CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma.

BACKGROUND AND PURPOSE: Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there is an inevitably high rate of drug resistance associated with regorafenib, which reduces its effectiveness in clinical treatment. Thus, there is an urgent need to find a potential way to solve the problem of regorafenib resistance. The metabolite of disulfiram complexed with copper, the Diethyldithiocarbamate-copper complex (CuET), has been found to be an effective anticancer drug candidate. In the present study, we aimed to evaluate the effect of CuET on regorafenib resistance in HCC and uncover the associated mechanism. EXPERIMENTAL APPROACH: Regorafenib-resistant HCC strains were constructed by applying an increasing concentration gradient. This study employed a comprehensive range of methodologies, including the cell counting kit-8 (CCK-8) assay, colony formation assay, cell cycle analysis, wound healing assay, Transwell assay, tumor xenograft model, and immunohistochemical analysis. These methods were utilized to investigate the antitumor activity of CuET, assess the combined effect of regorafenib and CuET, and elucidate the molecular mechanism underlying CuET-mediated regorafenib resistance. KEY RESULTS: The inhibitory effect of regorafenib on cell survival, proliferation and migration was decreased in regorafenib-resistant MHCC-97H (MHCC-97H/REGO) cells compared with parental cells. CuET demonstrated significant inhibitory effects on cell survival, proliferation, and migration of various HCC cell lines. CuET restored the sensitivity of MHCC-97H/REGO HCC cells to regorafenib in vitro and in vivo. Mechanistically, CuET reverses regorafenib resistance in HCC by suppressing epithelial-mesenchymal transition (EMT) through inhibition of the ERK signaling pathway. CONCLUSION AND IMPLICATIONS: Taken together, the results of this study demonstrated that CuET inhibited the activation of the ERK signaling pathway, leading to the suppression of the epithelial-mesenchymal transition (EMT) and subsequently reversing regorafenib resistance in HCC both in vivo and in vitro. This study provides a new idea and potential strategy to improve the treatment of regorafenib-resistant HCC.

Effect of endoscopic sphincterotomy and endoscopic papillary balloon dilation endoscopic retrograde cholangiopancreatographies on the sphincter of Oddi.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP), with its clinical ad-vantages of less trauma and faster recovery, has become the primary treatment for choledocholithiasis. AIM: To investigate the effects of different ERCP procedures on the sphincter of Oddi. METHODS: The clinical data of 91 patients who underwent ERCP at Yixing Hospital of Traditional Chinese Medicine between February 2018 and February 2021 were analyzed retrospectively. The patients were divided into endoscopic sphincterotomy (EST, n = 24) and endoscopic papillary balloon dilation (EPBD, n = 67) groups. The duration of operation, pancreatic development, pancreatic sphincterotomy, intubation difficulties, stone recurrence, and incidence of reflux cholangitis and cholecystitis were statistically analyzed in patients with a history of choledocholithiasis, pancreatitis, and Oddi sphincter dysfunction in the EST and EPBD groups. RESULTS: Differences in hypertension, diabetes, increased bilirubin, small diameter of the common bile duct, or ampullary diverticulum between the two groups were not significant. Statistically significant differences were observed between the two groups concerning sex and age (< 60 years). Patients with a history of choledocholithiasis, pancreatitis, and Oddi sphincter dysfunction were higher in the EST group than in the EPBD group. The number of cases of pancreatic development, pancreatic duct sphincterotomy, and difficult intubation were higher in the EST group than in the EPBD group. The number of Oddi's sphincter manometries, ERCP surgical outcomes, and guidewires entering the pancreatic duct several times in EST group were lower than those in the EPBD group. The numbers of stone recurrences, reflux cholangitis, and cholecystitis were higher in the EST group than in the EPBD group. CONCLUSION: In summary, common bile duct stones, pancreatitis history, and multiple guided wire introductions into the pancreatic duct are independent risk factors for EST and EPBD. Based on this evidence, this study can provide actionable insights for clinicians and researchers.

High freeze-thaw stability of Pickering emulsion stabilized by SPI-maltose particles and its effect on frozen dough.

Pickering emulsions with good freeze-thaw stability are essential in frozen food applications. This study developed a high freeze-thaw stabilized soy protein isolate (SPI)-maltose (M) Pickering emulsion and applied it to frozen doughs to investigate and reveal its impacts on the processing properties of the frozen dough. The results showed that after the freeze-thaw cycle, with a volume ratio of 1:2 of SPI to M, the appropriate amount of M changed the structure of SPI. This resulted in the Pickering emulsion prepared by the SPI exhibiting the least droplet coalescence and the best freeze-thaw stability. The results of dough rheological properties, textural properties, and binding capacity with water demonstrated that Pickering emulsions effectively inhibited the loss of gluten protein network structure in the dough after freeze treatment and increased the binding capacity of gluten proteins with starch and water in the dough. The best results were obtained with the incorporation of 3 % SPI-M high freeze-thaw stability, where the amount of bound water following three freeze-thaw cycles was 4.27 times higher than in doughs without Pickering emulsion. Overall, this study is significant for enhancing the freeze-thaw stability of Pickering emulsions stabilized by proteins and providing a new application route for Pickering emulsions.

Ionones from cigar tobacco leaves.

Phytochemical studies on cigar tobacco leaves led to the isolation of 18 ionone-type compounds, including previously undescribed cigatobanes E (1) and F (2). Additionally, compounds vomifoliol acetate (3), dehydrovomifoliol (4), 8,9-dihydromegastigmane-4,6-diene-3-one (5), 7α,8α-epoxyblumenol B (6), 3-oxoactinidol (12), and loliolide acetate (15), 4ß-hydroxy-dihydroactinidiolide (17), were found in tobacco leaves for the first time. The structural elucidation of all compounds was accomplished through rigorous spectral analysis.

Intelligent alert system for predicting invasive mechanical ventilation needs via noninvasive parameters: employing an integrated machine learning method with integration of multicenter databases.

The use of invasive mechanical ventilation (IMV) is crucial in rescuing patients with respiratory dysfunction. Accurately predicting the demand for IMV is vital for clinical decision-making. However, current techniques are invasive and challenging to implement in pre-hospital and emergency rescue settings. To address this issue, a real-time prediction method utilizing only non-invasive parameters was developed to forecast IMV demand in this study. The model introduced the concept of real-time warning and leveraged the advantages of machine learning and integrated methods, achieving an AUC value of 0.935 (95% CI 0.933-0.937). The AUC value for the multi-center validation using the AmsterdamUMCdb database was 0.727, surpassing the performance of traditional risk adjustment algorithms (OSI(oxygenation saturation index): 0.608, P/F(oxygenation index): 0.558). Feature weight analysis demonstrated that BMI, Gcsverbal, and age significantly contributed to the model's decision-making. These findings highlight the substantial potential of a machine learning real-time dynamic warning model that solely relies on non-invasive parameters to predict IMV demand. Such a model can provide technical support for predicting the need for IMV in pre-hospital and disaster scenarios.

Pitfalls in Developing Machine Learning Models for Predicting Cardiovascular Diseases: Challenge and Solutions.

UNSTRUCTURED: In recent years, there has been an explosive development of artificial intelligence (AI), which has been widely applied in the healthcare field. As a typical AI technology, machine learning (ML) models have emerged as great potential in predicting cardiovascular diseases (CVDs) by leveraging large amounts of medical data for training and optimization, which are expected to play a crucial role in reducing the incidence and mortality rates of CVDs. Although the field has become a research hotspot, there are still many pitfalls that researchers need to pay close attention to. These pitfalls may affect the predictive performance, credibility, reliability, reproducibility of the studied models, ultimately reducing the value of the research and affecting the prospects for clinical application. Therefore, identifying and avoiding these pitfalls is a crucial task before implementing the research. However, there is currently a lack of comprehensive summary on this topic. This viewpoint aims to analyze the existing problems in terms of data quality, dataset characteristics, model design and statistical methods as well as clinic implication, and provide possible solutions to these problems, like gathering objective data, improving training, repeating measurements, increasing sample size, preventing overfitting using statistical methods, utilizing specific AI algorithms to address targeted issues, standardizing outcomes and evaluation criteria, as well as enhancing fairness and replicability, with the goal of offering reference and assistance to researchers, algorithm developers, policy makers, and clinical practitioners.

Improved optimization for the neural-network quantum states and tests on the chromium dimer.

The advent of Neural-network Quantum States (NQS) has significantly advanced wave function ansatz research, sparking a resurgence in orbital space variational Monte Carlo (VMC) exploration. This work introduces three algorithmic enhancements to reduce computational demands of VMC optimization using NQS: an adaptive learning rate algorithm, constrained optimization, and block optimization. We evaluate the refined algorithm on complex multireference bond stretches of H2O and N2 within the cc-pVDZ basis set and calculate the ground-state energy of the strongly correlated chromium dimer (Cr2) in the Ahlrichs SV basis set. Our results achieve superior accuracy compared to coupled cluster theory at a relatively modest CPU cost. This work demonstrates how to enhance optimization efficiency and robustness using these strategies, opening a new path to optimize large-scale restricted Boltzmann machine-based NQS more effectively and marking a substantial advancement in NQS's practical quantum chemistry applications.

Correlation between elevated HCLS1 levels and heart failure: A diagnostic biomarker.

The correlation between hematopoietic cell-specific lyn substrate 1 (HCLS1) expression levels and heart failure (HF) remains unclear. HF datasets GSE192886 and GSE196656 profiles were generated from GPL24676 and GPL20301 platforms in gene expression omnibus (GEO) database and differentially expressed genes (DEGs) were obtained, which was followed by weighted gene co-expression network analysis, protein-protein interaction (PPI) networks, functional enrichment analysis and comparative toxicogenomics database (CTD) analysis. Heatmaps of gene expression levels were plotted. TargetScan was used to screen miRNAs regulating central DEGs. A total of 500 DEGs were found and mainly concentrated in leukocyte activation, protein phosphorylation, and protein complexes involved in cell adhesion, PI3K Akt signaling pathway, Notch signaling pathway, and right ventricular cardiomyopathy. PPI network identified 15 core genes (HCLS1, FERMT3, CD53, CD34, ITGAL, EP300, LYN, VAV1, ITGAX, LEP, ITGB1, IGF1, MMP9, SMAD2, RAC2). Heatmap shows that 4 genes (EP300, CD53, HCLS1, LYN) are highly expressed in HF tissue samples. We found that 4 genes (EP300, CD53, HCLS1, LYN) were associated with heart diseases, cardiovascular diseases, edema, rheumatoid arthritis, necrosis, and inflammation. HCLS1 is highly expressed in HF and maybe its target.

Glucoconjugated monoterpene indole alkaloids with xanthine oxidase inhibitory activity from Ophiorrhiza japonica.

Continued interest in the bioactive alkaloids led to the isolation of five undescribed alkaloids (1-5), ophiorglucidines A-E, and seven known analogues (6-12) from the water-soluble fraction of Ophiorrhiza japonica. The structures were elucidated based on spectroscopic data and quantum calculations as well as X-ray crystallographic analysis. The structure of 1 was characterized as a hexacyclic skeleton including a double bridge linking the indole and the monoterpene moieties, which is the first report of a single crystal with this type of structure. Moreover, the inhibitory effect of zwitterionic indole alkaloid glycosides on xanthine oxidase was found for the first time. The alkaloids 2 and 3, both of which have a pentacyclic zwitterionic system, were more active than the reference inhibitor, allopurinol (IC50 = 11.1 µM) with IC50 values of 1.0 µM, and 2.5 µM, respectively. Structure-activity relationships analyses confirmed that the carbonyl group at C-14 was a key functional group responsible for the inhibitory effects of these alkaloids.

Utilizing synchronous care to improve cardiovascular and renal health among patients with type 2 diabetes: Proof-of-concept results from the DECIDE-CV clinical programme.

AIM: The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline-directed medical therapy (GDMT). METHODS: We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE-CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, renin-angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline-to-last-visit change in surrogate laboratory biomarkers. RESULTS: The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin-to-creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium-glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon-like peptide 1 receptor agonists (from 8% to 45%), renin-angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin-to-creatinine ratio and N-terminal proB-type natriuretic peptide levels significantly dropped from baseline (p < .05 for all). CONCLUSIONS: Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers.

Fatigue crack-based strain sensors achieving flow detection and motion monitoring for reconnaissance robot applications.

Crack-based flexible strain sensors with ultra-high sensitivity under tiny strain are highly desired for environmental perception and motion detection of novel flexible and miniature robots. However, previously reported methods for fabricating crack patterns have often sacrificed the cyclic stability of the sensor, leading to a trade-off relationship between the sensitivity and the cyclic stability. Here, a universal and simple strategy based on fatigue loading with an ultra-large cumulative strain of up to ∼1.2 × 107%, rather than the traditionally quasi-static pre-overloading methods, is proposed to introduce channel cracks in the sensing layer without sacrificing the cyclic stability. The developed flexible strain sensors exhibit high strain-sensitivity (gauge factor = 5798) under tiny strain (< 3%), high cyclic stability (15 000 cycles) and a low strain detecting limit (0.02%). Furthermore, a leaf-like mechanosensor is developed using the fatigue crack-based strain sensor for the realization of multifunctional applications in environment perception and micro-motion detection. Brilliant airflow sensing performance with a wide sensing range (0.93-11.93 m s-1) and a fast response time (0.28 s) for amphibious applications is demonstrated. This work provides a new strategy for overcoming limits of crack-based flexible strain sensors and the developed leaf-like mechanosensor shows great application potential in miniature and flexible reconnaissance robots.

Examining the impact of permissibility hypercapnia on postoperative delirium among elderly patients undergoing thoracoscopic-laparoscopic esophagectomy: A single-center investigative study.

OBJECTIVE: This study explores how permissive hypercapnia, a key aspect of lung protective ventilation, impacts postoperative delirium in elderly patients following thoracic surgery. METHODS: A single-center trial at The Second Hospital of Anhui Medical University involved 136 elderly patients undergoing thoracoscopic esophageal cancer resection. Randomly assigned to maintain PaCO2 35-45 mmHg (group N) or 46-55 mmHg (group H). Primary outcome: postoperative delirium (POD) incidence 1-3 days post-surgery. Secondary endpoints included monitoring rSO2, cardiovascular parameters (MAP, HR), pH, OI, and respiratory parameters (VT, RR, Cdyn, PIP) at specific time points. Perioperative tests assessed CRP/ALB ratio (CAR) and systemic inflammatory index (SII). VAS scores were documented for three postoperative days. RESULTS: Postoperatively, group H showed significantly lower POD incidence than group N (7.4% vs. 19.1%, P = 0.043). Group H exhibited higher PaCO2 and rSO2 during surgery (P < 0.05). Patients in group H maintained better cardiovascular stability with higher blood pressure and lower heart rate on T2-4 (P < 0.05). Respiratory parameters were more stable in group H with lower TV, RR, and PIP, and higher Cdyn during OLV (P < 0.05). Group H had lower pH and OI at T2-4 (P < 0.05). CRP and CAR levels rose less in group H on the first day and one week later (P < 0.05). CONCLUSIONS: Maintaining PaCO2 at 46-55 mmHg reduces POD incidence, possibly by enhancing rSO2 levels and stabilizing intraoperative respiration/circulation.

Recombinant Klotho protein protects pulmonary alveolar epithelial cells against sepsis-induced apoptosis by inhibiting the Bcl-2/Bax/caspase-3 pathway.

BACKGROUND: Inflammation-induced apoptosis of alveolar type II epithelial cells is a primary contributor to sepsis-induced acute respiratory distress syndrome (ARDS). Klotho is a single-pass transmembrane protein with anti-inflammatory and anti-apoptotic effects. However, the role and mechanism of Klotho in the development of ARDS remains unknown. OBJECTIVES: This study aimed to investigate the effect of Klotho on sepsis-induced apoptosis in human pulmonary alveolar epithelial cells (HPAEpiCs) together with the potential mechanism. MATERIAL AND METHODS: Cecal ligation and puncture (CLP) were performed to generate an in vivo sepsis model, and HPAEpiCs were treated with lipopolysaccharide (LPS) to mimic sepsis in vitro. Both models were administered recombinant Klotho protein. The morphology of the lung tissue was observed, and apoptotic cells and cell viability were detected. Interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α) levels were detected using enzyme-linked immunosorbent assay (ELISA), while the expression of Bcl-2, Bax and cleaved caspase-3 was detected with western blotting. RESULTS: Klotho reversed the CLP-induced decrease in mouse survival in vivo (p < 0.001) and increased inflammatory cell infiltration and inflammatory substance exudation in the lung tissue of mice with sepsis (both p < 0.001). Klotho also suppressed apoptosis (p < 0.001) as demonstrated by IL-1ß, IL-6 and TNF-α expression (all p < 0.001), and Bcl-2/Bax/caspase-3 pathway activation (p < 0.001). Klotho pretreatment significantly prevented LPS-induced apoptosis in vitro (p < 0.001), as demonstrated by IL-1ß, IL-6 and TNF-α upregulation (all p < 0.001); and Bcl-2/Bax/caspase-3 pathway activation in HPAEpiCs (p < 0.001). CONCLUSIONS: This study demonstrated that Klotho can ameliorate acute lung injury (ALI) induced by sepsis by inhibiting inflammatory responses and exerting anti-apoptotic effects by suppressing Bcl-2/Bax/caspase-3 pathway activation.

Energy stress-induced circDDX21 promotes glycolysis and facilitates hepatocellular carcinogenesis.

Cancer cells undergo metabolic reprogramming in response to hostile microenvironments, such as energy stress; however, the underlying mechanisms remain largely unclear. It is also unknown whether energy stress-responsive circular RNA (circRNA) is involved in the regulation of glucose metabolism. Here we report that circDDX21 is upregulated in response to glucose deprivation by the transcription factor c-Myc. Functionally, circDDX21 is shown to promote glycolysis by increasing PGAM1 expression. Mechanistically, circDDX21 interacts with the RNA binding protein PABPC1, disrupting its association with the ubiquitin E3 ligase MKRN3. This disassociation attenuates MKRN3-mediated PABPC1 ubiquitination and enhances the binding of PABPC1 to PGAM1 mRNA, thereby leading to PGAM1 mRNA stabilization. The ability of the circDDX21-PGAM1 axis to promote hepatocellular carcinogenesis is validated in a xenograft mouse model. Additionally, in clinical hepatocellular carcinoma tissues, there is a positive correlation between circDDX21 and PGAM1 expression. These findings establish circDDX21 as an important regulator of glycolysis and suggest circDDX21 as a potential therapeutic target for hepatocellular carcinoma.

Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

Impact of age and comorbid heart failure on the utility of smart voice-assistant devices.

Aims: The accuracy of voice-assisted technologies, such as Amazon Alexa, to collect data in patients who are older or have heart failure (HF) is unknown. The aim of this study is to analyse the impact of increasing age and comorbid HF, when compared with younger participants and caregivers, and how these different subgroups classify their experience using a voice-assistant device, for screening purposes. Methods and results: Subgroup analysis (HF vs. caregivers and younger vs. older participants) of the VOICE-COVID-II trial, a randomized controlled study where participants were assigned with subsequent crossover to receive a SARS-CoV2 screening questionnaire by Amazon Alexa or a healthcare personnel. Overall concordance between the two methods was compared using unweighted kappa scores and percentage of agreement. From the 52 participants included, the median age was 51 (34-65) years and 21 (40%) were HF patients. The HF subgroup showed a significantly lower percentage of agreement compared with caregivers (95% vs. 99%, P = 0.03), and both the HF and older subgroups tended to have lower unweighted kappa scores than their counterparts. In a post-screening survey, both the HF and older subgroups were less acquainted and found the voice-assistant device more difficult to use compared with caregivers and younger individuals. Conclusion: This subgroup analysis highlights important differences in the performance of a voice-assistant-based technology in an older and comorbid HF population. Younger individuals and caregivers, serving as facilitators, have the potential to bridge the gap and enhance the integration of these technologies into clinical practice. Study Registration: ClinicalTrials.gov Identifier: NCT04508972.

Diagnostic value of FNAC combined with BRAFV600E mutation detection in Hashimoto's thyroiditis complicated with papillary thyroid carcinoma.

Background: This study aimed to analyze the effect of preoperative fine needle aspiration cytology (FNAC) combined with BRAFV600E mutation detection as compared to that of fine needle aspiration cytology alone on the diagnostic performance of papillary thyroid carcinoma (PTC) combined with Hashimoto's thyroiditis (HT). Method: Patients with thyroid nodules in Hashimoto's thyroiditis, who underwent fine-needle aspiration cytology examination and BRAFV600E mutation detection in the puncture eluate at the outpatient clinic, were selected. Finally, 122 patients received surgical treatment and were included in the study. We used postoperative pathological results as the gold standard. Accordingly, we compared the sensitivity, specificity and accuracy of preoperative FNAC alone and FNAC combined with BRAFV600E mutation detection in for the diagnosis of PTC combined with HT. Results: For PTC patients with HT, the sensitivity of FNAC diagnosis was 93.69%, the specificity was 90.90% and the accuracy was 93.44%. However, the sensitivity, specificity and accuracy of FNAC combined with BRAFV600E mutation detection were 97.30%, 90.90% and 96.72%, respectively. Therefore, combined detection can improve the sensitivity and accuracy of diagnosis (p<0.05). Conclusion: FNAC combined with eluent BRAFV600E mutation detection can improve the sensitivity and accuracy of diagnosis of PTC in the background of HT.

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.