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.

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.

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.

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.

Hepatoprotective Role of 4-Octyl Itaconate in Concanavalin A-Induced Autoimmune Hepatitis.

4-Octyl itaconate (OI) is a novel anti-inflammatory metabolite that exerts protective effects in many various disease models. However, its function in autoimmune hepatitis- (AIH-) associated hepatic injury has not been investigated. In this study, we successfully used concanavalin A (Con A) to establish an AIH-associated liver injury model. Furthermore, we investigated the effect of OI in Con A-induced liver injury and found that OI mitigated Con A-induced histopathological damage. OI administration reduced serum levels of alanine transaminase and aspartate transaminase in Con A-treated mice and attenuated the infiltration of macrophages induced by Con A. Moreover, OI effectively inhibited the expression of proinflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-1ß induced by Con A. Furthermore, OI decreased hepatocyte apoptosis and malondialdehyde levels and increased the reduced glutathione/oxidized glutathione ratio in the Con A-induced liver injury model. In addition, we found that OI inhibited Con A-induced hepatocyte apoptosis in vitro, while Nrf2 deletion eliminated this effect. Furthermore, we administrated the Nrf2 inhibitor ML385 in OI+Con A-treated mice and found that ML385 eliminated the protective effect of OI in vivo. In addition, OI inhibited Con A-induced activation of nuclear factor-kappa B (NF-𝜅B) and the expression of proinflammatory cytokines in macrophages. Therefore, OI protected mice from Con A-induced liver damage and may be associated with Nrf2 activation and NF-𝜅B inhibition. Finally, our study revealed that OI inhibited TNF-α, or supernatants from Con A-treated RAW264.7 cells induced hepatocyte apoptosis. In conclusion, our study indicated that OI alleviated Con A-induced hepatic damage by reducing inflammatory response, oxidative stress, and apoptosis.

Lymph node ratio is a prospective prognostic indicator for locally advanced gastric cancer patients after neoadjuvant chemotherapy.

BACKGROUND: The accuracy of lymph node ratio (LNR) as a prognostic index remains to be proven for gastric cancer patients after neoadjuvant chemotherapy (NACT). This study sought to investigate the prognostic value of LNR in locally advanced gastric cancer (LAGC) patients after NACT. METHODS: LAGC patients with clinical TNM stages 2-3, Her2(-), and Eastern Cooperative Oncology Group, scores 0-2 are routinely scheduled with NACT. Patients with LAGC after NACT and surgical operation between January 2012 and October 2020 were retrospectively reviewed. The correlation between LNR and survival was investigated. RESULTS: Overall, 148 patients were enrolled: 103 with low-LNR (LNR ≤ 30%) and 45 with high-LNR (LNR > 30%). Approximately, 50.5% and 24.4% patients responded to NACT at the primary site in the low-LNR and high-LNR groups, respectively. The overall survival (OS) and progression-free survival (PFS) of low-LNR group were considerably better than those of high-LNR group (3-year OS: 81.9% vs 18.5%, P < 0.001; 3-year PFS: 72.6% vs 13.5%, P < 0.001). In the low-LNR group, OS and PFS were superior in patients with tumor regression grade (TRG) 0-2 than in those with TRG 3 (3-year OS: 89.2% vs 73.2%, P = 0.086; 3-year PFS: 80.3% vs 66.5%, P = 0.036). In association with OS and PFS, the degree of tumor differentiation, TRG, and LNR were identified as predictive factors, and LNR was identified as the independent prognostic factor in univariate and multivariate analyses, respectively. CONCLUSIONS: LNR is a prospective index of prognosis in patients with LAGC after NACT.

Procalcitonin as an Early Predictor of Intra-abdominal Infections Following Gastric Cancer Resection.

BACKGROUND: The purpose of this study was to investigate the prognostic value of postoperative procalcitonin (PCT) and C-reactive protein (CRP) for their ability to detect Intra-abdominal infections (IAIs) in patients after GC surgery. METHODS: Patients who underwent elective gastrectomy for primary GC were retrospectively enrolled between October 2018 and October 2019. The PCT and CRP levels and white blood cell (WBC) count were measured before surgery and on postoperative days (POD) 1, 3, 5, and 7. The differences in serum PCT, CRP, and WBC levels between IAIs and non-IAIs groups were compared. Diagnostic accuracy was determined by the area under the receiver operating characteristic curve. Univariate and multivariate logistic regression analyses identified independent clinical factors that predicted postoperative IAIs. RESULTS: A total of 155 patients who underwent GC surgery were enrolled. IAIs were observed in 12 patients (7.74%). The postoperative CRP and PCT values in the IAI group were higher than those in the non-IAI group. PCT had superior diagnostic accuracy on POD 3 (area under the curve 0.769) with an optimal cutoff value of 2.03 ng/mL, yielding 75% sensitivity, 87.4% specificity, and 97.6% negative predictive value. Multivariate analysis identified a PCT level of 2.03 mg/mL or greater on POD 3 as a significant predictive factor for IAIs after gastrectomy (odds ratio: 21.447, 95% confidence interval: 5.081-91.672). CONCLUSIONS: PCT values less than 2.03 ng/mL on POD 3 is an excellent negative predictor of IAIs, which may ensure a safe early discharge after gastric cancer surgery.

Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 cooperates with enhancer of zeste homolog 2 to promote hepatocellular carcinoma development by modulating the microRNA-22/Snail family transcriptional repressor 1 axis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy.

Targeting the WEE1 kinase strengthens the antitumor activity of imatinib via promoting KIT autophagic degradation in gastrointestinal stromal tumors.

BACKGROUND: Activating mutation of KIT or PDGFRA is the primary molecular mechanism for gastrointestinal stromal tumors (GISTs). Although imatinib has a revolutionary effect on GIST therapeutics, the benefits are not durable. Increasing reports have demonstrated that cell cycle checkpoint plays critical roles in GIST. Here, we explore the role of WEE1 kinase in GIST progression. METHODS: Oncomine public database, western blotting, and immunohistochemistry were used to analyze WEE1 expression in GISTs. Using MTT assays, colony formation analysis, and flow cytometry, we examined the role of WEE1 in GIST cells and the antitumor activity of the inhibitor MK1775 alone, or in combination with imatinib. Cycloheximide chase assay and pharmacological inhibition of autophagy and proteasome pathway were performed to analyze KIT expression. Additionally, autophagic markers Beclin1 and LC3B were detected by western blotting. RESULTS: Upregulated WEE1 expression was observed in GIST tissues and correlated with tumor size, mitotic count, and risk grade. Inhibition of WEE1 significantly suppressed GIST cell proliferation, induced apoptosis and cell cycle arrest. Imatinib and MK1775 co-treatment markedly enhanced the antitumor activity. Targeting WEE1 decreased the expression of KIT expression. Moreover, WEE1 stabilized KIT protein and KIT reduction observed upon WEE1 inhibition could be reversed by pharmacological inhibition of autophagy, but not proteasome pathway. WEE1 inhibition also increased Beclin1 expression and LC3B II/I ratio in GIST cells. CONCLUSIONS: Our data suggest that WEE1 plays a pivotal role in GIST proliferation. WEE1 inhibition could promote KIT autophagic degradation and, therefore, targeting WEE1 might represent a novel strategy for GIST therapies.

Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice.

Tert-butylhydroquinone (tBHQ) is an antioxidant compound that exhibits cytoprotective effect in many tissues under pathological condition. However, its role in carbon tetrachloride (CCL4) induced liver injury is still unclear. Here we established a carbon tetrachloride induced hepatic injury model in mice to determine whether tBHQ can mitigate CCL4 induced liver damage. In our study, we found tBHQ exhibited protective effects in CCL4 treated mice model. TBHQ markedly improved hepatic function and decreased hepatic histopathological damage in vivo. In addition, tBHQ reduced levels of pro-inflammatory cytokines in mice model. Moreover, tBHQ mitigated apoptosis of hepatocytes, oxidative stress and lipid peroxidation in vivo and in vitro. We also found the possible mechanism of protective effects of tBHQ was associated with activation of Nrf2/ heme oxygenase-1 (HO-1) pathway. In conclusion, our study revealed tBHQ can be a potential therapeutic drug in treatment of acute hepatic injury.

A Novel Model Predicts Postoperative Pathology of Colorectal High-Grade Intraepithelial Neoplasia.

BACKGROUND: To analyze the consistency of endoscopic biopsy of colorectal high-grade intraepithelial neoplasia (HGIN) and pathological diagnosis and to explore the value of preoperative examination in differentiating HGIN from invasive carcinoma. METHODS: Clinicopathological data of 79 patients with colorectal HGIN undergoing preoperative endoscopic biopsy from January 2012 to December 2017 were retrospectively analyzed. RESULTS: Pathologically, 57 cases (72.8%) were diagnosed as invasive carcinoma and 22 (27.8%) as HGIN. Tumor size ≥3 cm, ulcer on the surface of the lesion, HGIN without adenoma, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, lymph node enlargement, and spiculation of the peri-intestinal fat on computed tomography were associated with postoperative invasive carcinoma. Multivariate analysis showed that a longest diameter ≥3 cm, preoperative diagnosis of HGIN without adenoma, and spiculation of the peri-intestinal fat were independent factors for a postoperative diagnosis of invasive carcinoma. Depending on the weight of these three independent factors in binary logistic regression analysis, a comprehensive scoring model was established. When the score was ≥1.5, the sensitivity and specificity for the diagnosis of invasive carcinoma were 86.0% and 81.8%, respectively. Utilizing the prediction index, the area under the receiver operating characteristic curve was 0.869. CONCLUSIONS: A diagnosis of colorectal HGIN by colonoscopy is poorly consistent with the postoperative pathological diagnosis. The scoring model established in this study for identifying colorectal infiltrating carcinoma is simple and feasible. When the comprehensive score is ≥ 1.5, an aggressive approach of surgical treatment is recommended.

Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis.

Sepsis, frequently caused by infection of bacteria, is considered as an uncontrollable systematic inflammation response syndrome (SIRS). Maresin 1 (Mar1) is a new proresolving mediator with potent anti-inflammatory effect in several animal models. However, its effect in sepsis is still not investigated. To address this question, we developed sepsis model in BALB/c mice by cecal ligation and puncture (CLP) with or without Mar1 treatment. Our data showed that Mar1 markedly improved survival rate and decreased the levels of proinflammatory cytokines in CLP mice such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Furthermore, Mar1 reduced serum level of lipopolysaccharide (LPS) and enhanced the bacteria clearance in mice sepsis model. Moreover, Mar1 attenuated lung injury and decreased level of alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cre), and blood urea nitrogen (BUN) in serum in mice after CLP surgery. Treatment with Mar1 inhibited activation of nuclear factor kappa B (NF-κb) pathway. In conclusion, Mar1 exhibited protective effect in sepsis by reducing LPS, bacteria burden in serum, inhibiting inflammation response, and improving vital organ function. The possible mechanism is partly involved in inhibition of NF-κb activation.

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.

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.

HMGB1 recruits myeloid derived suppressor cells to promote peritoneal dissemination of colon cancer after resection.

Peritoneal metastasis of colorectal cancer is a major clinical issue and results in poor prognosis for patients after surgical resection. Here, we found that abdominal surgery trauma induced high release of high-mobility group box 1 (HMGB1) in the peritoneal cavity of mice. Recombinant HMGB1 injected in the peritoneal cavity recruited abundant myeloid derived suppressor cells (MDSCs) after the surgical trauma. HMGB1 Box-A and gemcitabine reduced the recruitment of MDSCs in the peritoneal cavity after the operation and ameliorated the peritoneal metastasis burden of colon cancer in mouse model. These results showed that abdominal surgery trauma leads to a large amount of HMGB1 released in the peritoneal cavity which recruits numerous MDSCs to promote peritoneal metastasis of colon cancer after curative surgery.

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.

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.