The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicenter Real-world clinical study.

BACKGROUND: The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. METHODS: Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analysed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. RESULTS: After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% versus [vs.] 59.0%; P<0.001), pathological complete response rate (14.36% vs. 6.41%; P=0.002) and major pathological response rate (39.49% vs. 26.15%; P=0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P=0.694) and proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P=0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P=0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence (odds ratio 0.62 [95% CI 0.41-0.92]; P=0.018). No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P=0.143). CONCLUSIONS: Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates, and reduced the risk for early recurrence among patients with LAGC. TRIAL REGISTRATION: Clinical Trials.gov.

Development and Validation of a Prognostic Model for Postoperative Anastomotic Recurrence in Siewert II or III Adenocarcinomas Without Neoadjuvant Therapy in an East Asian Population.

PURPOSE: Anastomotic recurrence leads to poor prognosis in patients with Siewert II or III adenocarcinoma who undergo radical gastrectomy and do not receive neoadjuvant therapy. We aimed to establish a prognostic model to evaluate the risk of postoperative anastomotic recurrence in patients with Siewert II or III adenocarcinoma who did not receive neoadjuvant therapy. METHODS: We included 366 patients with Siewert II or III adenocarcinoma who were treated with radical gastrectomy without neoadjuvant therapy at Fujian Provincial Hospital (FPH) between 2012 and 2018 as the development cohort. Cox regression was used to verify prognostic factors for anastomotic recurrence, and a nomogram was established. The nomogram was externally validated using a combined cohort of two external centers. Patients were classified into high- or low-risk groups according to the diagnostic threshold and nomogram scores, and recurrence-related survival analysis was analyzed. RESULTS: The average age was 64.6 years, and 285 patients were male. All surgeries were successfully performed (185 open vs 181 laparoscopic). The 3-year anastomotic recurrence rate was significantly lower in the low-risk group (3.5% vs 18.8%, P < 0.001). The predictive performance was verified in the external validation cohort. This model better stratified patient survival than the American Joint Committee on Cancer (AJCC) TNM staging system. CONCLUSIONS: This novel nomogram with surgical margin, postoperative tumor node metastasis (pTNM) stage, and neural invasion as prognostic factors has a significant predictive performance for the risk of anastomotic recurrence after radical gastrectomy in patients with Siewert II or III adenocarcinoma.

Discovery of N-(phenylsulfonyl)thiazole-2-carboxamides as potent α-glucosidase inhibitors.

In a search for novel nonsugar α-glucosidase inhibitors for diabetes treatment, a series of N-(phenylsulfonyl)thiazole-2-carboxamide derivatives were designed and synthesized, the α-glucosidase inhibitory activities were then evaluated. Several compounds with promising α-glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α-glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 µM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 µM). W24 was identified as a promising candidate in the development of α-glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α-glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol.

Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) is well-known to cause biofilm-associated drug resistance and infections that often lead to treatment failure. Herein, we reported a dual-acting antibiofilm strategy by inhibiting both the bacterial quorum sensing system and the iron uptake system. A series of coumarin derivatives were synthesized and evaluated, and compound 4t was identified as the most effective biofilm inhibitor (IC50 = 3.6 µM). Further mechanistic studies have confirmed that 4t not only inhibits the QS systems but also competes strongly with pyoverdine as an iron chelator, causing an iron deficiency in P. aeruginosa. Additionally, 4t significantly improved the synergistic antibacterial effects of ciprofloxacin and tobramycin by more than 200-1000-fold compared to the single-dose antibiotic treatments. Therefore, our study has shown that 4t is a potentially novel antibacterial synergist candidate to treat bacterial infections.

Discovery of CDK signature and CDK5 as potential biomarkers for predicting prognosis and immunotherapeutic response in gastric cancer peritoneal metastases.

Gastric cancer peritoneal metastases (GCPM) are a leading cause of death in gastric cancer patients. In this study, we focused on the expression of cyclin-dependent protein kinases (CDK), essential regulators of transcription, metabolism, and cell differentiation, in GCPM. Utilizing the GSE62254 cohort, we established a CDK signature (CDKS) model comprising ten CDK gene family members. Analysis of both the GSE62254 and TCGA cohorts revealed that patients with low CDKS had a worse prognosis compared to those with high CDKS. Furthermore, patients with high CDKS demonstrated positive responses from immunotherapy, as observed in the KIM cohort. We investigated the association between CDKS and the tumor microenvironment, including immune escape mechanisms. Immunohistochemistry analysis revealed a positive correlation between CDK5 and PD-L1 expression in gastric cancer. Furthermore, we found that CDK5 knockdown led to the inhibition of PD-L1 expression in gastric cancer cells. Our findings highlight the potential of CDKS as a prognostic biomarker and an indicator of immunotherapy response in gastric cancer patients. Moreover, our study suggests that targeting CDK5 could provide a new pathway for exploring immunotherapeutic research.

Gastric cancer peritoneal metastasis related signature predicts prognosis and sensitivity to immunotherapy in gastric cancer.

Gastric cancer peritoneal metastases (GCPM) is a leading cause of GC-related death. Early detection of GCPM is critical for improving the prognosis of advanced GC. Differentially expressed genes (DEGs) were identified in the GSE62254 database to distinguish between GCPM and non-GCPM. The gastric cancer peritoneal metastases signature (GCPMs) was developed using DEGs. We analysed the effectiveness of GCPMs as indicators for prognosis, chemotherapy, and immune therapy response in GC patients. Subsequently, we analysed the correlation between GCPMs and immune microenvironment as well as immune escape in GC patients. Random forest model and immunohistochemistry was utilized to identify the crucial genes that can aid in the diagnosis of GCPM. We identified five DEGs and utilized their expression to construct GCPMs. Patients with high GCPMs had a higher likelihood of a poor prognosis, while those with low GCPMs appeared to potentially benefit more from chemotherapy. GCPMs were a dependable marker for predicting the response to immunotherapy. Additionally, GCPMs was found to be significantly linked to stromal score and cancer-associated fibroblasts. SYNPO2 has been identified as the gene with the highest significance in the diagnosis of GCPM. Immunohistochemistry suggests that SYNPO2-positive expression in tumour cells, fibroblasts, inflammatory cell may be associated with promoting peritoneal metastasis in GC. GCPMs have shown to be a promising biomarker for predicting the prognosis and response of GC patients to chemotherapy and immunotherapy. The use of GCPMs for individual tumour evaluation may pave the way for personalized treatment for GC patients in the future.

The characteristics of the intestinal bacterial community from Oreochromis mossambicus and its interaction with microbiota from artificial fishery habitats.

BACKGROUND: Artificial habitats can allow many fish to flock together and interact and have been widely used to restore and protect fishery resources. The piece of research intends to elucidate the relationship of microbial communities between tilapia (Oreochromis mossambicus) intestines and artificial fishery habitats (water and sediments). Hence, 16 S rDNA sequencing technology was used to study the bacterial communities from intestines, water, and sediments. RESULTS: The results showed that the tilapia intestines had the lowest richness of Operational Taxonomic Units (OTUs) and the lowest diversity of the bacterial community compared to water and sediments. The intestine, water, and sediment microbial communities shared many OTUs. Overall, 663 shared OTUs were identified from the tilapia intestines (76.20%), the surrounding water (71.14%), and sediment (56.86%) in artificial habitats. However, there were unique OTUs that were detected in different sample types. There were 81, 77 and 112 unique OTUs observed in tilapia intestines, the surrounding water and sediment, respectively. Proteobacteria, Cyanobacteria, Actinobacteria, Firmicutes, Fusobacteria, and Bacteroidetes were the most common and dominant bacterial phyla between the tilapia intestines and habitats. In the two groups, the microbial communities were similar in the taxonomic composition but different in the abundance of bacterial phyla. Interestingly, Firmicutes increased, while Fusobacteria decreased in artificial habitats. These findings indicated that the artificial habitats had fewer effects on the water environment and indicated that the mode of artificial habitats could have an effect on the enriched bacteria in the tilapia intestines. CONCLUSIONS: This study analysed the bacterial communities of artificial habitats from the intestines, water, and sediments, which can explain the relationship between the tilapia intestines and habitats and strengthen the value of ecological services provided by artificial habitats.

Study of Nanoparticle-Polymer Interactions via the Mechanical Stretching of Surface-Enhanced Raman Scattering Substrates.

It is shown that the aligned electrospun fibers are a convenient platform for studying the mechanical effects on nanomaterials, particularly when using surface-enhanced Raman scattering as a sensitive tool of monitoring. The ligands on the surface of the embedded Au nanoparticles fall off easily with the shear force from the stretching, in contrast to the counterparts protected by polymer/silica shells. Upon stretching, the chains of Au nanoparticles will reversibly break, as revealed by the dramatic changes in the longitudinal plasmon absorption. It is believed that such a platform will open a window for understanding mechanical effects at the nanoscale, and also a new means for synthetic control.

Prediction and Screening Model for Products Based on Fusion Regression and XGBoost Classification.

Performance prediction based on candidates and screening based on predicted performance value are the core of product development. For example, the performance prediction and screening of equipment components and parts are an important guarantee for the reliability of equipment products. The prediction and screening of drug bioactivity value and performance are the keys to pharmaceutical product development. The main reasons for the failure of pharmaceutical discovery are the low bioactivity of the candidate compounds and the deficiencies in their efficacy and safety, which are related to the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the compounds. Therefore, it is very necessary to quickly and effectively perform systematic bioactivity value prediction and ADMET property evaluation for candidate compounds in the early stage of drug discovery. In this paper, a data-driven pharmaceutical products screening prediction model is proposed to screen drug candidates with higher bioactivity value and better ADMET properties. First, a quantitative prediction method for bioactivity value is proposed using the fusion regression of LGBM and neural network based on backpropagation (BP-NN). Then, the ADMET properties prediction method is proposed using XGBoost. According to the predicted bioactivity value and ADMET properties, the BVAP method is defined to screen the drug candidates. And the screening model is validated on the dataset of antagonized Erα active compounds, in which the mean square error (MSE) of fusion regression is 1.1496, the XGBoost prediction accuracy of ADMET properties are 94.0% for Caco-2, 95.7% for CYP3A4, 89.4% for HERG, 88.6% for hob, and 96.2% for Mn. Compared with the commonly used methods for ADMET properties such as SVM, RF, KNN, LDA, and NB, the XGBoost in this paper has the highest prediction accuracy and AUC value, which has better guiding significance and can help screen pharmaceutical product candidates with good bioactivity, pharmacokinetic properties, and safety.

Problematising formative assessment in an undeveloped region of China: voices from practitioners.

Despite the widely acknowledged pro-learning function of formative assessment and its wide adoption around the globe, the gaps between policy intention, interpretation and implementation remain a problem to be solved. While this problem is noted universally, it could be particularly serious in China, where Confucian Heritage Culture is deeply ingrained and education development is not quite balanced. This study, via interview data with English teachers and deans from eight universities in an undeveloped region of the Mid-western China, explores the overall environment for a formative assessment initiative that is currently in place. Data analysis reveals multiple issues, such as insufficient support, improper dissemination and ineffective training at the meso-level and the instructors' limited assessment ability, large class sizes and student's resistance at the micro-level. A conclusion is thus drawn that the overall environment in this region is by no means favourable for the effective implementation of formative assessment, and implications are derived for better realisation of assessment innovations in this and other undeveloped regions of China.

Ultrasonic Bending of Silver Nanowires.

We study silver nanowires as a model for the mechanical effects of ultrasonication. Their bending is caused by the outward push of shock waves against the inertia and fluid resistance. The structural analyses of a large number of cases reveal the principles of the mechanical effects on the freely suspended colloidal nanostructures. In addition to providing knowledge of the sonication effects, we believe that understanding would help to exploit sonication for nanoscale mechanical manipulation.

Scalable and continuous preparation of nano-stirbars by electrospinning.

Nano-stirbars are the most convenient and effective means for mixing in microscale systems. With electrospinning and ultrasonic breaking, a simple method is developed to continuously synthesize nano-stirbars without an external magnet. To validate the nano-stirbars, Au nanowires were grown on their surface to demonstrate the stirring with simultaneous catalysis.

Conditional survival and recurrence of remnant gastric cancer after surgical resection: A multi-institutional study.

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow-up strategies. A total of 298 patients were analyzed for their 3-year conditional overall survival (COS3), 3-year conditional disease-specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5-year overall survival (OS) and the 5-year disease-specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%-83.0%, Δ36.6% vs ≤T2: 82.4%-85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time-dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time-dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow-up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow-up model for RGC patients of different stages, which may affect the design of future clinical trials.

Priority of lymph node dissection for advanced esophagogastric junction adenocarcinoma with the tumor center located below the esophagogastric junction.

To clarify the priority of lymph node dissection (LND) in advanced Siewert type II and III AEG, in which the center of the tumor is located below the esophagogastric junction (EGJ).Data in 395 patients with advanced Siewert type II or III AEG was analyzed retrospectively. The index of estimated benefit from LND (IEBLD) was used to evaluate the efficacy of LND for each nodal station.The mean number of dissected LNs did not differ significantly between patients with type II and III AEG, nor did the mean number of retrieved LNs at each station significantly differ between the 2 groups. According to the IEBLD, the dissection of parahiatal LNs (No.19 and 20) and LNs along the distal portion of the stomach (No.5, 6, and 12a) seemed unlikely to be beneficial, whereas the dissection of Nos.1-3, 7, 9 and 11p yielded high therapeutic benefit (IEBLD>3.0) in both groups. The IEBLDs of No.4d, 8a, and 10 were much higher in type III than in type II AEG cases. No.10 LND may improve survival for type III AEG cases (IEBLD = 2.9), especially for subgroups with primary tumors invading the serosa layer, undifferentiated cancers, macroscopic type 3-4 tumors and tumors ≥50 mm in size (all IEBLDs > 4.0).For advanced AEG located below the EGJ, the dissection of paracardial LNs, lesser curvature LNs, and LNs around the celiac axis would promote higher survival benefits regardless of the Siewert subtype. Patients with type III AEG, especially those with serosa-invasive tumors, undifferentiated tumors, macroscopic type 3-4 tumors and tumors ≥50 mm in size may obtain relatively higher survival benefits from No. 10 lymphadenectomy.

Development and External Validation of Web-Based Models to Predict the Prognosis of Remnant Gastric Cancer after Surgery: A Multicenter Study.

BACKGROUND: Remnant gastric cancer (RGC) is a rare malignant tumor with poor prognosis. There is no universally accepted prognostic model for RGC. METHODS: We analyzed data for 253 RGC patients who underwent radical gastrectomy from 6 centers. The prognosis prediction performances of the AJCC7th and AJCC8th TNM staging systems and the TRM staging system for RGC patients were evaluated. Web-based prediction models based on independent prognostic factors were developed to predict the survival of the RGC patients. External validation was performed using a cohort of 49 Chinese patients. RESULTS: The predictive abilities of the AJCC8th and TRM staging systems were no better than those of the AJCC7th staging system (c-index: AJCC7th vs. AJCC8th vs. TRM, 0.743 vs. 0.732 vs. 0.744; P>0.05). Within each staging system, the survival of the two adjacent stages was not well discriminated (P>0.05). Multivariate analysis showed that age, tumor size, T stage, and N stage were independent prognostic factors. Based on the above variables, we developed 3 web-based prediction models, which were superior to the AJCC7th staging system in their discriminatory ability (c-index), predictive homogeneity (likelihood ratio chi-square), predictive accuracy (AIC, BIC), and model stability (time-dependent ROC curves). External validation showed predictable accuracies of 0.780, 0.822, and 0.700, respectively, in predicting overall survival, disease-specific survival, and disease-free survival. CONCLUSIONS: The AJCC TNM staging system and the TRM staging system did not enable good distinction among the RGC patients. We have developed and validated visual web-based prediction models that are superior to these staging systems.

Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer.

Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumorigenesis and development. Although the low expression of miR-125a-5p in gastric cancer has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in gastric cancer was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the GC islands in the miR-125a-5p region were hypermethylated in the tumour tissues. And the hypermethylation was negatively correlated with the miR-125a-5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR-125a-5p could directly suppress the Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, the Suv39H1 could induce demethylation of miR-125a-5p, resulting in re-activation of miR-125a-5p. What is more, overexpessing miR-125a-5p could also self-activate the silenced miR-125a-5p in gastric cancer cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo. Thus, we uncovered here that the epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer, suggesting that miR-125a-5p might be not only the potential prognostic value as a tumour biomarker but also potential therapeutic targets in gastric cancer.

Combined antihypertensive and statin therapy for the prevention of cardiovascular events in patients with hypertension without complications: protocol for a systematic review and meta-analysis.

INTRODUCTION: High blood pressure (BP) affects over 40% of adults over the age of 25 worldwide and is the leading global risk factor for death or disability. Hypertension is also the most important risk factor for endovascular atherosclerosis, which, when combined with other cardiovascular risk factors, leads to atherosclerotic cardiovascular disease (ASCVD). Statins are one of the most widely used drugs for the prevention of ASCVD. The recently announced study of Heart Outcomes Prevention Evaluation-3 suggests that cholesterol-lowering agents combined with antihypertensive therapy can prevent cardiovascular events and reduce the combined endpoint. We plan to conduct a systematic review and meta-analysis to evaluate whether combined antihypertensive and statin therapy is more beneficial than antihypertensive therapy alone in patients with hypertension without complications. METHODS AND ANALYSIS: We will perform a comprehensive search for randomised controlled trials evaluating combined antihypertensive and statin therapy for the treatment of patients with hypertension. The following English electronic databases will be searched: The Cochrane Library, EMBASE and PubMed. Outcomes will be categorised as short-term (≤6 months) or long-term (>6 months). When evaluating the effects of combined antihypertensive and statin therapy, a short-term outcome is usually defined as a change in BP or lipid levels, while a long-term outcome is usually defined as cardiovascular benefits or risks. The data screening and extraction will be conducted by two different reviewers. The quality of the RCTs will be assessed according to the Cochrane handbook risk of bias tool. ETHICS AND DISSEMINATION: This review does not require ethics approval and the results of the meta-analysis will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42017071935.

MicroRNA-329 inhibits cell proliferation and tumor growth while facilitates apoptosis via negative regulation of KDM1A in gastric cancer.

Altered expression of microRNA (miRNA) is strongly implicated in gastric cancer (GC). Here, we demonstrated a decreased expression of miRNA-329 in GC. Then we explored the regulatory mechanisms responsible for its effect on GC cells. GC tissues and their adjacent non-tumor tissues were collected. Complete follow-up was updated. A series of inhibitors, mimics, and siRNA against KDM1A were introduced to validate regulatory mechanisms for miR-497 and KDM1A in BGC-823 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay were employed for evaluating the expressions of miRNA-329, KDM1A, H3K4me1, and H3K4me2. Cell proliferation, cycle progression, and apoptosis were assessed by means of an MTT assay and flow cytometry. Cell colony formation was assessed. uman gastric cancer xenotransplanted into nude mice was studied. As opposed to adjacent tissues and gastritis tissues, miRNA-329 was highly expressed and KDM1A was low expressed in GC tissues. The patients with high miRNA-329 expression or low KDM1A expression had longer survival periods. The miRNA-329 mimics and siRNA against KDM1A decreased KDM1A expression and increased H3K4me1 and H3K4me2 expressions. Forced expression of miRNA-329 in gastric cancer cells significantly promotes their capacity of apoptosis but reduces proliferation, migration, and invasion. KDM1A is a direct downstream target for miRNA-329. In a nude mouse subcutaneous tumor system, in vivo tumor growth of BGC-823 was significantly inhibited after treatment of miRNA-329 mimics or siRNA against KDM1A. We conclude that miRNA-329 functions as a tumor suppressor in GC, which could be achieved via transcriptional suppression of KDM1A.