Prognostic heterogeneity of Ki67 in non-small cell lung cancer: A comprehensive reappraisal on immunohistochemistry and transcriptional data.

In the present study, the debatable prognostic value of Ki67 in patients with non-small cell lung cancer (NSCLC) was attributed to the heterogeneity between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). Based on meta-analyses of 29 studies, a retrospective immunohistochemical cohort of 1479 patients from our center, eight transcriptional datasets and a single-cell datasets with 40 patients, we found that high Ki67 expression suggests a poor outcome in LUAD, but conversely, low Ki67 expression indicates worse prognosis in LUSC. Furthermore, low proliferation in LUSC is associated with higher metastatic capacity, which is related to the stronger epithelial-mesenchymal transition potential, immunosuppressive microenvironment and angiogenesis. Finally, nomogram model incorporating clinical risk factors and Ki67 expression outperformed the basic clinical model for the accurate prognostic prediction of LUSC. With the largest prognostic assessment of Ki67 from protein to mRNA level, our study highlights that Ki67 also has an important prognostic value in NSCLC, but separate evaluation of LUAD and LUSC is necessary to provide more valuable information for clinical decision-making in NSCLC.

Targeting PNPO to suppress tumor growth via inhibiting autophagic flux and to reverse paclitaxel resistance in ovarian cancer.

Our previous study showed that pyridoxine 5'-phosphate oxidase (PNPO) is a tissue biomarker of ovarian cancer (OC) and has a prognostic implication but detailed mechanisms remain unclear. The current study focused on PNPO-regulated lysosome/autophagy-mediated cellular processes and the potential role of PNPO in chemoresistance. We found that PNPO was overexpressed in OC cells and was a prognostic factor in OC patients. PNPO significantly promoted cell proliferation via the regulation of cyclin B1 and phosphorylated CDK1 and shortened the G2M phase in a cell cycle. Overexpressed PNPO enhanced the biogenesis and perinuclear distribution of lysosomes, promoting the degradation of autophagosomes and boosting the autophagic flux. Further, an autolysosome marker LAMP2 was upregulated in OC cells. Silencing LAMP2 suppressed cell growth and induced cell apoptosis. LAMP2-siRNA blocked PNPO action in OC cells, indicating that the function of PNPO on cellular processes was mediated by LAMP2. These data suggest the existence of the PNPO-LAMP2 axis. Moreover, silencing PNPO suppressed xenographic tumor formation. Chloroquine counteracted the promotion effect of PNPO on autophagic flux and inhibited OC cell survival, facilitating the inhibitory effect of PNPO-shRNA on tumor growth in vivo. Finally, PNPO was overexpressed in paclitaxel-resistant OC cells. PNPO-siRNA enhanced paclitaxel sensitivity in vitro and in vivo. In conclusion, PNPO has a regulatory effect on lysosomal biogenesis that in turn promotes autophagic flux, leading to OC cell proliferation, and tumor formation, and is a paclitaxel-resistant factor. These data imply a potential application by targeting PNPO to suppress tumor growth and reverse PTX resistance in OC.

Nicotinamide mononucleotide induces autophagy and ferroptosis via AMPK/mTOR pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Herein, we investigated the role of nicotinamide mononucleotide (NMN) in HCC progression. HCC cells were treated with NMN (125, 250, and 500 µM), and then nicotinamide adenine dinucleotide (NAD+ ) and NADH levels in HCC cells were measured to calculate NAD+ /NADH ratio. Cell proliferation, apoptosis, autophagy and ferroptosis were determined. AMPK was knocked down to confirm the involvement of AMPK/mTOR signaling. Furthermore, tumor-inhibitory effect of NMN was investigated in xenograft models. Exposure to NMN dose-dependently increased NAD+ level and NAD+ /NADH ratio in HCC cells. After NMN treatment, cell proliferation was inhibited, whereas apoptosis was enhanced in both cell lines. Additionally, NMN dose-dependently enhanced autophagy/ferroptosis and activated AMPK/mTOR pathway in HCC cells. AMPK knockdown partially rescued the effects of NMN in vitro. Furthermore, NMN treatment restrained tumor growth in nude mice, activated autophagy/ferroptosis, and promoted apoptosis and necrosis in tumor tissues. The results indicate that NMN inhibits HCC progression by inducing autophagy and ferroptosis via AMPK/mTOR signaling. NMN may serve as a promising agent for HCC treatment.

Prognostic Value of Myosteatosis and Creatinine-to-Cystatin C Ratio in Patients with Pancreatic Cancer Who Underwent Radical Surgery.

BACKGROUND: Myosteatosis is correlated with poor prognosis in some malignancies. The creatinine-to-cystatin ratio (CCR) is revealed to predict gastric cancer prognosis. However, the prognostic abilities of CCR and the combination of CCR and myosteatosis in patients with pancreatic cancer (PC) who underwent radical surgery remains unclear. METHODS: The retrospective cohort study included 215 patients with PC who underwent radical surgery (January 2016-October 2021). Clinicopathological and serological data were collected on admission. Myosteatosis and other body composition indices were assessed by using computed tomography. The cutoff value of CCR was determined by using the Youden index. Risk factors responsible for poor overall survival (OS) and disease-free survival (DFS) were determined by the Cox proportional hazards model. RESULTS: The myosteatosis group included 104 patients (average age, 61.3 ± 9.1 years). The best cutoff value for CCR was 1.09. CCR ≤ 1.09 was an independent predictive biomarker inversely corelated with OS (P = 0.036). Myosteatosis was an independent risk factor associated with OS and DFS (P = 0.032 and P = 0.004, respectively). Patients with concomitant myosteatosis and CCR ≤ 1.09 had the worst OS (P = 0.016). CONCLUSIONS: Myosteatosis and CCR are prognostic biomarkers for survival in PC patients who underwent radical surgery. Patients with the coexistence of myosteatosis and CCR ≤ 1.09 deserve more attention.

Picea wilsonii NAC31 and DREB2A Cooperatively Activate ERD1 to Modulate Drought Resistance in Transgenic Arabidopsis.

The NAC family of transcription factors (TFs) regulate plant development and abiotic stress. However, the specific function and response mechanism of NAC TFs that increase drought resistance in Picea wilsonii remain largely unknown. In this study, we functionally characterized a member of the PwNAC family known as PwNAC31. PwNAC31 is a nuclear-localized protein with transcriptional activation activity and contains an NAC domain that shows extensive homology with ANAC072 in Arabidopsis. The expression level of PwNAC31 is significantly upregulated under drought and ABA treatments. The heterologous expression of PwNAC31 in atnac072 Arabidopsis mutants enhances the seed vigor and germination rates and restores the hypersensitive phenotype of atnac072 under drought stress, accompanied by the up-regulated expression of drought-responsive genes such as DREB2A (DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2A) and ERD1 (EARLY RESPONSIVE TO DEHYDRATION STRESS 1). Yeast two-hybrid and bimolecular fluorescence complementation assays confirmed that PwNAC31 interacts with DREB2A and ABF3 (ABSCISIC ACID-RESPONSIVE ELEMENT-BINDING FACTOR 3). Yeast one-hybrid and dual-luciferase assays showed that PwNAC31, together with its interaction protein DREB2A, directly regulated the expression of ERD1 by binding to the DRE element of the ERD1 promoter. Collectively, our study provides evidence that PwNAC31 activates ERD1 by interacting with DREB2A to enhance drought tolerance in transgenic Arabidopsis.

The Response of Growth and Transcriptome Profiles of Tea Grey Blight Disease Pathogen Pestalotiopsis theae to the Variation of Exogenous L-Theanine.

Tea grey blight disease is one of the most destructive diseases that infects tea and is caused by the pathogen Pestalotiopsis theae (Sawada) Steyaert. L-theanine is a unique non-protein amino acid of the tea plant. Different concentrations of L-theanine exhibit significant inhibitory effects on the growth and sporulation ability of the pathogen causing tea grey blight disease. To understand the effect mechanism of L-theanine on P. theae, transcriptome profiling was performed on the pathogenic mycelium treated with three different concentrations of L-theanine: no L-theanine treatment (TH0), 20 mg/mL theanine treatment (TH2), and 40 mg/mL theanine treatment (TH4). The colony growths were significantly lower in the treatment with L-theanine than those without L-theanine. The strain cultured with a high concentration of L-theanine produced no spores or only a few spores. In total, 2344, 3263, and 1158 differentially expressed genes (DEGs) were detected by RNA-sequencing in the three comparisons, Th2 vs. Th0, Th4 vs. Th0, and Th4 vs. Th2, respectively. All DEGs were categorized into 24 distinct clusters. According to GO analysis, low concentrations of L-theanine primarily affected molecular functions, while high concentrations of L-theanine predominantly affected biological processes including external encapsulating structure organization, cell wall organization or biogenesis, and cellular amino acid metabolic process. Based on KEGG, the DEGs of Th2 vs. Th0 were primarily involved in pentose and glucuronate interconversions, histidine metabolism, and tryptophan metabolism. The DEGs of Th4 vs. Th0 were mainly involved in starch and sucrose metabolism, amino sugar, and nucleotide sugar metabolism. This study indicated that L-theanine has a significant impact on the growth and sporulation of the pathogen of tea grey blight disease and mainly affects amino acid metabolism, carbohydrate metabolism, and cellular structure-related biosynthesis processes of pathogenic fungi. This work provides insights into the direct control effect of L-theanine on pathogenic growth and also reveals the molecular mechanisms of inhibition of L-theanine to P. theae.

Revocable and Traceable Undeniable Attribute-Based Encryption in Cloud-Enabled E-Health Systems.

The emerging cloud storage technology has significantly improved efficiency and productivity in the traditional electronic healthcare field. However, it has also brought about many security concerns. Ciphertext policy attribute-based encryption (CP-ABE) holds immense potential in achieving fine-grained access control, providing robust security for electronic healthcare data in the cloud. However, current CP-ABE schemes still face issues such as inflexible attribute revocation, relatively lower computational capabilities, and key management. To address these issues, this paper introduces a revocable and traceable undeniable ciphertext policy attribute-based encryption scheme (MA-RUABE). MA-RUABE not only enables fast and accurate data traceability, effectively preventing malicious user key leakage, but also includes a direct revocation feature, significantly enhancing computational efficiency. Furthermore, the introduction of a multi-permission mechanism resolves the issue of centralization of power caused by single-attribute permissions. Furthermore, a security analysis demonstrates that our system ensures resilience against chosen plaintext attacks. Experimental results demonstrate that MA-RUABE incurs lower computational overhead, effectively enhancing system performance and ensuring data-sharing security in cloud-based electronic healthcare systems.

Investigating agricultural water sustainability in arid regions with Bayesian network and water footprint theories.

Water scarcity is a significant constraint in agricultural ecosystems of arid regions, necessitating sustainable development of agricultural water resources. This study innovatively combines Bayesian theory and Water Footprint (WF) to construct a Bayesian Network (BN). Water quantity and quality data were evaluated comprehensively by WF in agricultural production. This evaluation integrates WF and local water resources to establish a sustainability assessment framework. Selected nodes are incorporated into a BN and continuously updated through structural and parameter learning, resulting in a robust model. Results reveal a nearly threefold increase of WF in the arid regions of Northwest China from 1989 to 2019, averaging 189.95 × 108 m3 annually. The region's agricultural scale is expanding, and economic development is rapid, but the unsustainability of agricultural water use is increasing. Blue WF predominates in this region, with cotton having the highest WF among crops. The BN indicates a 70.1 % probability of unsustainable water use. Sensitivity analysis identifies anthropogenic factors as primary drivers influencing water resource sustainability. Scenario analysis underscores the need to reduce WF production and increase agricultural water supply for sustainable development in arid regions. Proposed strategies include improving irrigation methods, implementing integrated water-fertilizer management, and selecting drought-resistant, economically viable crops to optimize crop planting structures and enhance water use efficiency in current agricultural practices in arid regions. This study not only offers insights into water management in arid regions but also provides practical guidance for similar agricultural contexts. The BN model serves as a flexible tool for informed decision-making in dynamic environments.

Coca-Cola consumption vs fragmentation in the management of patients with phytobezoars: A prospective randomized controlled trial.

BACKGROUND: Gastric phytobezoars (GPBs) are very common in northern China. Combined therapy involving carbonated beverage consumption and endoscopic lithotripsy has been shown to be effective and safe. Existing studies on this subject are often case reports highlighting the successful dissolution of phytobezoars through Coca-Cola consumption. Consequently, large-scale prospective investigations in this domain remain scarce. Therefore, we conducted a randomized controlled trial to examine the effects of Coca-Cola consumption on GPBs. AIM: To evaluate the impact of Coca-Cola on GPBs, including the dissolution rate, medical expenses, ulcer rate, and operation time. METHODS: A total of 160 consecutive patients diagnosed with GPBs were allocated into two groups (a control group and an intervention group) through computer-generated randomization. Patients in the intervention group received a Coca-Cola-based regimen (Coca-Cola 2000-4000 mL per day for 7 d), while those in the control group underwent emergency fragmentation. RESULTS: Complete dissolution of GPBs was achieved in 100% of the patients in the intervention group. The disparity in expenses between the control group and intervention group (t = 25.791, P = 0.000) was statistically significant, and the difference in gastric ulcer occurrence between the control group and intervention group (χ2 = 6.181, P = 0.013) was also statistically significant. CONCLUSION: Timely ingestion of Coca-Cola yields significant benefits, including a complete dissolution rate of 100%, a low incidence of gastric ulcers, no need for fragmentation and reduced expenses.

Synthesis optimization and separation mechanism of ZSM-5 zeolite membranes for pervaporation dehydration of organic solvents.

Pervaporation (PV), as an energy-efficient mixture separation technology, plays an important role in the chemical industry. In this work, no organic templates were needed to produce high-performance ZSM-5 membranes with an extremely low Si/Al ratio of 3.3 on α-Al2O3 tubular supports using 100 nm nanoseeds. The effects of preparation parameters on the crystalline phase structures, micromorphologies, and PV separation performance of ZSM-5 membranes were comprehensively investigated. The results revealed that the Si/Al ratio of gels significantly affected both the Si/Al ratio and the crystal orientation of the final ZSM-5 membrane. The optimized ZSM-5 membrane with a thickness of 1.8 µm was utilized to dehydrate various organic solvents via PV, and the influence of the operating parameters on PV dehydration performance was evaluated and is described herein. Furthermore, the permeation behaviors of single gases and PV were examined using permeate molecules within a similar size range to reveal the PV mechanism of the ZSM-5 membrane. The results demonstrated that gas permeation followed Knudsen diffusion, while PV permeation was decreased with decreases in the affinity of molecules, revealing an adsorption-diffusion mechanism that dominated PV dehydration through the ZSM-5 membrane. Moreover, the as-synthesized ZSM-5 membrane had good water permselectivity for water/acetone (e.g., total flux = 1.03 kg/(m2 h), α = 307) and for water/isopropanol (e.g., total flux = 1.49 kg/(m2 h), α = 1070) mixtures compared with other membranes reviewed in the literature. The synthesized ZSM-5 membrane also exhibited excellent reproducibility, high stability, and attractive PV separation performance, demonstrating its significant potential application in the PV dehydration of organic solvents.

Susceptibility to e-cigarette among high school students: a study based on the ecological model of health behavior.

Introduction: Youth e-cigarette (EC) use has rapidly increased in the last few years. It is crucial to identify the susceptible youth and prevent them from EC uptake. This study was conducted to investigate factors that affect youth susceptibility to EC use. Methods: This study employed a cross-sectional survey design, utilizing multi-center stratified cluster sampling method to select two junior high schools and two senior high schools in Shanghai, Guangzhou, and Chengdu. One-third of classes of each grade in the selected schools were involved in this survey. After obtaining the informed consent of parents, an anonymous and self-administered questionnaire was distributed to students. Questionnaire was designed based on the Ecological Models of Health Behavior. Associations between EC susceptibility and covariates were identified using multivariate logistic regression. Results: Among 2,270 students who had never vaped, 38.0% were susceptible to ECs. Logistic regression analysis identified factors on different levels affecting the susceptibility. Individual factors included senior high school students (OR = 1.34, 95% CI: 1.08-1.65), sensation seeker (OR = 1.11, 95%CI: 1.08-1.14), poor academic performance (OR = 1.24, 95% CI: 1.01-1.54), ever cigarette user (OR = 2.27, 95% CI: 1.29-4.01), unaware of the second-hand smoke from vaping (OR = 1.56, 95% CI: 1.25-1.96), agreeable with "I do not want to hang around vapers" (OR = 0.79, 95% CI: 0.64-0.97), agreeable with "ECs are more fashionable than cigarette" (OR = 2.50, 95% CI: 1.72-3.62) and favorable attitudes toward vaping (OR = 5.09, 95% CI: 3.78-6.85) were significantly associated with susceptibility to ECs. At interpersonal level, students who believe they would not be punished by parents for vaping increased susceptibility (OR = 1.27, 95% CI:1.01-1.59). At community level, exposure of EC advertising (OR = 1.81, 95% CI:1.46-2.25), exposure to hazard information (OR = 0.76, 95% CI: 0.59-0.97) and seeing vaping in daily life (OR = 2.11, 95% CI: 1.62-2.74), were statistically significantly associated with youth susceptibility to ECs. Conclusion: EC susceptibility was observed in a substantial proportion of adolescents who had never vaped, influenced by factors on different levels. This research underscores the urgent need for comprehensive intervention strategies to prevent the youth susceptibility to ECs.

EGR3 Polymorphism Is a Potential Susceptibility Factor of Schizophrenia Risk in a Chinese Population.

Objective: The purpose of this study was to evaluate the association between the single nucleotide polymorphisms (SNPs) (EGR3 rs1996147; EGR4 rs3813226, rs6747506; ERBB3 rs2292238; and ERBB4 rs707284, rs7560730) and the risk of schizophrenia (SZ) in a Chinese population. Materials and Methods: We conducted a case-control study, including 248 patients with SZ and 236 healthy controls matched for age and sex. The Mass-array platform was used to detect all the genotypes of the SNPs. Results: The results revealed that the EGR3 rs1996147 AA genotype was associated with borderline decreased SZ risk (AA vs. GG: adjusted OR = 0.43, 95% CI: 0.18-1.02, p = 0.06). However, no significant correlation was found between the other SNPs and overall SZ risk. Subgroup analysis also failed to show any significant association between all SNPs and the risk of SZ. Conclusion: In summary, this study revealed that the EGR3 rs1996147 AA genotype was associated with a borderline risk for SZ.

Sugar import mediated by sugar transporters and cell wall invertases for seed development in Camellia oleifera.

Seed development and yield depend on the transport and supply of sugar. However, an insufficient supply of nutrients from maternal tissues to embryos results in seed abortion and yield reduction in Camellia oleifera. In this study, we systematically examined the route and regulatory mechanisms of sugar import into developing C. oleifera seeds using a combination of histological observations, transcriptome profiling, and functional analysis. Labelling with the tracer carboxyfluorescein revealed a symplasmic route in the integument and an apoplasmic route for postphloem transport at the maternal-filial interface. Enzymatic activity and histological observation showed that at early stages [180-220 days after pollination (DAP)] of embryo differentiation, the high hexose/sucrose ratio was primarily mediated by acid invertases, and the micropylar endosperm/suspensor provides a channel for sugar import. Through Camellia genomic profiling, we identified three plasma membrane-localized proteins including CoSWEET1b, CoSWEET15, and CoSUT2 and one tonoplast-localized protein CoSWEET2a in seeds and verified their ability to transport various sugars via transformation in yeast mutants and calli. In situ hybridization and profiling of glycometabolism-related enzymes further demonstrated that CoSWEET15 functions as a micropylar endosperm-specific gene, together with the cell wall acid invertase CoCWIN9, to support early embryo development, while CoSWEET1b, CoSWEET2a, and CoSUT2 function at transfer cells and chalazal nucellus coupled with CoCWIN9 and CoCWIN11 responsible for sugar entry in bulk into the filial tissue. Collectively, our findings provide the first comprehensive evidence of the molecular regulation of sugar import into and within C. oleifera seeds and provide a new target for manipulating seed development.

TM-Score predicts immunotherapy efficacy and improves the performance of the machine learning prognostic model in gastric cancer.

Immunotherapy is becoming increasingly important, but the overall response rate is relatively low in the treatment of gastric cancer (GC). The application of tumor mutational burden (TMB) in predicting immunotherapy efficacy in GC patients is limited and controversial, emphasizing the importance of optimizing TMB-based patient selection. By combining TMB and major histocompatibility complex (MHC) related hub genes, we established a novel TM-Score. This score showed superior performance for immunotherapeutic selection (AUC = 0.808) compared to TMB, MSI status, and EBV status. Additionally, it predicted the prognosis of GC patients. Subsequently, a machine learning model adjusted by the TM-Score further improved the accuracy of survival prediction (AUC > 0.8). Meanwhile, we found that GC patients with low TM-Score had a higher mutation frequency, higher expression of HLA genes and immune checkpoint genes, and higher infiltration of CD8+ T cells, CD4+ helper T cells, and M1 macrophages. This suggests that TM-Score is significantly associated with tumor immunogenicity and tumor immune environment. Notably, based on the RNA-seq and scRNA-seq, it was found that AKAP5, a key component gene of TM-Score, is involved in anti-tumor immunity by promoting the infiltration of CD4+ T cells, NK cells, and myeloid cells. Additionally, siAKAP5 significantly reduced MHC-II mRNA expression in the GC cell line. In addition, our immunohistochemistry assays confirmed a positive correlation between AKAP5 and human leukocyte antigen (HLA) expression. Furthermore, AKAP5 levels were higher in patients with longer survival and those who responded to immunotherapy in GC, indicating its potential value in predicting prognosis and immunotherapy outcomes. In conclusion, TM-Score, as an optimization of TMB, is a more precise biomarker for predicting the immunotherapy efficacy of the GC population. Additionally, AKAP5 shows promise as a therapeutic target for GC.

The Efficacy and Safety of Minocycline-Containing Quadruple Therapies Against Helicobacter pylori Infection: A Retrospective Cohort Study.

Background: Minocycline, a derivative of tetracycline, has anti-Helicobacter pylori (H. pylori) properties and can be used to treat H. pylori infection. However, only a few randomized controlled trials (RCTs) have investigated the efficacy of minocycline-containing quadruple therapy (MCQT) in treating H. pylori infection. This study aimed to determine the efficacy and safety of MCQT and investigate the factors influencing both aspects. Methods: This was a retrospective cohort study. Patients diagnosed with H. pylori infection between January 1, 2022, and July 31, 2023 at. The primary outcome was the eradication rate of H. pylori, and the secondary outcome was the number and type of adverse events. Results: A total of 828 patients were included in this study. The overall H. pylori eradication rate among the included patients at 95% confidence interval (CI) (Range 0.864 to 0.907) was 88.53%. The H. pylori eradication rate for patients who received MCQT regimen as the primary therapy was 92.28% (95% CI: 0.901-0.945), significantly higher than that of patients who received MCQT as rescue therapy (80.81%; 95% CI: 0.761-0.855, P=0.003). Adverse events, including dizziness, abdominal distension, diarrhea, nausea, abdominal discomfort, constipation, headache, rash, sleep disorder, palpitation, backache, and anorexia, occurred in 185 (22.34%) patients, with dizziness being the most common (75/828, 9.06%). Compliance with MCQT therapy was an independent factor influencing H. pylori eradication in patients receiving MCQT as a primary therapy. Compliance and presence or absence of H. pylori infection symptoms at the time of screening were independent factors influencing H. Pylori eradication in patients receiving MCQT as rescue therapy. Factors that influenced the occurrence of adverse events included reasons for H. pylori infection screening, residence, treatment compliance, and the use of acid-suppressant regimens. Conclusion: MCQT regimens were effective in H. pylori infection eradication, and the treatment resulted only in fewer adverse events when used as primary or rescue therapies for H. pylori infection treatment. Future prospective studies with larger sample sizes and more comprehensive data are needed to validate our findings.

Genetic characterization of Tibetan pigs adapted to high altitude under natural selection based on a large whole-genome dataset.

The Qinghai-Tibet Plateau is a valuable genetic resource pool, and the high-altitude adaptation of Tibetan pigs is a classic example of the adaptive evolution of domestic animals. Here, we report the presence of Darwinian positive selection signatures in Tibetan pigs (TBPs) using 348 genome-wide datasets (127 whole-genome sequence datasets (WGSs) and 221 whole-genome single-nucleotide polymorphism (SNP) chip datasets). We characterized a high-confidence list of genetic signatures related response to high-altitude adaptation in Tibetan pigs, including 4,598 candidate SNPs and 131 candidate genes. Functional annotation and enrichment analysis revealed that 131 candidate genes are related to multiple systems and organs in Tibetan pigs. Notably, eight of the top ten novel genes, RALB, NBEA, LIFR, CLEC17A, PRIM2, CDH7, GK5 and FAM83B, were highlighted and associated with improved adaptive heart functions in Tibetan pigs high-altitude adaptation. Moreover, genome-wide association analysis revealed that 29 SNPs were involved in 13 candidate genes associated with at least one adaptive trait. In particular, among the top ten candidate genes, CLEC17A is related to a reduction in hemoglobin (HGB) in Tibetan pigs. Overall, our study provides a robust SNP/gene list involving genetic adaptation for Tibetan pig high-altitude adaptation, and it will be a valuable resource for future Tibetan pig studies.

IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-ß signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-ß upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.