fracture characteristics more accurately,and yields fracture half-lengths that better match engineering reality,enabling a quantitative segmented characterization of the near-wellbore section with high fracture conductivity and the far-wellbore section with low fracture conductivity.The novelty of this paper is the analysis of pressure performances caused by the fracture dynamics and polymer rheology,as well as an analysis method that derives formation and fracture parameters based on the pressure and its derivative curves.

Effects of diamond particle size on microstructure and properties of diamond/Al-12Si composites prepared by vacuum-assisted pressure infiltration

Diamond/aluminium composites have attracted attention in the field of thermal management of electronic packaging for their excellent properties.In order to solve the interfacial problem between diamond and aluminium,a novel process combining pressure infiltration with vacuum-assisted technology was proposed to prepare diamond/aluminum composites.The effect of diamond particle size on the microstructure and properties of the diamond/Al-12Si composites was investigated.The results show that the diamond/Al-12Si composites exhibit high relative density and a uniform microstructure.Both thermal conductivity and coefficient of thermal expansion increase with increasing particle size,while the bending strength exhibits the opposite trend.When the average diamond particle size increases from 45μm to 425μm,the thermal conductivity of the composites increases from 455 W·m^(-1)·K^(-1)to 713 W·m^(-1)·K^(-1)and the coefficient of thermal expansion increases from 4.97×10^(-6)K^(-1)to 6.72×10^(-6)K^(-1),while the bending strength decreases from 353 MPa to 246 MPa.This research demonstrates that high-quality composites can be prepared by the vacuum-assisted pressure infiltration process and the thermal conductivity of the composites can be effectively improved by increasing the diamond particle size.

Microstructure and Oxidation Behavior of ZrB_(2)-SiC Ceramics Fabricated by Tape Casting and Reactive Melt Infiltration

ZrB_(2)-based ceramics typically necessitate high temperature and pressure for sintering,whereas ZrB_(2)-SiC ceramics can be fabricated at 1500℃using the process of reactive melt infiltration with Si.In comparison to the conventional preparation method,reactive synthesis allows for the more facile production of ultra-high temperature ceramics with fine particle size and homogeneous composition.In this work,ZrSi_(2),B4C,and C were used as raw materials to prepare ZrB_(2)-SiC via combination of tape casting and reactive melt infiltration herein referred to as ZBC ceramics.Control sample of ZrB_(2)-SiC was also prepared using ZrB_(2) and SiC as raw materials through an identical process designated as ZS ceramics.Microscopic analysis of both ceramic groups revealed smaller and more uniformly distributed particles of the ZrB_(2) phase in ZBC ceramics compared to the larger particles in ZS ceramics.Both sets of ceramics underwent cyclic oxidation testing in the air at 1600℃for a cumulative duration of 5 cycles,each cycle lasting 2 h.Analysis of the oxidation behavior showed that both ZBC ceramics and ZS ceramics developed a glassy SiO_(2)-ZrO_(2) oxide layer on their surfaces during the oxidation.This layer severed as a barrier against oxygen.In ZBC ceramics,ZrO_(2) is finely distributed in SiO_(2),whereas in ZS ceramics,larger ZrO_(2) particles coexist with glassy SiO_(2).The surface oxide layer of ZBC ceramics maintains a dense structure because the well-dispersed ZrO_(2) increases the viscosity of glassy SiO_(2),preventing its crystallization during the cooling.Conversely,some SiO_(2) in the oxide layer of ZS ceramics may crystallize and form a eutectic with ZrO_(2),leading to the formation of ZrSiO_(4).This leads to cracking of the oxide layer due to differences in thermal expansion coefficients,weakening its barrier effect.An analysis of the oxidation resistance shows that ZBC ceramics exhibit less increase in oxide layer thickness and mass compared to ZS ceramics,suggesting superior oxidation resistance of ZBC ceramics.

Infiltration,runoff,and slope stability behaviors of infinite slope with macropores based on an improved Green–Ampt model

Infiltration–runoff–slope instability mechanism of macropore slope under heavy rainfall is unclear.This paper studied its instability mechanism with an improved Green–Ampt(GA)model considering the dual-porosity(i.e.,matrix and macropore)and ponding condition,and proposed the infiltration equations,infiltration–runoff coupled model,and safety factor calculation method.Results show that the infiltration processes of macropore slope can be divided into three stages,and the proposed model is rational by a comparative analysis.The wetting front depth of the traditional unsaturated slope is 17.2%larger than that of the macropore slope in the early rainfall stage and 27%smaller than that of the macropore slope in the late rainfall stage.Then,macropores benefit the slope stability in the early rainfall but not in the latter.Macropore flow does not occur initially but becomes pronounced with increasing rainfall duration.The equal depth of the wetting front in the two domains is regarded as the onset criteria of macropore flow.Parameter analysis shows that macropore flow is delayed by increasing proportion of macropore domain(ω_(f)),whereas promoted by increasing ratio of saturated permeability coefficients between the two domains(μ).The increasing trend of ponding depth is sharp at first and then grows slowly.Finally,when rainfall duration is less than 3 h,ωf andμhave no significant effect on the safety factor,whereas it decreases with increasingωf and increases with increasingμunder longer duration(≥3 h).With the increase ofω_(f),the slope maximum instability time advances by 10.5 h,and with the increase ofμ,the slope maximum instability time delays by 3.1 h.

Integrated numerical simulation of hydraulic fracturing and production in shale gas well considering gas-water two-phase flow

Based on the displacement discontinuity method and the discrete fracture unified pipe network model,a sequential iterative numerical method was used to build a fracturing-production integrated numerical model of shale gas well considering the two-phase flow of gas and water.The model accounts for the influence of natural fractures and matrix properties on the fracturing process and directly applies post-fracturing formation pressure and water saturation distribution to subsequent well shut-in and production simulation,allowing for a more accurate fracturing-production integrated simulation.The results show that the reservoir physical properties have great impacts on fracture propagation,and the reasonable prediction of formation pressure and reservoir fluid distribution after the fracturing is critical to accurately predict the gas and fluid production of the shale gas wells.Compared with the conventional method,the proposed model can more accurately simulate the water and gas production by considering the impact of fracturing on both matrix pressure and water saturation.The established model is applied to the integrated fracturing-production simulation of practical horizontal shale gas wells.The simulation results are in good agreement with the practical production data,thus verifying the accuracy of the model.

Effect of slope angle on fractured rock masses under combined influence of variable rainfall infiltration and excavation unloading

Intense precipitation infiltration and intricate excavation processes are crucial factors that impact the stability and security of towering and steep rock slopes within mining sites.The primary aim of this research was to investigate the progression of cumulative failure within a cracked rock formation,considering the combined effects of precipitation and excavation activities.The study was conducted in the Huangniuqian eastern mining area of the Dexing Copper Mine in Jiangxi Province,China.An engineering geological investigation was conducted,a physical model experiment was performed,numerical calculations and theoretical analysis were conducted using the matrix discrete element method(Mat-DEM),and the deformation characteristics and the effect of the slope angle of a fractured rock mass under different scenarios were examined.The failure and instability mechanisms of the fractured rock mass under three slope angle models were analyzed.The experimental results indicate that as the slope angle increases,the combined effect of rainfall infiltration and excavation unloading is reduced.A novel approach to simulating unsaturated seepage in a rock mass,based on the van Genuchten model(VGM),has been developed.Compared to the vertical displacement observed in a similar physical experiment,the average relative errors associated with the slope angles of 45,50,and 55were 2.094%,1.916%,and 2.328%,respectively.Accordingly,the combined effect of rainfall and excavation was determined using the proposed method.Moreover,the accuracy of the numerical simulation was validated.The findings contribute to the seepage field in a meaningful way,offering insight that can inform and enhance existing methods and theories for research on the underlying mechanism of ultra-high and steep rock slope instability,which can inform the development of more effective risk management strategies.

Ablation behaviour and mechanical performance of ZrB_(2)-ZrC-SiC modified carbon/carbon composites prepared by vacuum infiltration combined with reactive melt infiltration

The development of advanced aircraft relies on high performance thermal-structural materials,and carbon/carbon com-posites(C/C)composited with ultrahigh-temperature ceramics are ideal candidates.However,the traditional routes of compositing are either inefficient and expensive or lead to a non-uniform distribution of ceramics in the matrix.Compared with the traditional C/C-ZrC-SiC composites prepared by the reactive melt infiltration of ZrSi_(2),C/C-ZrB_(2)-ZrC-SiC composites prepared by the vacuum infiltration of ZrB_(2) combined with reactive melt infiltration have the higher content and more uniform distribution of the introduced ceramic phases.The mass and linear ablation rates of the C/C-ZrB_(2)-ZrC-SiC composites were respectively 68.9%and 29.7%lower than those of C/C-ZrC-SiC composites prepared by reactive melt infiltration.The ablation performance was improved because the volatilization of B_(2)O_(3),removes some of the heat,and the more uniformly distributed ZrO_(2),that helps produce a ZrO2-SiO2 continu-ous protective layer,hinders oxygen infiltration and decreases ablation.

BMI1 overexpression is correlated with a poor prognosis and immune infiltration in hepatocellular carcinoma

Background:Owing to the occurrence of primary or secondary tolerance,the efficacy of immunotherapy for hepatocellular carcinoma(HCC)patients is limited.Therefore,the mechanism underlying this tolerance needs to be further investigated.B cell–specific Moloney murine leukemia virus integration site 1(BMI1)is associated with cancer stem cell tumorigenesis,progression,and the maintenance of the self-renewal.However,the effect of BMI1 expression on immune infiltration and prognosis in HCC is still unclear.Methods:To assess the relationship between BMI1 expression and HCC prognosis and immune infiltration,the GEPIA database,TIMER database,and K-M plotter were used.TIMER database was used to determine the levels ofBMI1 in various tumor tissues and corresponding normal tissues,and examine the association between BMI1 expression and tumor-infiltrating immune cells.GEPIA database was applied to determine BMI1 expression in various tumor tissues and corresponding normal tissues.K-M Plotter was used to study the relationships among BMI1 expression,clinicopathological features,and survival rates.Results:BMI1 expression was markedly higher in various solid tumors compared with that in the respective normal tissues,including HCC,and high expression led to poor relapse-free survival and overall survival in HCC patients.BMI1 overexpression was also correlated with the infiltration of immune cells(eg,B cells,CD8+T cells,CD4+T cells,dendritic cells,neutrophils,and macrophages)and positively associated with different subsets of T cells,monocytes,and M1 macrophages,among others.Conclusions:This study demonstrates that high BMI1 expression is strongly correlated with immune infiltration and poor prognosis in HCC.Increased expression of BMI1 might thus be a potential mechanism of immune tolerance in this disease.

Simulation of Two-Phase Flowback Phenomena in Shale Gas Wells

The gas-water two-phaseflow occurring as a result of fracturingfluidflowback phenomena is known to impact significantly the productivity of shale gas well.In this work,this two-phaseflow has been simulated in the framework of a hybrid approach partially relying on the embedded discrete fracture model(EDFM).This model assumes the region outside the stimulated reservoir volume(SRV)as a single-medium while the SRV region itself is described using a double-medium strategy which can account for thefluid exchange between the matrix and the micro-fractures.The shale gas adsorption,desorption,diffusion,gas slippage effect,fracture stress sensitivity,and capillary imbibition have been considered.The shale gas production,pore pressure distribution and water saturation distribution in the reservoir have been simulated.The influences of hydraulic fracture geometry and nonorthogonal hydraulic fractures on gas production have been determined and discussed accordingly.The simulation results show that the daily gas production has an upward and downward trend due to the presence of a large amount of fracturingfluid in the reservoir around the hydraulic fracture.The smaller the angle between the hydraulic fracture and the wellbore,the faster the daily production of shale gas wells decreases,and the lower the cumulative production.Nonplanar fractures can increase the control volume of hydraulic fractures and improve the production of shale gas wells.

Arbitrary High-Order Fully-Decoupled Numerical Schemes for Phase-Field Models of Two-Phase Incompressible Flows

Due to the coupling between the hydrodynamic equation and the phase-field equation in two-phase incompressible flows,it is desirable to develop efficient and high-order accurate numerical schemes that can decouple these two equations.One popular and efficient strategy is to add an explicit stabilizing term to the convective velocity in the phase-field equation to decouple them.The resulting schemes are only first-order accurate in time,and it seems extremely difficult to generalize the idea of stabilization to the second-order or higher version.In this paper,we employ the spectral deferred correction method to improve the temporal accuracy,based on the first-order decoupled and energy-stable scheme constructed by the stabilization idea.The novelty lies in how the decoupling and linear implicit properties are maintained to improve the efficiency.Within the framework of the spatially discretized local discontinuous Galerkin method,the resulting numerical schemes are fully decoupled,efficient,and high-order accurate in both time and space.Numerical experiments are performed to validate the high-order accuracy and efficiency of the methods for solving phase-field models of two-phase incompressible flows.

Current status of nerve infiltration by skip metastases in colorectal cancer

Colorectal cancer(CRC)is a prevalent malignant tumor,with the global new cases reaching 1.9316 million and deaths reaching 935,200 in 2022.In China,therewere 555,500 new cases of CRC,with an age-standardized incidence rate of 24.07 per 10million,and 286,200 deaths.China accounts for approximately 30%of new cases and deaths from CRC worldwide,with East Asia accounting for over 75%.Initially,CRC presents as local tumor growth,but it has the potential to spread to other body parts over time.Perineural infiltration(PNI)is a relatively less discussed route of diffusion,yet it plays a crucial role in the progression and prognosis of CRC.PNI often occurs alongside local lymph nodes and distant metastases,posing challenges for treatment and management.Clinical symptoms,radiographic findings,and histopathological examination can be used to diagnose PNI with skipmetastasis.Symptoms commonly include local pain,paresthesia,andmotor impairment.Imaging helps identify the mass’s location and relationship to nerves,whereas histopathological examination confirms the diagnosis.Treatment of PNI skipmetastases is similar to other CRC metastases,including surgical resection,chemotherapy,radiotherapy,and targeted therapy.Surgical resection is the primary therapeutic approach,but the wider range of metastasis in PNI skip transfer may limit its feasibility.In cases where surgical resection is not possible,chemotherapy,radiotherapy,and targeted therapy are used to control tumor metastasis.In conclusion,PNI skip metastases increase the risk of poor prognosis for CRC,requiring a comprehensive approach with multiple treatments to prevent disease progression.Early detection and treatment are vital to improving prognosis.

Transcriptome sequencing reveals novel biomarkers and immune cell infiltration in esophageal tumorigenesis

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most common malignancies worldwide,and its development comprises a multistep process from intraepithelial neoplasia(IN)to carcinoma(CA).However,the critical regulators and underlying molecular mechanisms remain largely unknown.AIM To explore the genes and infiltrating immune cells in the microenvironment that are associated with the multistage progression of ESCC to facilitate diagnosis and early intervention.METHODS A mouse model mimicking the multistage development of ESCC was established by providing warter containing 4-nitroquinoline 1-oxide(4NQO)to C57BL/6 mice.Moreover,we established a control group without 4NQO treatment of mice.Then,transcriptome sequencing was performed for esophageal tissues from patients with different pathological statuses,including low-grade IN(LGIN),high-grade IN(HGIN),and CA,and controlled normal tissue(NOR)samples.Differentially expressed genes(DEGs)were identified in the LGIN,HGIN,and CA groups,and the biological functions of the DEGs were analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The CIBERSORT algorithm was used to detect the pattern of immune cell infilt-ration.Immunohistochemistry(IHC)was also conducted to validate our results.Finally,the Luminex multiplex cytokine analysis was utilized to measure the serum cytokine levels in the mice.RESULTS Compared with those in the NOR group,a total of 681541,and 840 DEGs were obtained in the LGIN,HGIN,and CA groups,respectively.Using the intersection of the three sets of DEGs,we identified 86 genes as key genes involved in the development of ESCC.Enrichment analysis revealed that these genes were enriched mainly in the keratinization,epidermal cell differentiation,and interleukin(IL)-17 signaling pathways.CIBERSORT analysis revealed that,compared with those in the NOR group,M0 and M1 macrophages in the 4NQO group showed stronger infiltration,which was validated by IHC.Serum cytokine analysis revealed that,compared with those in the NOR group,IL-1βand IL-6 were upregulated,while IL-10 was downregulated in the LGIN,HGIN,and CA groups.Moreover,the expression of the representative key genes,such as S100a8 and Krt6b,was verified in external human samples,and the results of immunohistochemical staining were consistent with the findings in mice.CONCLUSION We identified a set of key genes represented by S100a8 and Krt6b and investigated their potential biological functions.In addition,we found that macrophage infiltration and abnormal alterations in the levels of inflam-mation-associated cytokines,such as IL-1β,IL-6,and IL-10,in the peripheral blood may be closely associated with the development of ESCC.

Numerical Simulation of Oil-Water Two-Phase Flow in Low Permeability Tight Reservoirs Based on Weighted Least Squares Meshless Method

In response to the complex characteristics of actual low-permeability tight reservoirs,this study develops a meshless-based numerical simulation method for oil-water two-phase flow in these reservoirs,considering complex boundary shapes.Utilizing radial basis function point interpolation,the method approximates shape functions for unknown functions within the nodal influence domain.The shape functions constructed by the aforementioned meshless interpolation method haveδ-function properties,which facilitate the handling of essential aspects like the controlled bottom-hole flow pressure in horizontal wells.Moreover,the meshless method offers greater flexibility and freedom compared to grid cell discretization,making it simpler to discretize complex geometries.A variational principle for the flow control equation group is introduced using a weighted least squares meshless method,and the pressure distribution is solved implicitly.Example results demonstrate that the computational outcomes of the meshless point cloud model,which has a relatively small degree of freedom,are in close agreement with those of the Discrete Fracture Model(DFM)employing refined grid partitioning,with pressure calculation accuracy exceeding 98.2%.Compared to high-resolution grid-based computational methods,the meshless method can achieve a better balance between computational efficiency and accuracy.Additionally,the impact of fracture half-length on the productivity of horizontal wells is discussed.The results indicate that increasing the fracture half-length is an effective strategy for enhancing production from the perspective of cumulative oil production.

Screening and immune infiltration analysis of ferroptosis-related genes in pancreatic cancer with predictions for traditional Chinese medicine treatments

Background:This study aims to explore the involvement of ferroptosis-related genes and pathogenesis in pancreatic cancer and predict potential therapeutic interventions using Traditional Chinese Medicine(TCM).Methods:We utilized gene expression datasets,ferroptosis upregulated genes and applied machine learning algorithms,including LASSO and SVM-RFE,to identify key ferroptosis-related genes in pancreatic cancer.Perform Gene Ontology,Kyoto Encyclopedia of Genes and Genomes,and Disease Ontology enrichment analysis,immune infiltration analysis and correlation analysis between immune infiltrating cells and characteristic genes on differentially expressed genes using the R software package.Retrieve potential traditional Chinese medicine for targeted ferroptosis gene therapy for pancreatic cancer through Coremine and Herb databases.Results:Seventeen feature genes were identified,with significant implications for immune cell infiltration in pancreatic cancer.The results of immune cell infiltration analysis showed that B cells naive,B cells memory,T cells regulatory,and M0 macrophages were significantly upregulated in pancreatic cancer patients;Mast cells resting were significantly downregulated.Chinese herbal medicines such as ginkgo,turmeric,ginseng,Codonopsis pilosula,Zedoary turmeric,deer tendons,senna leaves,Guanmu Tong,Huangqi,and Banzhilian are potential drugs for targeted ferroptosis gene therapy for pancreatic cancer.Conclusion:TIMP1 emerged as a key gene,with several TCM herbs predicted to modulate its expression,offering new avenues for treatment.