18F-FDG PET/CT Radiomics-Based Multimodality Fusion Model for Preoperative Individualized Noninvasive Prediction of Peritoneal Metastasis in Advanced Gastric Cancer.

PURPOSE: This study was designed to develop and validate a machine learning-based, multimodality fusion (MMF) model using 18F-fluorodeoxyglucose (FDG) PET/CT radiomics and kernelled support tensor machine (KSTM), integrated with clinical factors and nuclear medicine experts' diagnoses to individually predict peritoneal metastasis (PM) in advanced gastric cancer (AGC). METHODS: A total of 167 patients receiving preoperative PET/CT and subsequent surgery were included between November 2006 and September 2020 and were divided into a training and testing cohort. The PM status was confirmed via laparoscopic exploration and postoperative pathology. The PET/CT signatures were constructed by classic radiomic, handcrafted-feature-based model and KSTM self-learning-based model. The clinical nomogram was constructed by independent risk factors for PM. Lastly, the PET/CT signatures, clinical nomogram, and experts' diagnoses were fused using evidential reasoning to establish the MMF model. RESULTS: The MMF model showed excellent performance in both cohorts (area under the curve [AUC] 94.16% and 90.84% in training and testing), and demonstrated better prediction accuracy than clinical nomogram or experts' diagnoses (net reclassification improvement p < 0.05). The MMF model also had satisfactory generalization ability, even in mucinous adenocarcinoma and signet ring cell carcinoma which have poor uptake of 18F-FDG (AUC 97.98% and 89.71% in training and testing). CONCLUSIONS: The 18F-FDG PET/CT radiomics-based MMF model may have significant clinical implications in predicting PM in AGC, revealing that it is necessary to combine the information from different modalities for comprehensive prediction of PM.

SCD1 promotes the stemness of gastric cancer stem cells by inhibiting ferroptosis through the SQLE/cholesterol/mTOR signalling pathway.

Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.

Variability in soybean yield responses to elevated atmospheric CO2: Insights from non-structural carbohydrate remobilisation during seed filling.

The increasing atmospheric CO2 concentration (e[CO2]) has mixed effects on soybean most varieties' yield. This study elucidated the effect of e[CO2] on soybean yield and the underlying mechanisms related to photosynthetic capacity, non-structural carbohydrate (NSC) accumulation, and remobilisation. Four soybean cultivars were cultivated in open-top chambers at two CO2 levels. Photosynthesis rates were determined from R2 to R6. Plants were sampled at R5 and R8 to determine carbohydrate concentrations. There were significant variations in yield responses among the soybean cultivars under e[CO2], from no change in DS1 to a 22% increase in SN14. DS1 and SN14 had the smallest and largest increase, respectively, in daily carbon assimilation capacity. Under e[CO2], DS1, MF5, and XHJ had an increase in Ci, at which point the transition from Rubisco-limited to ribulose-1,5-bisphosphate regeneration-limited photosynthesis occurred, in contrast with SN14. Thus, the cultivars might have distinct mechanisms that enhance photosynthesis under e[CO2] conditions. A positive correlation was between daily carbon assimilation response to e[CO2] and soybean yield, emphasising the importance of enhanced photosynthate accumulation before the R5 stage in determining yield response to e[CO2]. E[CO2] significantly influenced NSC accumulation in vegetative organs at R5, with variation among cultivars. There was enhanced NSC remobilisation during seed filling, indicating cultivar-specific responses to the remobilisation of sucrose and soluble sugars, excluding sucrose and starch. A positive correlation was between leaf and stem NSC remobilisation and yield response to e[CO2], emphasising the role of genetic differences in carbohydrate remobilisation mechanisms in determining soybean yield variation under elevated CO2 levels.

Effects of residual foaming agent and defoamer on defoaming-flocculation-filterpress characteristics of earth pressure balance shield muck.

Foaming agents as a combination of several components are usually used as soil conditioning during earth pressure balance shield (EPBS) tunnelling. These residues in waste EPBS muck lead to a series of new challenges for in-situ recycling, i.e., foams overflow flocculation tank. This study investigates the effects of residual foaming agent components and defoamers on defoaming-flocculation-filterpress characteristics of EPBS muck using an improved flocculation and filterpress system. Residual foam height (Hf), defoaming ratio (DFR), antifoaming ratio (AFR), total suspended substance (TSS), turbidity, moisture content (MC), and zeta potential (ZP) were selected as characterization indices. The microstructure of filterpress cakes was analyzed using a scanning electron microscope. Results demonstrate that an enhancement within 0.0-1.0wt.% for sodium fatty alcohol polyoxyethylene ether sulfate (AES) and alpha olefin sulfonate (AOS) significantly reduces DFR and AFR. The MC and ZP decline, while the Hf and turbidity enhance. The combinations of nonionic surfactants alkyl polyglycoside (APG) and fatty alcohol-polyoxyethylene ether (AEO) in a concentration range of 0.0-1.0wt.% with 0.2wt.% AES causes the Hf, DFR, AFR, turbidity, and ZP to exhibit absolutely different variations. The MC with the growth in both APG and AEO presents a trend of first decreasing and then increasing. By increasing foam stabilizers sodium carboxymethyl cellulose (CMC) and guar gum (GG) within 0.02-0.10wt.%, the AFR, TSS, and ZP enhance in varying degrees, while the Hf, DFR, and MC gradually reduce. With the increase of defoamers hydroxyl silicone oil-glycerol polyoxypropylene ether (H-G) and dimethyl silicone oil-glycerol polyoxypropylene ether (D-G) within 0.002-0.010wt.%, the DFR and AFR are significantly improved, while the TSS, turbidity, MC, and ZP display varying degrees of reduction. Moreover, defoaming-flocculation-filterpress mechanisms of EPBS muck are explored to provide a useful reference for actual in-situ recycling projects.

Survey of Heterodera glycines population abundance and virulence phenotypes during 2021-2022 in Heilongjiang Province.

Soybean cyst nematode (SCN), Heterodera glycines, poses a significant threat to global soybean production. Heilongjiang, the largest soybean-producing province in China, contributes over 40% to the country's total yield. This province has much longer history of SCN infestation. To assess the current situation in Heilongjiang, we conducted a survey to determine the SCN population density and virulence phenotypes during 2021-2022 and compared the data with a previous study in 2015. A total of 377 soil samples from 48 counties representing eleven major soybean-planting regions were collected. The prevalence of SCN increased from 55.4% in 2015 to 59% in the current survey. The population densities ranged from 80 to 26,700 eggs and juveniles per 100 cm3 of soil. Virulence phenotypes were evaluated for 60 representative SCN populations using the HG type test, revealing nine different HG types. The most common virulence phenotypes were HG types 7 and 0, accounting for 56.7% and 20% of all SCN populations, respectively. The prevalence of populations with a reproductive index (FI) greater than 10% on PI548316 increased from 64.5% in 2015 to 71.7%. However, the FI on the commonly used resistance sources PI 548402 (Peking) and PI 437654 remained low at 3.3%. These findings highlight the increasing prevalence and changing virulence phenotypes of SCN in Heilongjiang. They also emphasize the importance of rotating soybean varieties with different resistance sources and urgently identifying new sources of resistance to combat SCN.

Data-Driven Design of Triple-Targeted Protein Nanoprobes for Multiplexed Imaging of Cancer Lymphatic Metastasis.

Targeted imaging of cancer lymphatic metastasis remains challenging due to its highly heterogeneous molecular and phenotypic diversity. Herein, triple-targeted protein nanoprobes capable of specifically binding to three targets for imaging cancer lymphatic metastasis, through a data-driven design approach combined with a synthetic biology-based assembly strategy, are introduced. Specifically, to address the diversity of metastatic lymph nodes (LNs), a combination of three targets, including C-X-C motif chemokine receptor 4 (CXCR4), transferrin receptor protein 1 (TfR1), and vascular endothelial growth factor receptor 3 (VEGFR3) is identified, leveraging machine leaning-based bioinformatics analysis and examination of LN tissues from patients with gastric cancer. Using this identified target combination, ferritin nanocage-based nanoprobes capable of specifically binding to all three targets are designed through the self-assembly of genetically engineered ferritin subunits using a synthetic biology approach. Using these nanoprobes, multiplexed imaging of heterogeneous metastatic LNs is successfully achieved in a polyclonal lymphatic metastasis animal model. In 19 freshly resected human gastric specimens, the signal from the triple-targeted nanoprobes significantly differentiates metastatic LNs from benign LNs. This study not only provides an effective nanoprobe for imaging highly heterogeneous lymphatic metastasis but also proposes a potential strategy for guiding the design of targeted nanomedicines for cancer lymphatic metastasis.

NIR Absorbing Organic Chromophores Combination with NSAIDs for Remodeling of the Inflammatory Microenvironment to Amplify Tumor Ferroptosis-Photothermal Synergistic Therapy.

Photothermal therapy has emerged as a promising approach for cancer treatment, which can cause ferroptosis to enhance immunotherapeutic efficacy. However, excessively generated immunogenicity will induce serious inflammatory response syndrome, resulting in a discounted therapeutic effect. Herein, a kind of NIR absorption small organic chromophore nanoparticles (TTHM NPs) with high photothermal conversion efficiency (68.33%) is developed, which can induce mitochondria dysfunction, generate mitochondrial superoxide, and following ferroptosis. TTHM NPs-based photothermal therapy is combined with Sulfasalazine (SUZ), a kind of nonsteroidal anti-inflammatory drugs, to weaken inflammation and promote ferroptosis through suppressing glutamate/cystine (Glu/Cys) antiporter system Xc- (xCT). Additionally, the combination of SUZ with PTT can induce immunogenic cell death (ICD), followed by promoting the maturation of DCs and the attraction of CD8+ T cell, which will secrete IFN-γ and trigger self-amplified ferroptosis via inhibiting xCT and simulating Acyl-CoA synthetase long-chain family member 4 (ACSL4). Moreover, the in vivo results demonstrate that this combination therapy can suppress the expression of inflammatory factors, enhance dendritic cell activation, facilitate T-cell infiltration, and realize effective thermal elimination of primary tumors and distant tumors. In general, this work provides an excellent example of combined medication and stimulates new thinking about onco-therapy and inflammatory response.

FPR3 reprograms glycolytic metabolism and stemness in gastric cancer via calcium-NFATc1 pathway.

Aerobic glycolysis accelerates tumor proliferation and progression, and inhibitors or drugs targeting abnormal cancer metabolism have been developing. Cancer stem-like cells (CSCs) significantly contribute to tumor initiation, metastasis, therapy resistance, and recurrence. Formyl peptide receptor 3 (FPR3), a member of FPR family, involves in inflammation, tissue repair, and angiogenesis. However, studies in exploring the regulatory mechanisms of aerobic glycolysis and CSCs by FPR3 in gastric cancer (GC) remain unknown. Here, we demonstrated that overexpressed FPR3 suppressed glycolytic capacity and stemness of tumor cells, then inhibited GC cells proliferation. Mechanistically, FPR3 impeded cytoplasmic calcium ion flux and hindered nuclear factor of activated T cells 1 (NFATc1) nuclear translocation, leading to the transcriptional inactivation of NFATc1-binding neurogenic locus notch homolog protein 3 (NOTCH3) promoter, subsequently obstructing NOTCH3 expression and the AKT/mTORC1 signaling pathway, and ultimately downregulating glycolysis. Additionally, NFATc1 directly binds to the sex determining region Y-box 2 (SOX2) promoter and modifies stemness in GC. In conclusion, our work illustrated that FPR3 played a negative role in GC progression by modulating NFATc1-mediated glycolysis and stemness in a calcium-dependent manner, providing potential insights into cancer therapy.

Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer.

Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

Classification of superficial suspected lymph nodes: non-invasive radiomic model based on multiphase contrast-enhanced ultrasound for therapeutic options of lymphadenopathy.

Background: Accurate determination of the types of lymphadenopathy is of great importance in disease diagnosis and treatment and is usually confirmed by pathological findings. Radiomics is a non-invasive tool that can extract quantitative information from medical images. Our study was designed to develop a non-invasive radiomic approach based on multiphase contrast-enhanced ultrasound (CEUS) images for the classification of different types of lymphadenopathy. Methods: A total of 426 patients with superficial suspected lymph nodes (LNs) from three centres were grouped into a training cohort (n=190), an internal testing cohort (n=127), and an external testing cohort (n=109). The radiomic features were extracted from the prevascular phase, vascular phase, and postvascular phase of the CEUS images. Model 1 (the conventional feature model), model 2 (the multiphase radiomics model), and model 3 (the combined feature model) were established for lymphadenopathy classification. The area under the curve (AUC) and confusion matrix were used to evaluate the performance of the three models. The usefulness of the models was assessed in different threshold probabilities by decision curve analysis. Results: There were 139 patients (32.6%) with benign LNs, 110 patients (25.8%) with lymphoma, and 177 patients (41.5%) with metastatic LNs in our population. Finally, twenty features were selected to construct the radiomics models for these three types of lymphadenopathy. Model 2 integrating multiphase images of the CEUS yielded the AUCs of 0.838, 0.739, and 0.733 in the training cohort, internal testing cohort, and external testing cohort, respectively. After the combination of conventional features and radiomic features, the AUCs of model 3 improved to 0.943, 0.823 and 0.785 in the training cohort, internal testing cohort, and external testing cohort. Besides, model 3 had an accuracy of 81.05%, sensitivity of 80%, and specificity of 90.43% in the training cohort. Model performance was further confirmed in the internal testing cohort and external testing cohort. Conclusions: We constructed a combined feature model using a series of CEUS images for the classification of the lymphadenopathies. For patients with superficial suspected LNs, this model can help clinicians make a decision on the LN type noninvasively and choose appropriate treatments.

Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer with intraoperative detection of limited peritoneal metastasis: a Phase II study of CLASS-05 trial.

Background: Systemic chemotherapy for gastric cancer with peritoneal metastasis has limited clinical benefit; for those with intraoperative detection of occult peritoneal metastasis, cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is an alternative treatment. However, the feasibility and effects of this modality and criteria for selecting suitable groups remain unclear. This study aimed to explore the safety and efficacy of laparoscopic cytoreductive surgery (L-CRS) followed by HIPEC in gastric cancer with limited peritoneal metastasis, and this study also aimed to determine the optimized cut-off of the peritoneal cancer index. Methods: Between March 2017 and November 2019, patients diagnosed with gastric cancer peritoneal metastases by using laparoscopy and the Sugarbaker peritoneal cancer index of ≤12 were eligible for inclusion. All patients received L-CRS (including gastrectomy with D2 lymph node dissection) and resection of visible peritoneal metastasis, followed by post-operative HIPEC, and systemic chemotherapy. The primary end points were median progression-free survival and median survival time, and the secondary outcomes were morbidity and mortality within 30 days after surgery. Results: Thirty patients were eligible for analysis, of whom 19 (63.3%) were female, and the overall mean age was 53.0 years. The post-operative morbidity was 20% and the severe complication rate was 10%. The median survival time was 27.0 months with a 2-year overall survival rate of 52.3% and median progression-free survival was 14.0 months with a 2-year progression-free survival of 30.4%. Conclusions: L-CRS followed by HIPEC can be safely performed for gastric cancer with limited peritoneal metastasis and potential survival benefits.

Deep learning-based radiomics model can predict extranodal soft tissue metastasis in gastric cancer.

BACKGROUND: The potential prognostic value of extranodal soft tissue metastasis (ESTM) has been confirmed by increasing studies about gastric cancer (GC). However, the gold standard of ESTM is determined by pathologic examination after surgery, and there are no preoperative methods for assessment of ESTM yet. PURPOSE: This multicenter study aimed to develop a deep learning-based radiomics model to preoperatively identify ESTM and evaluate its prognostic value. METHODS: A total of 959 GC patients were enrolled from two centers and split into a training cohort (N = 551) and a test cohort (N = 236) for ESTM evaluation. Additionally, an external survival cohort (N = 172) was included for prognostic analysis. Four models were established based on clinical characteristics and multiphase computed tomography (CT) images for preoperative identification of ESTM, including a deep learning model, a hand-crafted radiomic model, a clinical model, and a combined model. C-index, decision curve, and calibration curve were utilized to assess the model performances. Survival analysis was conducted to explore the ability of stratifying overall survival (OS). RESULTS: The combined model showed good discrimination of the ESTM [C-indices (95% confidence interval, CI): 0.770 (0.729-0.812) and 0.761 (0.718-0.805) in training and test cohorts respectively], which outperformed deep learning model, radiomics model, and clinical model. The stratified analysis showed this model was not affected by patient's tumor size, the presence of lymphovascular invasion, and Lauren classification (p < 0.05). Moreover, the model score showed strong consistency with the OS [C-indices (95%CI): 0.723 (0.658-0.789, p < 0.0001) in the internal survival cohort and 0.715 (0.650-0.779, p < 0.0001) in the external survival cohort]. More interestingly, univariate analysis showed the model score was significantly associated with occult distant metastasis (p < 0.05) that was missed by preoperative diagnosis. CONCLUSIONS: The model combining CT images and clinical characteristics had an impressive predictive ability of both ESTM and prognosis, which has the potential to serve as an effective complement to the preoperative TNM staging system.

Impact of preoperative therapy on surgical outcomes of laparoscopic total gastrectomy for gastric/gastroesophageal junction cancer.

Objective: As laparoscopic surgery is widely applied for primarily treated gastric cancer (GC)/gastroesophageal junction cancer (GEJC) and gains many advantages, the feasibility of laparoscopic total gastrectomy (LTG) for GC/GEJC patients who have received preoperative therapy (PT) has come to the fore. This study aims to analyze the safety and feasibility of LTG after PT for GC/GEJC patients. Methods: We retrospectively analyzed the data of 511 patients with GC/GEJC undergoing LTG, of which 405 received LTG (LTG group) and 106 received PT+LTG (PT-LTG group) at Nanfang Hospital between June 2018 and September 2022. The surgical outcomes were compared between the two groups. Results: The surgical duration was significantly longer in the PT-LTG group (P<0.001), while the incidence of intraoperative complications (P=1.000), postoperative complications (LTG group vs. PT-LTG group: 26.2% vs. 23.6%, P=0.587), the classification of complication severity (P=0.271), and postoperative recovery was similar between two groups. Notably, the incidence of anastomotic complications of esophagojejunostomy was also comparable between the two groups (LTG group vs. PT-LTG group: 5.9% vs. 5.7%, P=0.918). The univariate and multivariate analysis confirmed that positive proximal margin [positive vs. negative: odds ratio (OR)=14.094, 95% confidence interval (95% CI): 2.639-75.260, P=0.002], rather than PT, has an impact on anastomotic complications after LTG (OR=0.945, 95% CI: 0.371-2.408, P=0.905). Conclusions: PT did not increase the surgical risk of LTG for GC/GEJC. Therefore, considering the positive effect of PT on long-term survival, the broader application of PT and LTG for GC/GEJC is supported by our findings.

Identification of cytochrome P450 gene family and functional analysis of HgCYP33E1 from Heterodera glycines.

The cytochrome P450 (CYP) genes of nematode play a crucial role in the metabolic detoxification of xenobiotics including pesticides. Heterodera glycines, also known as the soybean cyst nematode, is a sedentary endoparasite that infests plant roots, causing high annual economic losses in soybean production regions globally. In this study, we identified 36 CYP genes at a genome-wide level of the H. glycines isolate TN10 using all CYPs from Caenorhabditis elegans as queries. Subsequently, a full-length cDNA of HgCYP33E1 which was significantly up-regulated by the conventional nematicide abamectin was initially cloned from H. glycines. It presented significantly higher expressions in the second-stage juvenile (J2) compared to other parasitic stages of H. glycines. qRT-PCR analysis suggested that the expression of HgCYP33E1 was also xenobiotically induced by soybean root exudate and the metabolites of biocontrol agents. Using RNA interference (RNAi), we investigated the function of HgCYP33E1 in H. glycines parasitism and nematicide selectivity. Compared to the control and dsGFP-treated group, silencing of HgCYP33E1 did not affect the J2 behaviors and the early invasion ability, while it decreased the number of J4s in soybean roots after 18-d inoculation with the dsHgCYP33E1-treated nematodes. In addition, knockdown of HgCYP33E1 in H. glycines resulted in an increase in J2 mortality after 24-h incubation with abamectin compared to the GFP dsRNA-soaked and the control group. These findings revealed the potential role of HgCYP33E1 in the xenobiotic detoxification pathway of H. glycines. Moreover, our data also provided valuable gene information for studying the functions of the CYP family in H. glycines host adaption.

Clinical outcomes of conversion surgery following immune checkpoint inhibitors and chemotherapy in stage IV gastric cancer.

BACKGROUND: The clinical benefit of conversion surgery following immunochemotherapy in patients with stage IV gastric cancer (GC) remains uncertain. This study aims to clarify the clinical outcomes of conversion surgery for such patients. METHODS: This retrospective cohort study enroled consecutive patients with stage IV GC treated with a combination of immune checkpoint inhibitors and chemotherapy and/or anti-human epidermal growth factor receptor-2 targeted therapy as first-line therapy. Cumulative survival curves were estimated using Kaplan-Meier method. Logistic regression and Cox regression analyses were conducted to identify factors associated with conversion surgery and survival, respectively. RESULTS: Among the 136 patients included in the study. The disease control rate was 72.1% (98/136), with objective response rate in 58.8% (80/136) and complete response rate in 5.9% (8/136). Among 98 patients with disease control, 56 patients underwent palliative immunochemotherapy with median progression-free survival (PFS) and overall survival at 9.2 and 16.2 months, respectively; the remaining 42 patients underwent conversion surgery, yielding an unreached median PFS over a 19.0-month median follow-up, accompanied by 1-year overall survival and PFS rates of 96.6% and 89.1%, respectively. The R0 resection rate reached 90.5% (38/42). 7 out of 42 patients achieved pathological complete response, of whom three patients demonstrated human epidermal growth factor receptor-2 positivity. No serious complications leading to death were observed during the perioperative period. Multivariate analysis indicated that programmed death ligand 1 combined positive score greater than or equal to 5 (odds ratio, 0.22; 95% CI, 0.08-0.57; P =0.002) favored successful conversion surgery, while signet ring cell carcinoma (hazard ratio, 6.29; 95% CI, 1.56-25.36; P =0.010) was the poor prognostic factor associated with survival in patients who underwent conversion surgery. CONCLUSIONS: Conversion surgery holds the potential for significant survival benefits in stage IV GC patients who have achieved a favourable clinical response to immunochemotherapy. Individuals with signet ring cell carcinoma may experience increased post-conversion surgery recurrence.

Research Advances in the Plant-Nematode Interaction.

Nematodes, which are highly important and abundant animals in the animal kingdom, demonstrate remarkable adaptability to various environments [...].

HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFß1.

Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFß1 expression and activates the TGFß1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

Persulfidation maintains cytosolic G6PDs activity through changing tetrameric structure and competing cysteine sulfur oxidation under salt stress in Arabidopsis and tomato.

Glucose-6-phosphate dehydrogenases (G6PDs) are essential regulators of cellular redox. Hydrogen sulfide (H2 S) is a small gasotransmitter that improves plant adaptation to stress; however, its role in regulating G6PD oligomerization to resist oxidative stress remains unknown in plants. Persulfidation of cytosolic G6PDs was analyzed by mass spectrometry (MS). The structural change model of AtG6PD6 homooligomer was built by chemical cross-linking coupled with mass spectrometry (CXMS). We isolated AtG6PD6C159A and SlG6PDCC155A transgenic lines to confirm the in vivo function of persulfidated sites with the g6pd5,6 background. Persulfidation occurs at Arabidopsis G6PD6 Cystine (Cys)159 and tomato G6PDC Cys155, leading to alterations of spatial distance between lysine (K)491-K475 from 42.0 Å to 10.3 Å within the G6PD tetramer. The structural alteration occurs in the structural NADP+ binding domain, which governs the stability of G6PD homooligomer. Persulfidation enhances G6PD oligomerization, thereby increasing substrate affinity. Under high salt stress, cytosolic G6PDs activity was inhibited due to oxidative modifications. Persulfidation protects these specific sites and prevents oxidative damage. In summary, H2 S-mediated persulfidation promotes cytosolic G6PD activity by altering homotetrameric structure. The cytosolic G6PD adaptive regulation with two kinds of protein modifications at the atomic and molecular levels is critical for the cellular stress response.