Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy.

BACKGROUND: Recently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress. METHODS: We performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling. RESULTS: We first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction. CONCLUSIONS: Collectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

Lacticaseibacillus casei K11 exerts immunomodulatory effects by enhancing natural killer cell cytotoxicity via the extracellular regulated-protein kinase pathway.

PURPOSE: Probiotics can serve as immunomodulators that regulate the activation of immune cells. This study aimed to screen potential probiotic strains that can enhance NK cell toxicity to improve host immunity. METHODS: In this investigation, we examined three potential probiotic strains, namely Lactiplantibacillus plantarum YZX21 (YZX21), Bifidobacterium bifidum FL-276.1 (FL-276.1) and Lacticaseibacillus casei K11 (K11), to assess their capacity in modulating NK cytotoxicity both in vitro and in vivo, while elucidating the underlying mechanisms involved. RESULTS: The findings demonstrated that K11 exhibited superior efficacy in enhancing NK cytotoxicity. Subsequent analysis revealed that K11 significantly augmented the secretion of perforin and granzyme B by NK cells through activation of receptors NKp30 and NKp46 via the extracellular signal-regulated kinase (ERK) pathway. Furthermore, heat-inactivated K11 also enhanced NK cell activity to an extent comparable to live bacteria, with lipoteichoic acid from K11 identified as a crucial factor mediating the activation of NK cell cytotoxicity. CONCLUSION: Our study suggests that K11 may have potential applications as probiotics or postbiotics for regulating NK cell cytotoxicity to enhance immunity.

Serum cytokines and creatinine/cystatin C ratio as prognostic biomarkers in advanced cancer patients treated with anti-PD-1/PD-L1 therapy.

OBJECTIVE: Immune checkpoint inhibitors (ICIs), specifically targeting the programmed cell death protein-1 or its ligand (PD-1/PD-L1), have been extensively used in the treatment of a spectrum of malignancies, although the predictive biomarkers remain to be elucidated. This study aims to investigate the association between baseline circulating levels of cytokines and the creatinine/cystatin C ratio (CCR) with the treatment outcomes of ICIs in patients with advanced cancer. METHODS: The pre-treatment circulating levels of 10 cytokines (PD-L1, CTLA4, CXCL10, LAG3, HGF, CCL2, MIG, GRANB, IL-18, and IL-6) were measured via automated capillary-based immunoassay platform in the serum of 65 advanced cancer patients treated with anti-PD-1/PD-L1-based systemic therapy and 10 healthy volunteers. The levels of cytokines and CCR were quantified and categorized into high and low groups based on the median value. The associations of serum cytokines and CCR with response to treatment, survival, and immune-related adverse events were assessed. RESULTS: Elevated circulating levels of 6 cytokines (PD-L1, CXCL10, HGF, CCL2, MIG, and IL-6) were observed in cancer patients compared with that in healthy volunteers. The correlation coefficients between cytokines, CCR and nutritional risk index were also calculated. In the cancer cohort (N = 65), low circulating HGF (P = 0.023, P = 0.029), low IL-6 (P = 0.002, P < 0.001), and high CCR (P = 0.031, P = 0.008) were associated with significantly improved progression-free survival (PFS) and overall survival (OS). Multi-variable COX analyses adjusted for clinicopathological factors revealed that low HGF, low IL-6, and high CCR were independent favorable prognostic factors for PFS (P = 0.028, P = 0.010, and P = 0.015, respectively) and OS (P = 0.043, P = 0.003, and P = 0.026, respectively). Grade 2 irAEs occurred more frequently in patients with low levels of circulating CCL2 and LAG3. CONCLUSIONS: Pre-treatment circulating levels of serum IL-6, HGF, and CCR may serve as independent predictive and prognostic biomarkers in advanced cancer patients treated with ICIs-based systemic therapy. These findings might help to identify potential patients who would benefit from these therapies.

The probiotic fermented milk of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 alleviates constipation via improving gastrointestinal motility and gut microbiota.

Constipation is directly related to the intestinal microenvironment, in which the promotion of gastrointestinal (GI) motility and improvement of gut microbiota distribution are important for alleviating symptoms. Herein, after the intervention of probiotic fermented milk (FMMIX) containing Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 for 14 d in Kunming mice with loperamide-induced constipation, the results indicated that FMMIX significantly increased the secretion of serum motilin, gastrin and 5-hydroxytryptamine, as well as decreased the secretion of peptide YY, vasoactive intestinal peptide, and nitric oxide in mice. As determined by immunohistochemical analysis, FMMIX promoted an augmentation in the quantity of Cajal interstitial cells. In addition, the mRNA and protein expression of c-kit and stem cell factor (SCF) were upregulated to facilitate intestinal motility. High-throughput sequencing and gas chromatography techniques revealed that FMMIX led to an increase in the relative abundance of beneficial bacteria (Lactobacillus, Oscillospira, Ruminococcus, Coprococcus, and Akkermansia), reduced the presence of harmful bacteria (Prevotella), and resulted in elevated levels of short-chain fatty acids (SCFA) with a superior improvement compared with unfermented milk. Untargeted metabolomics revealed significant upregulation of functional metabolites such as l-pipecolinic acid, dl-phenylalanine, and naringenin in FMMIX, presumably playing a potential role in constipation relief. Overall, our results showed that FMMIX had the potential to alleviate constipation symptoms in mice by improving the secretion of serum GI regulatory peptides and neurotransmitters, increasing the expression of c-kit and SCF proteins, and modulating the gut microbiota structure and SCFA levels, and may be associated with an increase in these functional metabolites. This suggested that FMMIX could be a promising adjunctive strategy for managing constipation symptoms and could contribute to the development of functional foods aimed at improving gut health.

A deep learning-based recognition for dangerous objects imaged in X-ray security inspection device.

Several limitations in algorithms and datasets in the field of X-ray security inspection result in the low accuracy of X-ray image inspection. In the literature, there have been rare studies proposed and datasets prepared for the topic of dangerous objects segmentation. In this work, we contribute a purely manual segmentation for labeling the existing X-ray security inspection dataset namely, SIXRay, with the pixel-level semantic information of dangerous objects. We also propose a composition method for X-ray security inspection images to effectively augment the positive samples. This composition method can quickly obtain the positive sample images using affine transformation and HSV features of X-ray images. Furthermore, to improve the recognition accuracy, especially for adjacent and overlapping dangerous objects, we propose to combine the target detection algorithm (i.e., the softer-non maximum suppression, Softer-NMS) with Mask RCNN, which is named as the Softer-Mask RCNN. Compared with the original model (i.e., Mask RCNN), the Softer-Mask RCNN improves by 3.4% in accuracy (mAP), and 6.2% with adding synthetic data. The study result indicates that our proposed method in this work can effectively improve the recognition performance of dangerous objects depicting in the X-ray security inspection images.

Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4.

Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.

Non-convex optimization based optimal bone correction for various beam-hardening artifacts in CT imaging.

Tube of X-ray computed tomography (CT) system emitting a polychromatic spectrum of photons leads to beam hardening artifacts such as cupping and streaks, while the metal implants in the imaged object results in metal artifacts in the reconstructed images. The simultaneous emergence of various beam-hardening artifacts degrades the diagnostic accuracy of CT images in clinics. Thus, it should be deeply investigated for suppressing such artifacts. In this study, data consistency condition is exploited to construct an objective function. Non-convex optimization algorithm is employed to solve the optimal scaling factors. Finally, an optimal bone correction is acquired to simultaneously correct for cupping, streaks and metal artifacts. Experimental result acquired by a realistic computer simulation demonstrates that the proposed method can adaptively determine the optimal scaling factors, and then correct for various beam-hardening artifacts in the reconstructed CT images. Especially, as compared to the nonlinear least squares before variable substitution, the running time of the new CT image reconstruction algorithm decreases 82.36% and residual error reduces 55.95%. As compared to the nonlinear least squares after variable substitution, the running time of the new algorithm decreases 67.54% with the same residual error.

Asprosin is associated with anorexia and body fat mass in cancer patients.

PURPOSE: Increasing evidence suggests that many adipokines are involved in cancer-related anorexia and cachexia syndrome (CACS), although the underlying mechanism remains to be clarify. Asprosin is a new peptide hormone mainly secreted by white adipose tissues that can increase appetite and body weight. In this cross-sectional study, we tested whether asprosin may intervene in the development of CACS. METHODS: The fasting plasma asprosin levels were determined via enzyme-linked immune-sorbent assay. Anorexia was determined using the anorexia/cachexia subscale (A/CS) of the functional assessment of anorexia/cachexia therapy (FAACT) questionnaire. The body composition was assessed using bioelectrical impedance analysis. The association of plasma asprosin with anorexia, cachexia, and nutritional status was analyzed. RESULTS: One hundred twenty treatment-naïve patients with pathological confirmed gastrointestinal or lung cancer and 14 mild gastritis patients were recruited. We found no significant difference in asprosin levels between subgroups of patients by age, sex, cancer types or stage. Correlation analysis suggested that asprosin levels were positively associated with body fat mass (r = 0.248, p = 0.043). No correlations were found between asprosin levels and hemoglobin, white blood cell count, blood platelet count, albumin, C-reactive protein, glucose, cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, body mass index, body fat percentage, protein, skeletal muscle, muscle mass, lean body mass, and basal metabolic rate. Furthermore, asprosin levels were not significantly different between patients with or without cachexia. However, patients with anorexia had significantly lower asprosin levels compared with patients without anorexia. No significant difference in asprosin levels between gastritis and gastric cancer patients. Similarly, no significant change of asprosin levels occurred postoperatively in 10 gastric cancer patients. CONCLUSIONS: Patients with anorexia had significantly lower asprosin levels compared with patients without anorexia. We therefore speculated that asprosin might intervene in the development of cancer anorexia and serve as a potential therapeutic target.

Identification and analysis of KLF13 variants in patients with congenital heart disease.

BACKGROUND: The protein Kruppel-like factor 13 (KLF13) is a member of the KLF family and has been identified as a cardiac transcription factor that is involved in heart development. However, the relationship between KLF13 variants and CHDs in humans remains largely unknown. The present study aimed to screen the KLF13 variants in CHD patients and genetically analyze the functions of these variants. METHODS: KLF13 variants were sequenced in a cohort of 309 CHD patients and population-matched healthy controls (n = 200) using targeted sequencing. To investigate the effect of variants on the functional properties of the KLF13 protein, the expression and subcellular localization of the protein, as well as the transcriptional activities of downstream genes and physical interactions with other transcription factors, were assessed. RESULTS: Two heterozygous variants, c.487C > T (P163S) and c.467G > A (S156N), were identified in two out of 309 CHD patients with tricuspid valve atresia and transposition of the great arteries, respectively. No variants were found among healthy controls. The variant c.467G > A (S156N) had increased protein expression and enhanced functionality compared with the wild type, without affecting the subcellular localization. The other variant, c.487C > T (P163S), did not show any abnormalities in protein expression or subcellular localization; however, it inhibited the transcriptional activities of downstream target genes and physically interacted with TBX5, another cardiac transcription factor. CONCLUSION: Our results show that the S156N and P163S variants may affect the transcriptional function of KLF13 and physical interaction with TBX5. These results identified KLF13 as a potential genetic risk factor for congenital heart disease.

Potential probiotic characterization of Lactobacillus reuteri from traditional Chinese highland barley wine and application for room-temperature-storage drinkable yogurt.

The aim of this study was to select probiotic strains that could be used in drinkable yogurt to yield viable cells following storage at room temperature (RT). The uniquely high altitude conditions in Tibet and the alcoholic environment of certain products, such as the highland barley wine homemade in Tibet, may induce unusual characteristics of microbial strains. A total of 27 lactic acid bacteria were isolated from homemade highland barley wines. One strain, Lactobacillus reuteri WHH1689, demonstrated no ability for lactose utilization, exhibited a high survival rate during storage at RT in drinkable yogurts, and produced very weak post-acidification. This strain showed great resistance to conditions simulating the gastrointestinal tract, including strong adherence to HT-29 cells and inhibitory activity against Escherichia coli, Shigella flexneri, Salmonella paratyphi ß, and Staphylococcus aureus. A dextran sulfate sodium (DSS)-induced mouse model was used to evaluate the in vivo influence of Lb. reuteri WHH1689 on the intestinal flora and showed that strain WHH1689 increased viable counts of bifidobacteria in feces of mice. The probiotic strain selected in this study-with its high survival at RT and lack of serious post-acidification problems-may provide significant improvements for dairy industry products by extending the storage time of dairy products with living cells.

Pharmaceutical Analysis in the Plant Endomembrane System.

Vesicle trafficking is an essential cellular process conserved in eukaryotes to precisely transport proteins to their destinations. The plant endomembrane system plays a pivotal role in orchestrating this vesicle-mediated protein transport process, making its study essential for a comprehensive understanding of plant growth and development. Pharmaceutical analysis proves highly useful in investigating the plant endomembrane system. To facilitate further studies in this area, we present a summary of several commonly used chemical inhibitors in this chapter, providing a practical resource for researchers interested in the plant endomembrane system.

Engineering Spin Polarization of the Surface-Adsorbed Fe Atom by Intercalating a Transition Metal Atom into the MoS2 Bilayer for Enhanced Nitrogen Reduction.

The precise control of spin states in transition metal (TM)-based single-atom catalysts (SACs) is crucial for advancing the functionality of electrocatalysts, yet it presents significant scientific challenges. Using density functional theory (DFT) calculations, we propose a novel mechanism to precisely modulate the spin state of the surface-adsorbed Fe atom on the MoS2 bilayer. This is achieved by strategically intercalating a TM atom into the interlayer space of the MoS2 bilayer. Our results show that these strategically intercalated TM atoms can induce a substantial interfacial charge polarization, thereby effectively controlling the charge transfer and spin polarization on the surface Fe site. In particular, by varying the identity of the intercalated TM atoms and their vacancy filling site, a continuous modulation of the spin states of the surface Fe site from low to medium to high can be achieved, which can be accurately described using descriptors composed of readily accessible intrinsic properties of materials. Using the electrochemical dinitrogen reduction reaction (eNRR) as a prototypical reaction, we discovered a universal volcano-like relation between the tuned spin and the catalytic activity of Fe-based SACs. This finding contrasts with the linear scaling relationships commonly seen in traditional studies and offers a robust new approach to modulating the activity of SACs through interfacial engineering.

Biodegradation of humic acids by Streptomyces rochei to promote the growth and yield of corn.

Humic acids (HAs) are organic macromolecules that play an important role in improving soil properties, plant growth and agronomic parameters. However, the feature of relatively complex aromatic structure makes it difficult to be degraded, which restricts the promotion to the crop growth. Thus, exploring microorganisms capable of degrading HAs may be a potential solution. Here, a HAs-degrading strain, Streptomyces rochei L1, and its potential for biodegradation was studied by genomics, transcriptomics, and targeted metabolomics analytical approaches. The results showed that the high molecular weight HAs were cleaved to low molecular aliphatic and aromatic compounds and their derivatives. This cleavage may be associated with the laccase (KatE). In addition, the polysaccharide deacetylase (PdgA) catalyzes the removal of acetyl groups from specific sites on the HAs molecule, resulting in structural changes. The field experiment showed that the degraded HAs significantly promote the growth of corn seedlings and increase the corn yield by 3.6 %. The HAs-degrading products, including aromatic and low molecular weight aliphatic substances as well as secondary metabolites from S. rochei L1, might be the key components responsible for the corn promotion. Our findings will advance the application of HAs as soil nutrients for the green and sustainable agriculture.

Direct optical imaging of graphene in vitro by nonlinear femtosecond laser spectral reshaping.

Nonlinear optical microscopy, based on femtosecond laser spectral reshaping, characterized and imaged graphene samples made from different methods, both on slides and in a biological environment. This technique clearly discriminates between graphene flakes with different numbers of layers and reveals the distinct nonlinear optical properties of reduced graphene oxide as compared to mechanically exfoliated or chemical vapor deposition grown graphene. The nonlinearity makes it applicable to scattering samples (such as tissue) as opposed to previous methods, such as transmission. This was demonstrated by high-resolution imaging of breast cancer cells incubated with graphene flakes.

Streptococcus thermophilus JM905-Strain Carbon Source Utilization and Its Fermented Milk Metabolic Profile at Different Fermentation Stages.

The metabolic utilization of different carbon sources by Streptococcus thermophilus JM905(S. thermophilus JM905) was determined using a high-throughput microbial phenotyping system, and changes in fermentation characteristics of S. thermophilus JM905 fermented milk were investigated at different fermentation periods, with changes in pH, water-holding capacity, viscosity, nuisance odor, and viable bacteria count being used to define the fermentation characteristics of the strain. Changes in the key metabolites, 2-hydroxybutyric acid, folic acid, L-lactic acid, D-glycerol-D-galactose-heptanol, (R)-leucine, L-aspartic acid, L-proline, D-arginine, L-isoleucine, hydra starch, L-lysine, L-tryptophan, and D-galactose, were clarified. Correspondingly, the fermented milk protein, amino acid, and fermented milk fat quality nutrient contents were determined to be 3.78 ± 0.054 g per 100 g, 3.405 ± 0.0234 g per 100 mL, and 0.161 ± 0.0030 g per 100 g, respectively. This study addressed strain carbon source utilization, changes in fermentation characteristics and metabolites during fermentation, with the aim of investigating the link between fermentation characteristics and metabolite quality components of Streptococcus thermophilus JM905 and its fermented milk with fermentation potential and to provide a useful reference for the screening of superior fermentation strains.

NPLOC4 is a potential target and a poor prognostic signature in lung squamous cell carcinoma.

Few prognostic biomarkers exist for lung squamous cell carcinoma (LUSC), which has a poor five-year survival rate. Using bioinformatics, this study evaluated NPLOC4 as a prognostic marker for patients with lung squamous cell carcinoma. Shorter survival periods and tumor growth were linked to high NPLOC4 expression.Disulfiram (DSF) combined with copper (Cu) targets NPLOC4 to achieve antitumor effects in lung squamous cell carcinoma. Thus, we investigated the effects of DSF with Cu in LUSC. Gene-set enrichment analysis identified ubiquitin-mediated proteolysis as the NPLOC4-associated mechanism influencing LUSC prognosis. In SK-MES-1 cell lines, DSF + Cu increased K48-linked ubiquitinated protein expression and apoptosis. This study identified NPLOC4 as a prognostic biomarker and a potential therapeutic target for LUSC.

Multicontrast nonlinear optical microscopy with a compact and rapid pulse shaper.

Homodyne detection can dramatically enhance measurement sensitivity for weak signals. In nonlinear optical microscopy it can make accessible a range of novel, intrinsic, contrast like nonlinear absorption and nonlinear phase contrast. Here a compact and rapid pulse shaper is developed, implemented, and demonstrated for homodyne detection in nonlinear microscopy with high-repetition rate mode-locked femtosecond lasers. With this method we generate two-photon absorption (TPA) and self-phase modulation images of gold nanostars in biological samples. Simultaneous imaging of two-photon luminescence and TPA also enables us to produce two-photon quantum yield images.

Cross-phase modulation imaging.

We demonstrate a cross-phase modulation measurement technique based on the sensitive detection of modulation transfer in a pump-probe setup. By modulating the amplitude of the pump beam and spectrally analyzing the probe beam, we achieve a rapid, background-free measurement of nonlinear phase modulation using power levels acceptable in biological imaging. This measurement technique would allow the extension of widely employed phase microscopy methods to the nonlinear regime, providing intrinsic and universal nonlinear contrast for biological imaging.

Disulfiram/copper induces antitumor activity against gastric cancer cells in vitro and in vivo by inhibiting S6K1 and c-Myc.

PURPOSE: Disulfiram (DSF) is an approved drug for the treatment of alcohol dependence. Accumulating evidence indicates that DSF, alone or in combination with copper (Cu), possesses strong antitumor activity in various malignancies. This study investigated the effects of DSF on gastric cancer (GC) and the potential mechanisms involved. METHODS: GC cell proliferation and apoptosis upon treatment with DSF with or without copper were analyzed using CCK-8 assay, colony formation assay, and flow cytometry. Glucose metabolism was investigated using glucose consumption and lactate production assays. The expression of caspase-3, Bcl-2, LC-3, P62, S6K1, c-Myc, GLUT1, PKM2, and LDHA was analyzed using western blot assay. In vivo nude mice studies were performed to verify the findings from in vitro analyses. RESULTS: Our study showed that DSF was highly toxic to GC cells in a Cu-dependent manner. Nontoxic concentrations of Cu enhanced the inhibitory effects of DSF on cell viability and colony formation. DSF also induced apoptotic and autophagic cell death in the presence of Cu. In addition, DSF/Cu inhibited glycolysis and xenograft growth of GC cells by suppressing the expression of S6K1, c-Myc, and their downstream molecules, including GLUT1, PKM2, and LDHA. CONCLUSION: Our study demonstrated that DSF/Cu exerted antitumor activity against GC cells both in vitro and in vivo. DSF/Cu may represent a promising therapeutic strategy for the treatment of GC.