GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models.

Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. In vitro, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.

The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions.

The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.

TEAD transcription factor family emerges as a promising therapeutic target for oral squamous cell carcinoma.

The treatment of oral squamous cell carcinoma (OSCC) remains a significant difficulty, as there has been no improvement in survival rates over the past fifty years. Hence, exploration and confirmation of new dependable treatment targets and biomarkers is imperative for OSCC therapy. TEAD transcription factors are crucial for integrating and coordinating multiple signaling pathways that are essential for embryonic development, organ formation, and tissue homeostasis. In addition, by attaching to coactivators, TEAD modifies the expression of genes such as Cyr61, Myc, and connective tissue growth factor, hence facilitating tumor progression. Therefore, TEAD is regarded as an effective predictive biomarker due to its significant connection with clinical parameters in several malignant tumors, including OSCC. The efficacy of existing drugs that specifically target TEAD has demonstrated encouraging outcomes, indicating its potential as an optimal target for OSCC treatment. This review provides an overview of current targeted therapy strategies for OSCC by highlighting the transcription mechanism and involvement of TEAD in oncogenic signaling pathways. Finally, the feasibility of utilizing TEAD as an innovative approach to address OSCC and its potential clinical applications were analyzed and discussed.

The Causal Relationship Between Immune Cells and Infertility: A Mendelian Randomisation Study.

OBJECTIVE: Infertility has emerged as a significant global public health concern, with a multitude of complex underlying causes. Epidemiological evidence indicates that immunological factors are significant contributors to the aetiology of infertility. However, previous studies on the relationship between immune inflammation and infertility have yielded inconclusive results. METHODS: Mendelian randomisation (MR) is an emerging statistical method that employs exposure-related genetic variation as an instrumental variable (IV) to infer causal relationships between immune cells and infertility by modelling the principle of random assignment in Mendelian genetics. In this study, MR was employed to assess the causal relationship between 731 immune cell signatures and infertility. The data utilized in this study were obtained from publicly available genome-wide association studies (GWAS) and validated IVs, which were employed to fulfil the essential assumptions of MR analysis. RESULTS: The Mendelian randomisation analysis revealed a total of 27 statistically significant immune cell phenotypes out of 731. The risk factor with the largest odds ratio (OR) was CD28- CD25++ CD8+ %T cell [OR, 1.21; 95% confidence interval (CI), 1.04-1.42], while the protective factor with the largest OR was activated and resting Treg AC (OR, 0.89; 95% CI, 0.82-0.97). CONCLUSION: The present study has demonstrated a correlation between certain characteristics of immune cells and female infertility. These results provide clues for further research into the immune mechanisms of infertility and may inform the development of novel therapeutic strategies.

Exploring Enzyme Encapsulation Efficiency in MOFs Using Eco-friendly Approaches.

The encapsulation of protein enzymes in metal-organic frameworks (MOFs) has been recognized as an effective enzyme immobilization approach. In this study, we demonstrated the influence of enzyme amount and the isoelectric points (pI) of different enzymes on the enzyme loading capacity in both mechanochemical (ball-milling) and water-based approaches. We found that increasing enzyme amounts enhances MOF enzyme loading without compromising activity, while the MOF shell protects encapsulated enzymes from proteinase K degradation through its size-sheltering mechanism. However, an excess of enzymes can hinder the formation of ZIF-90. Moreover, enzymes with low pI values (e.g., catalase, pI 5.4) facilitate encapsulation in MOFs, whereas enzymes with high pI values (e.g., lysozyme, pI 11.35) are more challenging to encapsulate. The simulation results revealed that increasing the enzyme amounts and pI values raises the activation energy necessary for MOF formation. This study highlights the crucial role of enzyme properties in the encapsulation process within MOFs, providing valuable insights for fabricating enzyme-MOF biocomposites for diverse applications, such as protein drug delivery.

Adversarial Exposure Attack on Diabetic Retinopathy Imagery Grading.

Diabetic Retinopathy (DR) is a leading cause of vision loss around the world. To help diagnose it, numerous cutting-edge works have built powerful deep neural networks (DNNs) to automatically grade DR via retinal fundus images (RFIs). However, RFIs are commonly affected by camera exposure issues that may lead to incorrect grades. The mis-graded results can potentially pose high risks to an aggravation of the condition. In this paper, we study this problem from the viewpoint of adversarial attacks. We identify and introduce a novel solution to an entirely new task, termed as adversarial exposure attack, which is able to produce natural exposure images and mislead the state-of-the-art DNNs. We validate our proposed method on a real-world public DR dataset with three DNNs, e.g., ResNet50, MobileNet, and EfficientNet, demonstrating that our method achieves high image quality and success rate in transferring the attacks. Our method reveals the potential threats to DNN-based automatic DR grading and would benefit the development of exposure-robust DR grading methods in the future.

[Traditional Chinese medicinal compress combined with herbal fumigation for acute epididymitis: A clinical observation].

OBJECTIVE: To observe the clinical efficacy of traditional Chinese medicinal (TCM) compress combined with herbal fumigation in the treatment of acute epididymitis. METHODS: This study included 74 cases of acute epididymitis treated in our hospital from December 2021 to December 2023. Using the single blind and random number methods, we divided the patients into a trial (n = 37) and a control group (n = 37). On the basis of routine medication with antibiotics, we treated the patients in the trial group by TCM compress combined with herbal fumigation and those in the control group by dyed pure water compress combined with herbal fumigation. At 3, 7 and 14 days of treatment, we obtained the pain scores and maximum epididymal diameters from the patients and compared them between the two groups before and after treatment. RESULTS: There were no statistically significant differences between the control and trial groups in the baseline pain scores (6.79 vs 6.85, P>0.05) and maximum epididymal diameters of the patients (ï¼»1.61 ± 0.39ï¼½ vs ï¼»1.59 ± 0.42ï¼½ cm, P>0.05) or in the pain scores after 3 days of treatment (4.63 ± 0.95 vs 4.45 ± 1.87, P>0.05). Compared with the controls, the patients of the trial group showed significantly lower pain scores (3.78 ±1.03 vs 1.02±0.36, P<0.05) and a higher overall effectiveness rate (75.68% vs 91.89%, P<0.05) at 7 days, and markedly shorter maximum epididymal diameters at 3 days (ï¼»1.45 ± 0.38ï¼½ vs ï¼»1.23 ± 0.72ï¼½ cm, P<0.05) and 7 days (ï¼»1.21 ± 0.29ï¼½ vs ï¼»0.98 ± 0.15ï¼½ cm, P<0.05). No statistically significant differences were observed between the control and trial groups in the pain scores (0.79 ± 1.12 vs 0.67 ± 0.86, P>0.05), maximum epididymal diameters (ï¼»0.94 ± 0.33ï¼½ vs ï¼»0.92 ± 0.21ï¼½ cm, P>0.05) or overall effectiveness rate (91.89% vs 97.30%, P>0.05) after 14 days of treatment. CONCLUSION: On the basis of routine medication with antibiotics, TCM compress combined with herbal fumigation can effectively relieve pain, reduce local swelling, accelerate recovery and shorten the course of treatment in patients with acute epididymitis, and is therefore worthy of clinical promotion and application.

3D printing for constructing biocarriers using sodium alginate/ε-poly-l-lysine ink: Enhancing microbial enrichment for efficient nitrogen removal in wastewater.

The microbial enrichment of traditional biocarriers is limited due to the inadequate consideration of spatial structure and surface charging characteristics. Here, capitalizing on the ability of 3D printing technology to fabricate high-resolution materials, we further designed a positively charged sodium alginate/ε-poly-l-lysine (SA/ε-PL) printing ink, and the 3D printed biocarriers with ideal pore structure and rich positive charge were constructed to enhance the microbial enrichment. The rheological and mechanical tests confirmed that the developed SA/ε-PL ink could simultaneously satisfy the smooth extrusion for printing process and the maintenance of 3D structure. The utilization of the ε-PL secondary cross-linking strategy reinforced the 3D mechanical structure and imparted the requisite physical properties for its application as a biocarrier. Compared with traditional sponge carriers, 3D printed biocarrier had a faster initial attachment rate and a higher biomass of 14.58 ± 1.18 VS/cm3, and the nitrogen removal efficiency increased by 53.9 %. Besides, due to the superior electrochemical properties and biocompatibility, the 3D printed biocarriers effectively enriched the electroactive denitrifying bacteria genus Trichococcus, thus supporting its excellent denitrification performance. This study provided novel insights into the development of new functional biocarriers in the wastewater treatment, thereby providing scientific guidance for practical engineering.

Decoding the Biomimetic Mineralization of Metal-Organic Frameworks in Water.

This study unveils the "green" metal-organic framework (MOF) structuring mechanism by decoding proton transfer in water during ZIF-8 synthesis. Combining in situ small- to wide-angle X-ray scattering, multiscale simulations, and quantum calculations, we reveal that the ZIF-8 early-stage nucleation and crystallization process in aqueous solution unfolds in three distinct stages. In stage I, imidazole ligands replace water in zinc-water cages, triggering an "acidity flip" that promotes proton transfer. This leads to the assembly of structures from single zinc ions to 3D amorphous cluster nuclei. In stage II, amorphous nuclei undergo a critical transformation, evolving into crystalline nuclei and subsequently forming mesoscale-ordered structures and crystallites. The process proceeds until the amorphous precursors are completely consumed, with the transformation kinetics governed by an energy barrier that determines the rate-limiting step. In stage III, stable crystallite nanoparticles form in solution, characterized by a temperature-dependent thermal equilibrium of molecular interactions at the crystal-solution interface. Beyond these core advancements, we explore the influence of encapsulated pepsin and nonencapsulated lysozyme on ZIF-8 formation, finding that their amino acid proton transfer capacity and concentration influence the resulting biomolecule-MOF composite's shape and encapsulation efficiency. The findings contribute to understanding the molecular mechanisms behind biomimetic mineralization and have potential implications for engineering proteins within amorphous MOF nuclei as protein embryo growth sites.

Multiple lymph nodes enlargement and fever as main manifestations of nocardiosis in immunocompetent individuals: Two case reports.

Nocardia farcinica is an aerobic gram-positive bacterium that is pathogenic to humans. It usually causes local and adjacent tissues' diseases at the entry of infection (most commonly occur in the lungs, skin, or central nervous system), which can also spread to other organs through the bloodstream such as joints, kidneys, and liver. However, these infections are often seen as opportunistic that occur in immunocompromised patients. Here, we report for the first time two immunocompetent patients lacking evidence of local infections, with multiple lymph node enlargements and fever as main clinical manifestations, finally diagnosed as nocardiosis by Metagenomic Next-Generation Sequencing testing (mNGS) from formalin-fixed and paraffin-embedded (FFPE) lymph node tissue, after all the other standard tests were negative. Both patients recovered after receiving anti-nocardia therapies. These two cases indicates that in healthy population, there may be more potential nocardia infections than we expected. Multiple lymph node enlargements and fever suggest a possibility of nocardiosis, especially in patients with fever of unknown origin (FUO). mNGS detection from FFPE lymph node tissue is an accurate, reliable and traceable method for diagnosis of nocardiosis.

Prognostic significance of serum Chemerin and neutrophils levels in patients with oral squamous cell carcinoma.

Objectives: Chemerin, as a novel multifunctional adipokine, is proposed to be involved in high cancer risk and mortality. The present study was aimed to evaluate the prognostic value of serum Chemerin and neutrophils in patients with oral squamous cell carcinoma (OSCC). Materials and methods: 120 patients with OSCC were included in this prospective cohort study. The levels of serum Chemerin were measured by enzyme-linked immunosorbent assay (ELISA). We also explored the possible effects of Chemerin on neutrophils' chemokines in OSCC using a real-time PCR, western blotting. Results: Levels of serum Chemerin, neutrophils and NLR were significantly higher among non-survivors compared to survivors of OSCC (both P < 0.05). Higher serum Chemerin levels were associated with advanced TNM stage, lymph node metastasis, differentiation and tumor recurrence (both P < 0.05). Serum Chemerin levels correlated with neutrophils and NLR levels (r = 0.708, r = 0.578, both P < 0.05). Based on ROC analysis, Chemerin + NLR predicted OSCC patient mortality with 81.54 % sensitivity and 87.27 % specificity, with an AUC of 0.8898. In a Kaplan-Meier analysis, high serum Chemerin levels, high neutrophil levels and high NLR levels were associated with shorter overall and disease-free survival (both P < 0.05). A univariate and multivariate Cox regression analysis showed that serum Chemerin and neutrophils were independent risk factors for OSCC. (both P < 0.05). QRT-PCR and western blotting results showed that Chemerin upregulated the expression of chemokines IL-17 and CXCL-5 in neutrophils (both P < 0.05). Conclusions: Our study suggests that measurement of serum Chemerin and neutrophils might be a useful diagnostic and prognostic biomarker for OSCC patients. Chemerin may promote neutrophils infiltration in OSCC through upregulation of chemokines IL17 and CXCL-5.

Realization of a two-dimensional Weyl semimetal and topological Fermi strings.

A two-dimensional (2D) Weyl semimetal, akin to a spinful variant of graphene, represents a topological matter characterized by Weyl fermion-like quasiparticles in low dimensions. The spinful linear band structure in two dimensions gives rise to distinctive topological properties, accompanied by the emergence of Fermi string edge states. We report the experimental realization of a 2D Weyl semimetal, bismuthene monolayer grown on SnS(Se) substrates. Using spin and angle-resolved photoemission and scanning tunneling spectroscopies, we directly observe spin-polarized Weyl cones, Weyl nodes, and Fermi strings, providing consistent evidence of their inherent topological characteristics. Our work opens the door for the experimental study of Weyl fermions in low-dimensional materials.

Supramolecular assemblies derived from methyl-substituted cucurbit[5]uril and lanthanide nitrates.

Interaction of the lanthanide nitrates M(NO3)3 (M = Gd, Eu) with methylcucurbit[5]uril (Me10Q[5]) in the presence of transition metal chlorides (ZnCl2 and FeCl3) in acidic media resulted in the isolation of the complexes [Me10Q[5]Gd(H2O)2Cl Gd(H2O)6](ZnCl4)2∙Cl∙8.9H2O (1) and [Me10Q[5]Eu(H2O)3Cl(H3O)](FeCl4)3 (2). The molecular structures of 1 and 2 have been determined by single crystal X-ray crystallography, and reveal discrete complexes which are involved in dense stacking with adjacent Me10Q[5]s linked via H-bonding and/or metal anions resulting in a supramolecular assembly.

Zinc finger protein 180 induces an apoptotic phenotype by activating METTL14 transcriptional activity in colorectal cancer.

Zinc finger protein 180 (ZNF180) is a multifunctional protein that interacts with nucleic acids and regulates various cellular processes; however, the function of ZNF180 in colorectal cancer (CRC) remains unclear. The present study investigated the role and function of ZNF180 in CRC, and aimed to reveal the underlying molecular mechanism. The results revealed that ZNF180 was downregulated in CRC tissues and was associated with a good prognosis in patients with CRC. Additionally, the expression of ZNF180 was downregulated by methylation in CRC. In vivo and in vitro experiments revealed that ZNF180 overexpression was functionally associated with the inhibition of cell proliferation and the induction of apoptosis. Mechanistically, chromatin immunoprecipitation­PCR and luciferase assays demonstrated that ZNF180 markedly regulated the transcriptional activity of methyltransferase 14, N6­adenosine­methyltransferase non­catalytic subunit (METTL14) by directly binding to and activating its promoter region. Simultaneous overexpression of ZNF180 and knockdown of METTL14 indicated that the reduction of METTL14 could suppress the effects of ZNF180 on the induction of apoptosis. Clinically, the present study observed a significant positive correlation between ZNF180 and METTL14 expression levels, and low expression of ZNF180 and METTL14 predicted a poor prognosis in CRC. Overall, these findings revealed a novel mechanism by which the ZNF180/METTL14 axis may modulate apoptosis and cell proliferation in CRC. This evidence suggests that this axis may serve as a prognostic biomarker and therapeutic target in patients with CRC.

Downregulated expression of lncRNA TUBA4B predicts unfavorable prognosis and suppresses glioma progression by sponging miR-183 to regulate SMAD4 expression.

Introduction: Accumulating evidence has proved that long non-coding RNAs (lncRNAs) are involved in progression of glioma. Nevertheless, the role of TUBA4B in glioma remains unclear. Material and methods: The expression of the target gene was measured by quantitative RT-PCR. The prognostic role of TUBA4B was analyzed by Meier survival analysis. Cell proliferation, colony formation, apoptosis, cell cycle, migration and invasion were detected by MTS, soft agar colony forming assay, flow cytometry, and transwell assay. The target interaction of the target gene was validated by the luciferase reporter assay, biotin pull-down assay, and RNA immunoprecipitation. Results: We found that the expression of TUBA4B was lower in glioma tissues and cells. Moreover, patients with a low TUBA4B expression level exhibited poorer prognosis than those with high TUBA4B expression. Meanwhile, ROC analysis revealed that TUBA4B had diagnostic value to distinguish tumor patients from the healthy population. Overexpression of TUBA4B prohibited the malignancy of glioma, such as inhibition of proliferation, decrease of colony formation, arrest of the cell cycle, decline of migration and invasion, and promotion of cell apoptosis. In addition, we found that TUBA4B directly interacted with miR-183 and negatively regulated the expression of miR-183. We also observed that SMAD4 was a downriver target of miR-183 and TUBA4B subsequently exerted its tumor-suppressive effects by coordinating the expression of SMAD4 in glioma. Conclusions: This study revealed for the first time that TUBA4B could be a tumor suppressor gene in glioma by adjustment of the TUBA4B/miR-183/SMAD4 axis, which may provide a useful prognostic biomarker and promising therapeutic target for glioma treatment.

A non-image-forming visual circuit mediates the innate fear of heights in male mice.

The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in male mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naïve mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to height threats through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.

High expression of serine protease inhibitor kazal type 1 predicts poor prognosis and promotes the progression and invasion of oral tongue squamous cell carcinoma.

OBJECTIVE: This study aimed to investigate the expression of serine protease inhibitor kazal type 1 (SPINK1) and its carcinogenic effect in oral tongue squamous cell carcinoma (OTSCC). DESIGN: Initially, bioinformatics analysis was conducted using data from The Cancer Genome Atlas and Gene Expression Omnibus to compare SPINK1 mRNA expression between malignant and adjacent tissues. Subsequently, the impact of differential expression on survival and other clinical variables was examined. Additionally, histology microarray analysis was performed to assess SPINK1 protein expression in 35 cases of malignant and adjacent tissues. Finally, alterations in SPINK1 expression were evaluated to determine its biological phenotypes in OTSCC, including proliferation, apoptosis, invasion, and metastasis. RESULTS: OTSCC tissues exhibit higher levels of SPINK1 compared to surrounding cancerous tissues. Notably, increased SPINK1 expression correlates with the pathological N stage and independently predicts overall survival among patients with OTSCC. CONCLUSION: Suppression of SPINK1 inhibited OTSCC cell proliferation, invasion, and motility while promoting apoptosis. These findings suggest that SPINK1 may serve as a prognostic biomarker as well as a potential therapeutic target for managing OTSCC.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Disulfidptosis-related lncRNA signature reveals immune microenvironment and novel molecular subtyping of stomach adenocarcinoma.

The main challenge in treating stomach adenocarcinoma (STAD) is chemotherapy resistance, which is characterized by changes in the immune microenvironment. Disulfidptosis, a novel form of programmed cell death, is involved in STAD but its mechanism is not fully understood. Long non-coding RNAs (LncRNAs) may play a role in regulating disulfidptosis and influencing the immune microenvironment and chemotherapy resistance in STAD. This study aims to establish disulfidptosis-related lncRNA (DRL) features and explore their significance in the immune microenvironment and chemotherapy resistance in STAD patients. By analyzing RNA sequencing and clinical data from STAD patients and extracting disulfidptosis-related genes, we identified DRLs through co-expression, single-factor and multi-factor Cox regression, and Lasso regression analyses. We also investigated differences in the immune microenvironment, immune function, immune checkpoint gene expression, and chemotherapy resistance between different risk groups using various algorithms. A prognostic risk model consisting of 2 DRLs was constructed, with a strong predictive value for patient survival, outperforming other clinical-pathological factors in predicting 3-year and 5-year survival. Immune-related analysis revealed a strong positive correlation between T cell CD4+ cells and risk score across all algorithms, and higher expression of immune checkpoint genes in the high-risk group. In addition, high-risk patients showed better sensitivity to Erlotinib, Oxaliplatin, and Gefitinib. Furthermore, three novel molecular subtypes of STAD were identified based on the 2-DRLs features, with evaluation of the immune microenvironment and chemotherapy drug sensitivity for each subgroup, which holds significant implications for achieving precise treatment in STAD. Overall, our 2-DRLs prognostic model demonstrates high predictive value for patient survival in STAD, potentially providing new targets for individualized immune and chemical therapy.