Two-Year Outcomes and Biomarker Analysis of Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma After Neoadjuvant Chemotherapy and Immunotherapy from the Phase II WuhanUHGI001 Trial.

BACKGROUND: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. METHODS: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. RESULTS: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. CONCLUSIONS: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.

Multi-Scale Depthwise Separable Capsule Network for hyperspectral image classification.

Addressing the challenges in effectively extracting multi-scale features and preserving pose information during hyperspectral image (HSI) classification, a Multi-Scale Depthwise Separable Capsule Network (MDSC-Net) is proposed in this article for HSI classification. Initially, hierarchical features are extracted by MDSC-Net through the employment of parallel multi-scale convolutional kernels, while computational complexity is reduced via depthwise separable convolutions, thus reducing the overall computational load and achieving efficient feature extraction. Subsequently, to enhance the translational invariance of features and reduce the loss of pose information, features of various scales are processed in parallel by independent capsule networks, with improvements in max pooling achieved through dynamic routing. Lastly, features of different scales are concatenated and integrated through the concatenate operation, thereby facilitating precise analysis of multi-level information in the hyperspectral image classification process. Experimental comparisons demonstrate that MDSC-Net achieves average accuracies of 94%, 98%, and 99% on the Kennedy Space Center, University of Pavia, and Salinas datasets, respectively, indicating a significant performance advantage over recent HSI classification models and validating the effectiveness of the proposed model.

Analysis of clinicopathological characteristics and prognosis on primary gastric adenosquamous carcinoma.

Primary gastric adenosquamous carcinoma (PGASC) is a rare type of gastric cancer with limited research and poorly understood clinicopathological features. This study investigated the clinicopathological features and outcomes of PGASC. Patients with PGASC from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology and from the published literature were enrolled in this study. Survival curves were generated using the Kaplan-Meier method, and prognostic factors were identified through Cox proportional hazards regression models. This study identified 76 eligible cases of PGASC, with 45 cases from published literature and 31 from our center. The most prevalent symptoms were abdominal pain and dysphagia, with a median age of 62 years (range: 29-84 years). The primary lesions were predominantly in the proximal stomach, with a median tumor size of 6.5 cm (range: 1.5-16.0 cm). Tumor stages II, III, and IV were detected in 12 (16.7%), 43 (59.7%), and 17 (23.6%) patients, respectively. Most tumors were poorly differentiated in both the squamous cell carcinoma (SCC) component and adenocarcinoma (AC) component. The median survival time was 17 months (range: 2-122 months). The 1, 3, and 5-year overall survival (OS) was 60.7%, 31.1%, and 24.1%, respectively. Multivariate analysis revealed that OS was independently predicted by the proportion of SCC component, differentiation of AC component, and tumor stage. PGASC is a rare disease with a poor prognosis. A high proportion of SCC components, low differentiated AC components, and advanced tumor were associated with worse survival in patients with PGASC. Adjuvant therapy did not improve survival time.

IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.

Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.

Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury.

BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established. METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI. RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages. CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Optimization analysis of a Stokes polarimeter for broadband liquid crystal variable retarders under the optimal objective function.

A liquid crystal variable retarder (LCVR) is the core device to realize fast and high-precision broadband polarization imaging, and its ability to suppress the noise will have an impact on the polarization measurement results. In order to obtain better imaging quality and measurement accuracy, it is crucial to solve the optimization problem of the LCVR. In this paper, the optimal objective function for solving the optimization problem of the LCVR is analytically derived and verified based on the genetic algorithm in the band range of 350-700 nm. Meanwhile, considering that the minimum number of four measurements at this time cannot achieve the optimal state, the relationship between the number of measurements and the overall performance relative to the error propagation (optimized conditions number) is discussed. The results show that a better optimal set of angles can be obtained by using the optimal objective function. In this paper, a set of the most favorable angles is obtained, and the optimized average of the CN is 2.0000, which is reduced by 0.32% compared with previous optimization results and is closer to the ideal value of the CN. In addition, in this paper, the noise immunity of the set of most favorable angles is simulated and analyzed, and the optimized system can effectively improve the measured performance of the wide-band liquid crystal variable retarder polarimeter.

Interleukin-6 on postoperative day three as an early predictor of infections following laparoscopic gastric cancer resection.

BACKGROUND: To investigate the role of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) as early predictors of infectious complications after laparoscopic gastric cancer surgery. METHODS: Patients who underwent laparoscopic gastric cancer surgery between January 2020 and June 2022 were retrospectively enrolled. IL-6, PCT, and CRP levels were assessed before surgery and on postoperative days (PODs) 3 and 5. Differences in serum IL-6, PCT, and CRP levels between the infected and non-infected groups were compared. The diagnostic accuracy was determined using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 206 patients were enrolled, and 21 patients (10.19%) developed postoperative infections. Serum IL-6, PCT, and CRP levels in the infected group were significantly higher than those in the non-infected group on PODs 3 and 5. IL-6 with an optimal cutoff value of 84.00 pg/mL (AUC 0.84), PCT with an optimal cutoff value of 1.39 ng/mL (AUC 0.80), CRP with an optimal cutoff value of 150.00 mg/L (AUC 0.76) on POD 3 had superior diagnostic accuracy in predicting postoperative infections. Multivariate analysis identified PCT and IL-6 levels on POD 3 as independent risk factors, the AUC of the combination of IL-6 and PCT was 0.89. The Delong test showed no difference between the AUC of IL-6 alone and IL-6 combined with PCT prediction (P = 0.07, Z = 1.81). CONCLUSIONS: IL-6 level on POD 3 is an excellent predictor of infectious complications following laparoscopic gastric cancer surgery. Patients with IL-6 levels lower than 84.00 pg/mL on POD 3 can ensure safe early discharge with a low probability of infection.

Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response.

Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1-/- and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD-/- mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD-/- mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis.

ESRP1-driven alternative splicing of CLSTN1 inhibits the metastasis of gastric cancer.

Tumor metastasis severely limits the prognosis of gastric cancer patients. RNA-binding proteins (RBPs) are crucial in tumor metastasis, yet there is limited research into their involvement in gastric cancer. Here, we found that ESRP1, a RBP specific in epithelial cells, is important in regulating the metastasis of gastric cancer cells. ESRP1 is negatively correlated with distant metastasis and lymph node metastasis in gastric cancer patients. And we demonstrated that ESRP1 inhibit migration and invasion of gastric cancer in vitro and in vivo. Mechanistically, ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA. The post-splicing short CLSTN1 stabilizes the Ecadherin/ß-catenin binding structure, and promotes ß-catenin protein ubiquitination and degradation, thereby inhibiting the migration and invasion of gastric cancer cells. Our study highlights the role of ESRP1 in regulating metastasis of gastric cancer and extends its mechanism. These results provide a possibility for ESRP1 and CLSTN1 to become therapeutic targets for metastasis of gastric cancer.

Laparoscopic versus open gastrectomy for locally advanced gastric cancer after neoadjuvant chemotherapy: a comprehensive contrastive analysis with propensity score matching.

BACKGROUND: Laparoscopic gastrectomy (LG) is increasingly applied in locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy (NC). However, there is no study to comprehensively evaluate the clinicopathological, prognostic, and laboratory data such as nutrition, immune, inflammation-associated indexes, and tumor markers between LG and open gastrectomy (OG) for LAGC following NC. METHODS: The clinicopathological, prognostic, and laboratory data of LAGC patients with clinical stage of cT2-4aN1-3M0 who underwent gastrectomy after NC were retrospectively collected. The effects of LG and OG were compared after propensity score matching (PSM). RESULTS: This study enrolled 148 cases, of which 110 cases were included after PSM. The LG group had a shorter length of incision (P < 0.001) and was superior to OG group in terms of blood loss (P < 0.001), postoperative first flatus time (P < 0.001), and postoperative first liquid diet time (P = 0.004). No significant difference was found in postoperative complications (P = 0.482). Laboratory results showed that LG group had less reduced red blood cells (P = 0.039), hemoglobin (P = 0.018), prealbumin (P = 0.010) in 3 days after surgery, and less reduced albumin in 1 day (P = 0.029), 3 days (P = 0.015), and 7 days (P = 0.035) after surgery than the OG group. The systemic immune-inflammation index and systemic inflammatory response index were not significantly different between the two groups. As for oncological outcomes, there were no significant differences in postoperative tumor markers of CEA (P = 0.791), CA199 (P = 0.499), and CA724 (P = 0.378). The 5-year relapse-free survival rates (P = 0.446) were 46.9% and 43.3% in the LG and OG groups, with the 5-year overall survival rates (P = 0.742) being 46.7% and 52.1%, respectively; the differences were not statistically significant. Multivariate Cox regression analysis revealed that tumor size ≥ 4 cm (P = 0.021) and the absence of postoperative adjuvant chemotherapy (P = 0.012) were independent risk factors for overall survival. CONCLUSIONS: LG has faster gastrointestinal recovery, better postoperative nutritional status, and comparable oncological outcomes than OG, which can serve as an alternative surgical method for LAGC patients after NC.

Pedestrian detection algorithm integrating large kernel attention and YOLOV5 lightweight model.

In the context of intelligent driving, pedestrian detection faces challenges related to low accuracy in target recognition and positioning. To address this issue, a pedestrian detection algorithm is proposed that integrates a large kernel attention mechanism with the YOLOV5 lightweight model. The algorithm aims to enhance long-term attention and dependence during image processing by fusing the large kernel attention module with the C3 module. Furthermore, it addresses the lack of long-distance relationship information in channel and spatial feature extraction and representation by introducing the Coordinate Attention mechanism. This mechanism effectively extracts local information and focused location details, thereby improving detection accuracy. To improve the positioning accuracy of obscured targets, the alpha CIOU bounding box regression loss function is employed. It helps mitigate the impact of occlusions and enhances the algorithm's ability to precisely localize pedestrians. To evaluate the effectiveness of trained model, experiments are conducted on the BDD100K pedestrian dataset as well as the Pascal VOC dataset. Experimental results demonstrate that the improved attention fusion YOLOV5 lightweight model achieves an average accuracy of 60.3%. Specifically, the detection accuracy improves by 1.1% compared to the original YOLOV5 algorithm, and the accuracy performance index reaches 73.0%. These findings strongly indicate the proposed algorithm in significantly enhancing the accuracy of pedestrian detection in road scenes.

Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis.

Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1ß, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.

Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.

Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs). Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.

Exploring the efficacy of 18F-FDG PET/CT in hepatocellular carcinoma diagnosis: role of Ki-67 index and tumor differentiation.

PURPOSE: The sensitivity of [18F] fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) for detecting hepatocellular carcinoma (HCC) has not been clarified thoroughly. Our study seeks to explore the association between the Ki-67 index and FDG-avidity in HCC tumors using 18F-FDG PET/CT. METHODS: 112 HCC lesions from 109 patients detected by 18F-FDG PET/CT were included retrospectively between August 2017 and May 2022, comprising 82 lesions in the training cohort and 30 in the validation cohort to simulate prospective studies. In the training cohort, lesions were stratified by a lesion-to-liver maximum standardized uptake value (SUVmax) ratio cut-off of 1.59. The relationships between lesion-to-liver SUVmax ratios and several clinical factors including tumor differentiation, alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), hepatitis B virus (HBV) infection, Ki-67 index et al. were assessed. These findings were subsequently validated in the independent validation cohort. RESULTS: In the training cohort, group A1 lesions demonstrated a higher Ki-67 index (%, 40.00 [30.00, 57.50] vs. 10.00 [5.00, 28.75], p<0.001) than group A0, the positive correlation between FDG-avidity and Ki-67 index was revealed by multivariate analysis, OR=1.040, 95% CI of OR [1.004-1.077], p=0.030. The calculated cut-off value was 17.5% using the receiver operating characteristic (ROC) curve, with an area under curve (AUC) of 0.834 and 95% CI [0.742-0.926], p<0.001. These findings were further validated in the independent validation cohort, with similar results (AUC=0.875, 95% CI [0.750-1.000], p<0.001). CONCLUSION: In comparison to tumor differentiation, Ki-67 index demonstrates a stronger association with FDG-avidity in HCC tumors, and when the Ki-67 index exceeds 17.5%, 18F-FDG PET/CT might serve as a useful indicator for HCC.

Metformin promotes cGAS/STING signaling pathway activation by blocking AKT phosphorylation in gastric cancer.

The cGAS/STING signaling pathway plays a pivotal role in regulating innate immunity. Emerging novel drugs aim to regulate the anti-tumor immune response by activating innate immunity. The anti-diabetic drug metformin has been reported to exhibit anti-cancer effect against various types of cancer. However, the role of metformin in regulating the cGAS/STING signaling pathway in gastric cancer remains unknown. In our study, we first used bioinformatic analysis to detect that metformin is closely related to tumor immunity in multiple tumors. Next, we validated the function of metformin in activating the cGAS/STING signaling pathway in gastric cancer cell lines. In addition, KEGG pathway enrichment analysis showed that metformin is negatively correlated with the PI3K/AKT signaling pathway in gastric cancer. We further verified that metformin activates the cGAS/STING signaling pathway by blocking AKT phosphorylation. Moreover, we found that metformin regulates the AKT signaling pathway by mediating the transcription factor SOX2. Thus, our study indicates that metformin activates the cGAS/STING signaling pathway by suppressing SOX2/AKT and has promising potential in gastric cancer immunotherapy.

Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response.

Inflammatory bowel disease (IBD) is a chronic relapsing gastrointestinal disorder, while the treatment effect is not satisfactory. Immune responsive gene 1 (IRG1) is a highly expressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate. Studies have reported that IRG1/itaconate has a significant antioxidant effect. This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate sodium (DSS)-induced colitis in vivo and in vitro. In vivo experiments, we found IRG1/itaconate exerted protective effects against acute colitis by increasing mice weight, the length of colon, reducing disease activity index and colonic inflammation. Meanwhile, IRG1 deletion aggravated the macrophages/CD4+/CD8+ T-cell accumulation, and increased the release of interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), IL-6, the activation of nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, and gasdermin D (GSDMD) mediated pyroptosis. Four-octyl itaconate (4-OI), a derivative of itaconate, attenuated these changes, therefore relieved DSS-induced colitis. In vitro experiment, we found 4-OI inhibited the reactive oxygen species production, thereby inhibiting the activation of MAPK/NF-κB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages. Simultaneously, we found 4-OI inhibited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines. Finally, we found anti-TNF-α agent reduced the severity of DSS-induced colitis and inhibited gasdermin E (GSDME)-mediated pyroptosis in vivo. Meanwhile, our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-α in vitro. Taken together, IRG1/itaconate exerted a protective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-mediated pyroptosis, which could be a promising candidate for IBD therapy.

Safety and efficacy of tislelizumab plus chemotherapy versus chemotherapy alone as neoadjuvant treatment for patients with locally advanced gastric cancer: real-world experience with a consecutive patient cohort.

Objectives: Immunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC. Methods: The data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared. Results: A total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4 min vs. 237.6 ± 68.4 min, P=0.732), intraoperative blood loss (157.8 ± 75.9 ml vs. 149.1 ± 92.5 ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P<0.001) were significantly lower in the NACT group. The postoperative complication rates were 24.4% and 26.0% in the NACT and NACT plus tislelizumab groups with no significant difference (P=0.823). In subgroup analysis, tumor regression grade (TRG) (TRG 3: 72.3% vs. 23.5%, P<0.001) and ypN stage (stages 2-3: 46.8% vs. 5.9%, P=0.003) in the NACT group were significantly higher compared with the NACT plus tislelizumab group in esophagogastric junction carcinoma. Conclusion: Compared with the S-1 and oxaliplatin (SOX) or 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) NACT regimen, NACT plus tislelizumab significantly improved the efficacy and R0 resection rate of LAGC without increasing the incidence of perioperative complications, particularly in esophagogastric junction carcinoma.

Trigeminal nerve stimulation for prolonged disorders of consciousness: A randomized double-blind sham-controlled study.

BACKGROUND: Trigeminal nerve stimulation (TNS) has been proposed as a promising intervention for coma awakening. However, the effect of TNS on patients with prolonged disorders of consciousness (pDoC) is still unclear. OBJECTIVE: This study aimed to investigate the therapeutic effects of TNS in pDoC caused by stroke, trauma, and anoxia. METHODS: A total of 60 patients (male =25, female =35) aged over 18 who were in a vegetative state or minimally conscious state were randomly assigned to the TNS (N = 30) or sham TNS (N = 30) groups. 4 weeks of intervention and a followed up for 8 weeks were performed. The Glasgow Coma Scale (GCS) and Coma Recovery Scale-Revised (CRS-R) scores as primary outcomes were assessed at baseline and at 2, 4, 8, and 12 weeks. RESULTS: The score changes in the TNS group over time for CRS-R (2-week: mean difference = 0.9, 95% CI = [0.3, 1.5], P = 0.006; 4-week: 1.6, 95% CI = [0.8, 2.5], P < 0.001; 8-week: mean difference = 2.4, 95% CI = [1.3, 3.5], P < 0.001; 12-week: mean difference = 2.3, 95% CI = [1.1, 3.4], P < 0.001) and GCS (4-week: mean difference = 0.7, 95% CI = [0.3, 1.2], P = 0.002; 8-week: mean difference = 1.1, 95% CI = [0.6, 1.7], P < 0.001; 12-week: 1.1, 95% CI = [0.5, 1.7], P = 0.003) were higher than those in the sham group. 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) revealed that the metabolism of the right parahippocampal cortex, right precuneus, and bilateral middle cingulate cortex was significantly increased in TNS group. CONCLUSION: The results of this study indicate that TNS could increase local brain metabolism and may promote functional recovery in patients with prolonged disorders of consciousness. REGISTRATION INFORMATION: Name of the registry: Chinese Clinical Trial Registry. REGISTRATION NUMBER: ChiCTR1900025573. The date that the study was submitted to a registry: 2019-09-01. The date when the first patient was enrolled was 2021-01-20.

4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer.

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas of investigation, particularly in cancers. The present study aimed to explore the role of cuproptosis in colorectal cancer progression. The genetic alterations of cuproptosis in colon cancer were evaluated using a database. MTT assays, colony formation, and flow cytometry were used to examine the effect of elesclomol-Cu and 4-Octyl itaconate (4-OI) on colorectal cancer cell and oxaliplatin-resistant cell viability. The anti-tumor effect of elesclomol with 4-OI was verified in vivo assay. The results showed that FDX1, SDHB, DLAT, and DLST genes were more highly expressed in normal tissues than those in primary tumor tissues. Patients with high expressions of these genes in tumor tissues had a better prognosis. Using MTT assay and colony formation analysis, elesclomol-Cu pulse treatment showed significant inhibition of cell viability in HCT116, LoVo, and HCT116-R cells. In addition, flow cytometry revealed elesclomol-Cu significantly promoted apoptosis. Tetrathiomolybdate, a copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, a glucose metabolism inhibitor, sensitized cuproptosis. Furthermore, galactose further promoted cuproptosis. Interestingly, 4-OI significantly enhanced cuproptosis which was irrelevant to ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis was inhibited by 4-OI through GAPDH, one of the key enzymes of glycolysis, sensitizing cuproptosis. Meanwhile, FDX1 knockdown weakened the ability of 4-OI to promote cuproptosis. In vivo experiments, 4-OI with elesclomol-Cu showed better anti-tumor effects. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.